OVERVIEW OF TREATMENT PLAN
The usual treatment of AML includes an initial program termed the induction phase. Induction may involve the simultaneous use of multiple agents or a planned sequence of therapy called timed sequential treatment. Once a remission is obtained, further treatment is indicated to preserve the remission state. Remission is defined as elimination of the leukemic cell population in marrow as judged by microscopy and flow cytometry and the restitution of marrow hematopoiesis resulting in a normal or virtually normal white cell, hemoglobin, and platelet concentrations in the blood. The postinduction treatment can consist of cytotoxic chemotherapy, HSC transplantation, or low-dose maintenance chemotherapy, depending upon patient performance status and risk factors. If relapse occurs, treatment options may include different chemotherapy regimens, allogeneic HSC transplantation, or other investigational regimens, often as part of a clinical trial.
Most patients with AML should be advised to undergo treatment promptly after diagnosis. Patients younger than 60 years of age have a poorer outcome as the time from diagnosis to treatment lengthens.576 Although remission rates are lower in older patients, a significant proportion enter remission. Occasionally, very elderly patients refuse treatment or are so ill from unrelated illnesses that treatment may be unreasonable. Age per se is not a contraindication to treatment, and septuagenarians and octogenarians who are fit can enter remissions. Treatment can be tailored to the decreased tolerance of older patients, some of whom have a smoldering course (see “Treatment of Older Patients” below). Associated problems, such as hemorrhagic manifestations, severe anemia, or infections, should be treated in parallel.
PREPARATION OF THE PATIENT
Orientation of the patient and the family should provide them with an understanding of the disease, the treatment planned, and the adverse effects of treatment, as well as information about long-term prognosis to the extent this can be provided while awaiting cytogenetic and molecular markers. Socioeconomic status and distance from the treatment center have minimal effects on survival in AML,577 but impaired Karnofsky performance status and instrumental activities of daily living score do impact outcomes.578
Pretreatment laboratory examination should include blood cell counts, cytochemistry analysis and immunophenotyping of leukemic cells from blood or marrow, marrow examination including cytogenetic and molecular analyses to include FLT3 ITD, NPM-1, CEBPα, and KIT mutation status in CBF leukemias, if available. If these are not available, they can performed later as required based on AML subtype from a cryopreserved specimen. Blood chemistry studies, chest radiography, electrocardiogram, and determination of partial thromboplastin time, prothrombin time, and fibrinogen level should be obtained. More extensive evaluation of coagulation factors should be made if (1) clotting times are abnormal, (2) bleeding is exaggerated for the level of the platelet count, or (3) APL or acute monocytic leukemia is the phenotype. Early HLA typing is useful so that compatible platelet products can be provided if alloimmunization (Chap. 139) occurs and for patients who will become marrow transplantation candidates (Chap. 23). Herpes simplex virus and cytomegalovirus serotyping may be helpful, especially if transplantation is a consideration. HIV and hepatitis serology is indicated in patients with appropriate risk factors, and patients should have a baseline cardiac scan to determine ejection fraction prior to administration of an anthracycline antibiotic.
A peripherally inserted central catheter or a tunneled central venous catheter should be placed. This access to the circulation facilitates administration of chemotherapy, blood components, antibiotics, and other intravenous fluids and medications. It also permits sampling blood for analysis without patient discomfort or concern about venous access. Meticulous skin care at the catheter exit site is required to minimize tunnel infections. Central venous catheters have become a major source of infection during neutropenia, especially with Gram-positive organisms.579 In some patients with severe coagulopathy such as those with APL, a tunneled catheter may be best deferred to avoid significant bleeding or vessel activation during insertion. In those with neurologic symptoms, a head computed tomographic study or MRI followed by a lumbar puncture should be obtained. Before procedures, adequate platelet counts and control of coagulopathy should be achieved, if possible.
Therapy for hyperuricemia is required if (1) the pretreatment uric acid level is greater than 7 mg/dL (0.4 mmol/L), (2) the marrow is packed with blast cells, or (3) the blood blast cell count is moderately or markedly elevated. Allopurinol 300 mg/day orally should be given. Allopurinol can cause allergic dermatitis and should not be used if the uric acid level is less than 7 mg/dL and the total white cell count is less than approximately 20 × 109/L, as long as hydration is adequate and urine flow is high (>150 mL/h). The dermatitis may appear when antibiotics are instituted. This concurrence may confound the decision to continue antibiotics. Thus, allopurinol should be discontinued after the risk of acute hyperuricosuria or tumor lysis has passed (usually 4 to 7 days). Recombinant urate oxidase (rasburicase) can be used to prevent urate-induced nephropathy. This preparation, although costly, can reduce plasma urate levels by approximately 80 percent within 4 hours of the first drug dose. It is well tolerated, and the recommended dose of rasburicase is 0.2 mg/kg daily for 5 to 7 days intravenously, although shorter courses are usually effective.580
Attention to decreasing pathogen exposure by assiduous hand washing and meticulous care of catheter and intravenous sites is important, especially when the total neutrophil count is less than 0.5 × 109/L. Care of the patient in a single room is advisable to provide privacy during periods of intensive care and to help decrease the risk of exogenously acquired infection until the neutrophil count recovers.
The cytotoxic therapy of AML rests on two tenets: (1) two competing populations of cells are present in marrow—a normal polyclonal and a leukemic monoclonal population; and (2) profound suppression of the leukemic cells to the point they are inapparent in the marrow aspirate and biopsy is required to permit restoration of polyclonal hematopoiesis.581,582 Although these two principles hold in most cases, two deviations from these guidelines are (1) the predisposition of patients with APL to enter remission despite cellular posttherapy marrow583 and (2) the rare presence of monoclonal hematopoiesis in some cases of AML during remission (see “Results of Treatment” below). AML is a heterogeneous disease, and subgroups with different prognosis can be identified. In the future, incorporation of knowledge about the biology of the particular AML subtype may be utilized for adapted therapies, but at present, all subtypes of AML classified by cytogenetics or molecular changes with the exception of APL are approached similarly during induction, and often induction therapy must be started before knowledge of cytogenetic and molecular factors is available.584
The goal of induction therapy in AML is achievement of complete remission (<2 percent blasts in the marrow), a neutrophil count greater than 1000/μL, and a platelet count greater than 100,000/μL. An International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards has redefined outcomes in an effort to standardize reporting and comparison of data (see “Course and Prognosis: Results of Treatment: Definition of Remission” below).585 Other treatment guidelines have been published.586,587 The majority of adults enter remission with standard induction therapy, but for patients with high-risk disease, consideration can be given to an experimental approach, and complete remission rates do not reach 100 percent, so clinical trial participation can be considered during induction chemotherapy. How durable a complete remission will be attained in an individual patient often is difficult to predict at diagnosis. Gene-expression profiling can separate some patients into prognostic groups that may indicate patients with a high risk of not responding to standard approaches.105
Anthracycline Antibiotic or Anthraquinone and Cytarabine Current standard induction treatment for non-APL AML involves drug regimens with two or more agents that include an anthracycline antibiotic or an anthraquinone and cytarabine (see “Special Therapeutic Considerations: Acute Promyelocytic Leukemia” below for therapy of APL).588-617 Remission rates in the studies cited range from approximately 55 to 90 percent in adult subjects, depending on the composition of the population treated (Table 88–6). The two most important variables are the age of the patients and the proportion of patients with therapy-induced leukemia or an antecedent clonal myeloid disease. In the studies listed in Table 88–6, the median age of the patient populations was much younger (approximately 50 years) than the median age of the population of AML patients at large (approximately 70 years); thus the results cannot be generalized (see “Treatment of Older Patients” below). A combination of anthracycline and cytarabine has been the standard induction therapy since 1973.11,12 A now classic standard induction regimen is cytarabine 100 mg/m2 daily by continuous infusion on days 1 through 7 and daunorubicin at 45 to 90 mg/m2 on days 1 through 3, the “7 plus 3” regimen. Dose or schedule modulation of the anthracycline or cytarabine, addition of other agents such as etoposide, in various schedules of administration, represent attempts to improve upon results obtained with “7 plus 3” therapy.
Table 88–6.Remission Induction for Acute Myelogenous Leukemia: Examples of Cytosine Arabinoside and Anthracycline Antibiotic Combinations ||Download (.pdf) Table 88–6. Remission Induction for Acute Myelogenous Leukemia: Examples of Cytosine Arabinoside and Anthracycline Antibiotic Combinations
|Cytarabine ||Anthracycline Antibiotic ± Another Agent ||No. of Patients ||Age Range in Years (Median) ||Complete Remissions (%) ||Year of Report ||Reference |
|100 mg/m2, days 1–7 ||DNR 50 mg/m2 days 1–5 ||407 ||15–64 (47) ||77.5 ||2011 ||596 |
|100 mg/m2, days 1–7 ||IDA 12 mg/m2 days 1–3 ||525 ||15–64 (47) ||78.2 ||2011 ||596 |
|100 mg/m2, days 1–7 ||DNR 45 mg/m2, days 1–3 ||330 ||17–60 (47) ||57 ||2009 ||593 |
|100 mg/m2, days 1–7 ||DNR 90 mg/m2, days 1–3 ||327 ||18–60 (48) ||71 ||2009 ||593 |
|200 mg/m2, days 1–7 ||DNR 60 mg/m2, days 1–3 ||200 ||16–60 (45) ||72 ||2004 ||611 |
|200 mg/m2, days 1–7 || |
DNR 60 mg/m2, days 1–3
Cladribine 5 mg/m2, days 1–5
|200 ||16–60 (45) ||69 ||2004 ||611 |
|200 mg/m2 twice per day for 10 days (some in this report received FLAG-IDA vs. H-DAT) || |
DNR 50 mg/m2, days 1, 3, 5
Thioguanine 100 mg/m2 twice per day, days 10–20
Gemtuzumab ozogamicin 3 mg/m2, day 1
|64 ||18–59 (46.5) ||91 ||2003 ||609 |
|3 g/m2 every 12 h for 8 doses ||60 mg/m2 DNR daily for 2 days ||122 ||Adults ||80 ||2000 ||603 |
|100 mg/m2 daily for 7 days (2 courses always given) ||IDA 12 mg/m2 daily for 3 days ||153 ||NR ||63 ||2000 ||589 |
|500 mg/m2 by continuous infusion, days 1–3, 8–10 || |
Mitoxantrone 12 mg/m2 for 3 days
Etoposide 200 mg/m2 days 8–10
|133 ||15–70 (43) ||60 ||1996 ||606 |
|100 mg/m2 daily for 7 days ||DNR 45 mg/m2 for 3 days ||113 ||NR (55) ||59 ||1992 ||588 |
|100 mg/m2 daily for 7 days ||IDA 13 mg/m2 for 3 days ||101 ||NR (56) ||70 ||1992 ||588 |
Induction in Patients who are FLT3 Mutation Positive Midostaurin, a multitargeted kinase inhibitor, is approved by the FDA for use in AML patients with FLT3 ITD or TKD point mutations. In a phase 3 study of 717 younger patients, those who received standard daunorubicin at 60 mg/m2 for 3 days with cytarabine at 200 mg/m2 for 7 days along with midostaurin at 50 mg twice per day from day 8 through 21 had better overall survival compared with the placebo group receiving chemotherapy alone. The hazard ratio was 0.78, and the 4–year overall survival was 51.4 percent in the midostaurin arm vs. 44.3 percent in the placebo arm. Severe adverse events were not increased with midostaurin exposure. These patients also received midostaurin during the consolidation and maintenance treatment phases. The benefit was seen in both ITD and TKD FLT3 mutation subtypes, and it was also noted in those who underwent allogeneic stem cell transplantation.588a Whether this benefit is due to midostaurin’s multi-kinase inhibition or to a specific FLT3 inhibitory effect is not clear.588b It is also uncertain if this treatment will be applicable to older patients. Trials with more selective FLT3 inhibitors are underway in combination with cytarabine and daunorubicin induction chemotherapy.
Choice of Anthracycline Development of drug resistance is reduced with idarubicin relative to other anthracyclines. Idarubicin does not induce P-glycoprotein expression, but daunorubicin, doxorubicin, and epirubicin do.590 Idarubicin 12 mg/m2 gives better complete remission rates in younger adults than does daunorubicin 45 mg/m2, each given for 3 days. Amsacrine, aclarubicin, and mitoxantrone give improved results over standard-dose daunorubicin. In older adults, mitoxantrone may reduce cardiotoxicity, but this is controversial.591 In two randomized studies, high-dose daunorubicin (90 mg/m2) for 3 days resulted in superior complete remission rates as compared to 45 mg/m2 for 3 days when combined with cytarabine.592,593 When idarubicin 12 mg/m2 was compared to daunorubicin 80 mg/m2 for 3 days in patients 50 to 70 years of age, the remission rate with idarubicin was 83 percent compared to 40 percent with daunorubicin.594 Another analysis of idarubicin compared with high-dose daunorubicin in patients with AML showed idarubicin to result in a higher remission rate but not overall survival.595 In contrast, a randomized study showed no difference in remission and long-term efficacy between idarubicin 12 mg/m2 daily for 3 days as compared to daunorubicin, 50 mg/m2 daily for 5 days.596 In light of these studies, many therapists, when using daunorubicin, use the 90 mg/m2 dose for 3 days in younger patients, and this is in keeping with the current National Comprehensive Cancer Network (NCCN) guidelines.597 This benefit of higher dose applies only to younger and favorable or intermediate-risk patients.593 Dexrazoxane may be given during induction to reduce the risk of cardiotoxicity in patients at higher than usual risk because of a history of coronary artery disease or congestive heart failure, but this is rarely used in adults.598 Other regimens that incorporate fludarabine with cytarabine can be used in those patients for which an anthracycline would not be ideal.
High-Dose versus Standard-Dose Cytarabine High-dose cytarabine does not increase complete remission rates and increases toxicity compared to conventional doses, especially in older patients (for doses of these regimens, see “Intensive Consolidation Therapy” below). Patients receiving high-dose cytarabine have more leukopenia, thrombocytopenia, gastrointestinal problems, and eye toxicity. Disease-free survival and overall survival may be better than that achieved with standard therapy, leading some investigators to suggest use of high-dose therapy for induction in patients younger than age 50 years, but this approach is not a standard one, and these studies do not take into account the role of high-dose cytarabine in postremission therapy.599 Some studies show that marrow blast clearance is higher after an induction with high-dose cytarabine and that there is an improvement in disease-free survival for patients 50 years of age or younger.600 When high-dose cytarabine was compared to intermediate doses in induction therapy, no improvement in outcome was noted, and higher incidences of grades 3 and 4 toxic effects were noted.600 A trial in younger patients with multiple arms; fludarabine, high-dose cytarabine, and G-CSF (FLAG regimen) with idarubicin resulted in a higher remission rate than did standard daunorubicin plus cytarabine with or without etoposide. Relapse rates were also less with the high-dose cytarabine induction (38 vs. 55 percent).601 A superior remission rate and survival was achieved in younger patients (<46 years) induced with a regimen containing high-dose cytarabine, 82 versus 76 percent rate of remission and a 52 versus 43 percent rate of overall survival. These differences were also seen in secondary AML cases and in those with FLT3-ITD mutations.602 Also, complete remission rates of greater than 60 percent have been noted with high-dose cytarabine in patients with poor-risk cytogenetics.603,604
Timed Sequential Therapy and Other Drugs Timed sequential therapy, which uses agents in a scheduled sequence rather than concurrently, may prolong remission duration.605,606,607 Timed sequential chemotherapy combining mitoxantrone intravenously (IV) on days 1 to 3, etoposide IV on days 8 to 10, and cytarabine IV on days 1 to 3 and 8 to 10 resulted in a complete remission in 60 percent of patients, but treatment-related death in 9 percent of patients. Median disease-free survival was 9 months.605
Adding ATRA,608 gemtuzumab ozogamicin,609 fludarabine,610 cladribine or topotecan611,612 to induction regimens has not improved results significantly. A recent randomized study showed that the addition of the purine analogue cladribine, but not fludarabine, to daunorubicin and cytarabine improved the remission rate and prolonged survival in patients younger than 60 years of age.613 The addition of bortezomib to daunorubicin and cytarabine in those 60 to 75 years of age resulted in a remission rate of 65 percent. This was a single-arm trial with dose escalation of bortezomib.614 There are preliminary reports suggesting that the addition of gemtuzumab ozogamicin to standard induction chemotherapy may increase disease-free survival in patients with low- and standard-risk cytogenetic abnormalities,615 and inhibitors of FLT3 ITD are now being examined, but no data are available regarding utility of this approach.616 A recent prospective comparison of five different treatment strategies, adjusted for differences in prognostic characteristics, did not show clinically relevant differences in outcome when compared to a standard cytarabine and anthracycline containing arm.617 Thus, the standard practice guideline for AML, other than promyelocytic leukemia, recommends standard-dose cytarabine plus an anthracycline antibiotic as treatment.587
Hematopoietic Cytokines to Enhance Chemotherapy G-CSF and granulocyte-monocyte colony-stimulating factor (GM-CSF), when used in untreated leukemia, can increase the percentage of leukemic cells in the DNA synthetic phase, resulting in blast population expansion during short-term administration. This process could render the cells more sensitive to simultaneous chemotherapy, but clinical benefit from growth-factor priming has not been observed618,619 despite an increased ratio of intracellular cytosine arabinoside triphosphate to deoxycytidine-5′-triphosphate and enhanced cytarabine incorporation into the DNA of AML blasts.619 Remission rates or overall survival did not differ among adult patients who received cytarabine plus idarubicin or cytarabine plus amsacrine with or without G-CSF given concurrently, but relapse rates decreased in patients who received G-CSF.620 GM-CSF priming in a younger patient group treated with timed-sequential therapy increased complete remission rates but did not impact overall survival.621 Thus, these growth factors are not generally considered useful as enhancers of chemotherapy. A study did, however, suggest that an improved event-free survival and overall survival was noted in patients treated with high-dose cytarabine during remission induction,622 and complete remissions have occurred in hypoplastic AML after G-CSF treatment without chemotherapy.623
Reinduction Therapy Patients who have persistent leukemia after the first course of induction chemotherapy generally are given the same regimen a second time. The effect is usually assessed by marrow aspirate and biopsy 7 to 10 days after completion of chemotherapy (the “14-day marrow” examination). For those with hypocellular marrow and no evidence of residual leukemic blasts, recovery of normal counts is awaited, and for those with a hypocellular marrow and a small number of residual blasts, additional therapy may be delayed until count recovery or until another marrow assessment. For those with significant amounts of leukemic cells remaining, repeating the original induction therapy or use of a high-dose cytarabine regimen can be considered. The patient’s long-term outcome is worse if two courses of treatment are required, even if a complete remission is achieved. Approximately 40 percent of patients with persistent AML after one course of induction therapy have a complete remission after a second course,624 and disease-free survival at 5 years is approximately 10 percent. In some European centers, two courses of induction chemotherapy are given routinely, but the impact on remission rates or overall survival is uncertain.625 The longer the time to remission after the first induction therapy, the shorter the duration of disease-free survival.626 High-risk cytogenetic abnormalities, antecedent hematologic disorders, and other poor prognostic factors can be used to assign nonresponders to an experimental chemotherapy regimen designed to treat refractory disease, rather than repeating induction therapy. In one study, overall response to reinduction was 53 percent. Those patients with poor risk cytogenetics and those with a marrow blast percentage of 60 percent or greater following the 7-plus-3 regimen induction treatment were found to have a low probability of achieving a complete remission with reinduction.627 Mortality during induction therapy correlates with age628 and, perhaps, leukocyte count.629
Special Considerations during Induction Therapy
Hyperleukocytosis Patients with blast counts greater than 100 × 109/L require prompt treatment to prevent the most serious complications of hyperleukocytosis: intracranial hemorrhage or pulmonary insufficiency. Hydration should be administered promptly to maintain urine flow greater than 100 mL/h/m2. Cytoreduction therapy can be initiated with hydroxyurea 1.5 to 2.5 g orally every 6 hours (total dose 6 to 10 g/day) for approximately 36 hours. Appropriate remission-induction therapy should be initiated as soon as possible after the leukocyte count has been decreased significantly. Simultaneous leukapheresis can decrease blast cell concentration by approximately 30 percent within several hours331,630,631 without contributing to uric acid or cellular phosphate release. Leukapheresis may improve acute disturbances resulting from the vascular effects of blast cells, but the procedure may not alter the long-term outcome with current therapeutic programs.339,340,630 Inhaled nitric oxide may improve the hypoxemia related to hyperleukocytosis.631
Antibiotic Therapy Pancytopenia is worsened or induced shortly after treatment is instituted. Absolute neutrophil counts less than 100/μL (0.1 × 109/L) are expected and are a sign of effective drug action. The patient usually becomes febrile (>38°C), often with associated rigors. Cultures of urine, blood, nasopharynx, and, if available, sputum should be obtained. Because the inflammatory response is blunted by severe neutropenia and monocytopenia, evidence of exudates on physical examination or imaging studies may be minimal or absent. Antibiotics should be started immediately after cultures are obtained.632 Chapter 24 describes antibiotic usage in the setting of intensive chemotherapy. Infections remain a major cause of therapy-associated morbidity and mortality.633,634 Gram-positive bacterial isolates now outnumber Gram-negative organisms.634 Cultures are often negative, but if fever and other signs are present, antibiotic therapy should be continued until neutrophil recovery.
Some centers use prophylactic antibacterial, antifungal, and/or antiviral antibiotics, whereas other centers do not. Antifungal prophylaxis can consist of low-dose amphotericin or azoles such as fluconazole, itraconazole, posaconazole, or voriconazole.635,636 In a randomized study in patients undergoing induction therapy, posaconazole was more effective in preventing invasive fungal infections than fluconazole or itraconazole.637 Voriconazole was not included in the comparison. Acyclovir, valacyclovir, or famciclovir prophylaxis during remission-induction therapy of patients with AML does not affect the duration of fever or the need for antibiotics. The incidence of bacteremia is not reduced, but acute oral infections are less severe.638 Liposomal amphotericin, the caspofungins and azoles are available for treatment of established fungal infections.639 Some centers use outpatient supportive therapy, including oral antimicrobials, immediately after induction therapy administration in adult AML.640
Hematopoietic Growth Factors to Treat Cytopenias Cytokine therapy as an adjunctive treatment for AML remains controversial.641 GM-CSF and G-CSF accelerate neutrophil recovery; neither GM-CSF nor G-CSF reproducibly decreases major morbidity or mortality. However, one study has shown decreased mortality from fungal infections in older patients.642 Use of cytokines during periods of cytopenia following induction therapy is safe, and nearly all trials have shown a modestly reduced duration of severe neutropenia with a variable effect on the incidence of severe infections, antibiotic usage, and duration of hospital stays. Although no increase in relapse has been noted when growth factors are started after completion of chemotherapy, no consistent enhancement of remission, event-free survival, or overall survival has been noted.643 Therefore, the cost-effectiveness and clinical effectiveness of growth factor usage is doubtful. Also, growth factor usage can cloud marrow interpretation when used during induction.
Component Transfusion Therapy Red cell transfusions should be used to keep the hemoglobin level greater than 7.0 g/dL, or higher in special cases (e.g., symptomatic coronary artery disease; Chap. 138). Platelet transfusions should be used for hemorrhagic manifestations related to thrombocytopenia and prophylactically if necessary to maintain the platelet count between 5 × 109/L and 10 × 109/L.644 Patients without coagulation abnormalities, anticoagulant use, sepsis, or other complications usually can maintain hemostasis with platelet counts of 5 to 10 × 109/L. Initially, random donor platelets can be used, although single-donor platelets or HLA-matched platelets may be preferable products and should be tried if random-donor platelets do not raise the platelet count significantly A no-prophylaxis platelet-transfusion strategy for blood cancers has been examined, but data support the need for prophylactic platelet transfusions.645 Family members may be effective donors, if allogeneic HSC transplantation is not being considered (Chap. 139). There are data that fever should result in increasing the platelet count used as a transfusion threshold, and there is some suggestion that higher hemoglobin values protect against bleeding related to thrombocytopenia.646
All red cell and platelet products should be depleted of leukocytes, and all products, including granulocytes for transfusions, should be irradiated to prevent transfusion-associated graft-versus-host disease (GVHD) in this immunosuppressed population (Chaps. 138 and 139).
Granulocyte transfusion should not be used prophylactically for neutropenia but may be used in patients with high fever, rigors, and bacteremia unresponsive to antibiotics, with blood fungal infections, or with septic shock. G-CSF administration to a volunteer donor increases neutrophil yield fourfold and results in posttransfusion blood neutrophil increments for more than 24 hours after transfusion.647 There is still ambiguity about the usefulness of this approach. GM-CSF administration may be warranted for treatment of major fungal infections (Chap. 24).
Jehovah’s Witnesses and others who refuse blood product support can survive tailored chemotherapy.648 In general, phlebotomy is minimized, and antifibrinolytics, hematinics, and growth factors are used to support such patients during severe cytopenias.
Therapy for Hypofibrinogenemic Hemorrhage Patients with evidence of intravascular coagulation (Chap. 129) or exaggerated primary fibrinolysis (Chap. 135) should be considered for platelet and fresh-frozen plasma administration before antileukemic therapy is started. Infusion of cryoprecipitate can be used for fibrinogen levels under approximately 125 mg/dL. If the findings are equivocal, patients should be monitored closely with measurements of fibrinogen levels, fibrin(ogen) degradation products, D-dimer assay, and coagulation times. Intravascular coagulation or primary fibrinolysis may occur in patients with APL and acute monocytic leukemia, but also may occur in occasional patients with other AML subtypes.
Management of Central Nervous System Disease CNS disease occurs in approximately one in 50 cases at presentation.649 Prophylactic therapy usually is not indicated, but examination of the spinal fluid after remission should be considered in (1) monocytic subtypes,508 (2) cases with extramedullary disease, (3) cases with inversion 16254 and t(8;21)263,266 cytogenetics, (4) CD7- and CD56-positive (neural-cell adhesion molecule) immunophenotypes,650 and (5) patients who present with very high blood blast cell counts. In these situations, the risk of meningeal leukemia or a brain myeloid sarcoma is heightened, but prophylactic intrathecal chemotherapy is not recommended if high-dose cytarabine is used for consolidation. Patients who present with neurologic symptoms should have a head computed tomogram or MRI to rule out hemorrhage or mass effect. If negative, a lumbar puncture should be performed. Treatment of meningeal leukemia can include high-dose intravenous cytarabine (which penetrates the blood–brain barrier), intrathecal methotrexate, intrathecal cytarabine, cranial radiation, or chemotherapy and radiation in combination.649 If CNS leukemia is present, intrathecal therapy is often given twice per week until blasts are cleared, and then once per week for 4 to 6 weeks. This therapy can be accomplished via the lumbar puncture route or through placement of an Ommaya reservoir. If there is a mass present, radiation or high-dose cytarabine with glucocorticoids can be considered.651 Systemic relapse commonly follows relapse in the meninges, and concurrent systemic treatment usually is indicated. Long-term success is unusual unless allogeneic HSC transplantation is possible. Unless the patient has neurologic symptoms, lumbar puncture generally is deferred until blood blast cells have cleared. No consensus exists on a trigger for platelet transfusion in adults with AML undergoing lumbar puncture, but a platelet count less than 20 × 109/L has been proposed as such a trigger,652 but many therapists use a higher platelet count (e.g., 50 × 109/L) as a safety threshold for lumbar puncture.
Management of Nonleukemic Myeloid Sarcoma Some patients present with myeloid (granulocytic) sarcomas without evidence of leukemia in the blood or marrow (see “Myeloid [Granulocytic] Sarcoma” earlier). Myeloid sarcoma may be the presenting finding in approximately 1 percent of patients with AML. Such patients should receive intensive AML induction therapy.262 Intensive therapy results in a longer nonleukemic period than patients who have undergone surgical resection or resection followed by local irradiation.250 Whether such patients should undergo allogeneic HSC transplantation in first remission irrespective of other factors has not been determined.653,654 Median relapse-free survival is approximately 12 months after AML-type chemotherapy.262 Patients with trisomy 8 have poorer survival rates.260
General Considerations Postremission therapy is intended to prolong remission duration and overall survival, but no consensus exists regarding the best approach. Postremission chemotherapy that does not produce profound prolonged cytopenias, closely simulating intensive induction therapy, has produced on average only slight prolongation of remission or life. Regimens that fall between these intensities have been used, with equivocal results. Intensive consolidation therapy after remission results in a somewhat longer remission duration and, more significantly, a subset of patients who have a remission of more than 3 years. The issue of postremission therapy and its impact is complicated by the large proportion of patients with AML who are older than 60 years of age and have limited tolerance for intensive therapy. In addition, a very small pool of leukemic stem cells may sustain the process, and elimination of these cells may require approaches other than intensive chemotherapy, especially in adults.
Several randomized trials have studied whether AML patients in first remission should receive consolidation chemotherapy alone, autologous transplantation, or allogeneic HSC transplantation, without reaching a consensus. Allogeneic transplantation was compared to autologous transplantation using unpurged marrow and two courses of intensive chemotherapy in 623 patients who had a complete remission after induction chemotherapy.655 Disease-free survival was 53 percent at 4 years for those receiving allogeneic transplantation, 48 percent for those receiving autologous transplantation, and 30 percent for patients receiving intensive chemotherapy. Overall survival after complete remission was similar in all three groups because patients who relapsed after chemotherapy could be rescued with allogeneic HSC transplantation. No significant difference in the 4-year disease-free survival between allogeneic HSC transplantation (42 percent) and other types of intensive postremission therapy (40 percent) has been found.656 In another study, only patients younger than 35 years of age with poor-risk cytogenetics had improved disease-free survival if they had a sibling donor and underwent allogeneic transplantation (43.5 percent vs. 18.5 percent at 4 years).657 Thus, in several studies, the early mortality after allogeneic HSC transplantation and the chemotherapy-induced remissions in patients who relapse following autologous transplantation or chemotherapy have led to comparable overall survival rates. However, leukemia-free survival was greater after allogeneic transplantation.658 In the last decade, treatment-related mortality from transplantation has declined and matched unrelated donor transplantations are as effective as those from a matched sibling donor, so currently, transplantation is recommended for all but good-prognosis patients (CBF leukemias or those with NPM1 mutation without a FLT3 mutation).659 A Markov decision analysis has shown that patients treated with allogeneic HSC transplantation have a longer life expectancy compared with those treated with chemotherapy among patients with an intermediate- or unfavorable-risk prognosis.660 A prospective matched-pairs analysis has also concluded that allogeneic HSC transplantation is the most effective postremission therapy for AML, especially for those 45 to 59 years of age and/or with high-risk cytogenetics.661 When quality of life was measured for patients in complete remission for 1 to 7 years, those treated with chemotherapy had the highest quality of life, whereas those who underwent allogeneic HSC transplantation had the lowest.662
The decision to utilize autologous or allogeneic HSC transplantation or high-dose cytarabine alone for consolidation should be individualized, based on the patient’s age and other prognostic factors, such as high-risk cytogenetic findings and antecedent hematologic disease. Patients with good-risk cytogenetics should receive up to four cycles of high-dose cytarabine. Patients with poor-risk cytogenetics should be considered for allogeneic HSC transplantation as soon as feasible. A meta-analysis has also shown that compared with nonallogeneic therapies, allogeneic HSC transplantation has superior relapse-free survival and overall survival for cases of AML classified intermediate and poor-risk, but not for cases considered good-risk AML in first remission.663
Intensive Consolidation Therapy For patients who do not receive high-dose chemotherapy with autologous or allogeneic transplantation in first remission, consolidation chemotherapy regimens containing high-dose cytarabine provide better results than intermediate-dose cytarabine,664,665 but these regimens are not universally accepted.666 Patients who are to have allogeneic HSC transplantation do not require four cycles of high-dose cytarabine, and may not benefit from even one, if a donor is readily available.667 RAS mutations are associated with benefit from high-dose cytarabine therapy.668 Patients with CBF leukemias such as t(8;21) also have particularly favorable responses to repetitive cycles of high-dose cytarabine. In patients who received three or more cycles, a relapse rate of 19 percent was reported.669
Other regimens, such as those containing gemtuzumab ozogamicin and fludarabine, have been used in postremission therapy, but whether they provide benefit over use of high-dose cytarabine has not been studied.670 Long-term disease-free survival at 5 years generally is approximately 30 percent when two to four cytarabine-containing regimens are administered.671,672 Adding mitoxantrone or amsacrine to high-doses cytarabine has not improved treatment outcomes in consolidation,673 and timed sequential chemotherapy used in consolidation did not improve outcome as compared with high-dose cytarabine.674 Most centers use four cycles of therapy. A cycle is 3 g/m2 twice daily on days 1, 3, and 5, providing six doses per cycle, with cycle durations dependent on normal blood count recovery. The optimal number of cycles for this therapy is not known.675 High-dose cytarabine can be administered at a dose of 3 g/m2 in a 1- to 3-hour intravenous infusion every 12 hours for up to 6 days (12 doses), but this schedule is almost never used because of its toxicity. There is some evidence that two cycles of intermediate-dose cytarabine (1 g/m2 every 12 hours for 6 days) may be a viable alternative to the 3 g/m2 for six doses schedules.676 When 36 g/m2 total dosing was compared with 12 g/m2 dosing in the first consolidation, there was no improvement in treatment outcomes.677 High-dose cytarabine frequently causes conjunctivitis and photophobia, and glucocorticoid eye drops are usually used every 6 hours until 24 hours after the last dose of the drug.678 Cerebellar function abnormalities also may occur, and these require cessation of drug administration. A 1-hour duration infusion of high-dose or reduced-dose (e.g., 2 g/m2) cytarabine may decrease the likelihood of severe cerebellar toxicity.678 Older patients and patients with renal insufficiency require dose attenuation (i.e., to 1 to 2 g/m2).679
Additional Maintenance Therapy
Various forms of less-intensive maintenance chemotherapy have been attempted after completion of intensive consolidation chemotherapy. Many of the regimens consist of monthly chemotherapy, for example, low-dose 6-thioguanine or cytarabine. Although improved disease-free survival was noted in some studies, no improvement in overall survival has been demonstrated in most studies.680 Some groups are examining the role of demethylating agents (e.g., 5-azacytidine or decitabine) as maintenance therapy.681
Autologous Stem Cell Infusion after Myeloablative Chemotherapy or Chemoradiotherapy for Consolidation Removal and cryopreservation of postremission marrow or collection of mobilized blood stem cells from patients with AML and reinfusion of these products following intensive chemotherapy and/or radiotherapy is a form of postremission therapy (Chap. 23).682 This approach is loosely referred to as autologous transplantation but does not cross transplantation barriers. Autologous marrow or blood stem cell rescue can be used in patients with AML who achieve a remission, do not have a compatible stem cell donor, and are as old as 70 years. With the availability of high-resolution HLA-matched unrelated donors, cord blood and haploidentical donors, the number of autologous stem cell transplants used in AML has diminished.
Various treatment regimens for autologous transplantation in AML have been used,683 such as busulfan-cyclophosphamide, busulfan-etoposide-cytarabine, high-dose cytarabine-mitoxantrone plus total-body irradiation, melphalan plus total-body irradiation, and cyclophosphamide plus total-body irradiation. A disease-free survival rate of approximately 40 percent at 3 years is average after such regimens in the age-range treated.684,685 Long-term disease-free survival can occur in patients who undergo this treatment for AML in second remission.686 Patients older than age 50 years have inferior outcomes, but no strict upper-age limit for this procedure has been determined.687 Administration of two or more courses of consolidation chemotherapy prior to harvest and transplant is associated with decreased relapse rates and improved disease-free survival. A marrow nucleated cell dose greater than 2 × 108/kg improves disease-free survival.688 Chemotherapy agents such as 4-hydroperoxycyclophosphamide have been used for purging residual leukemic cells in marrow before infusion,689,690 and antisense agents reportedly diminish leukemic cell contamination.691 Use of marrow grafts purged of residual leukemia cells has not significantly improved the results obtained with unpurged marrow in many studies, suggesting that low proportions of leukemic stem cells may not transplant easily or that they do not survive the freeze–thaw cycle to which autologous marrow is subjected as well as do normal HSCs.692 In addition, residual leukemia in the patient may contribute to relapse. For these reasons, marrow purging is rarely used in AML autografting (Chap. 23). In long-term cultures from patients newly diagnosed with AML, normal progenitors can be detected, and their numbers are increased by in vitro culture with cytokines.693 In oligoblastic myelogenous leukemia (high-risk myelodysplasia), secondary AML, and therapy-related AML, leukapheresis products obtained after chemotherapy and growth factor treatment contain normal progenitors,694 indicating mobilized stem cells may be relatively free of leukemic counterparts even in the absence of ex vivo purging.695 Early mortality may be decreased using blood stem cells because they engraft more rapidly, but relapse rates may be higher.696 Mobilized stem cells can be collected after high-dose cytarabine plus G-CSF or after G-CSF alone.697 There is a plateau in the survival curve after autologous stem cell transplantation at about 2.2 years,698 and there is evidence that autologous transplantation improves disease-free survival but not overall survival.699 The total number of CD34+ cells infused influences early engraftment, but durable engraftment is associated more closely with the CD34+/CD38– subset of cells in the graft.700
Chemoradiotherapy Plus Allogeneic Hematopoietic Stem Cell Transplantation for Consolidation Therapy
General Considerations Utilization of allogeneic HSC transplantation for AML is increasing in Europe and the United States.701 No strict upper-age limit for transplantation exists,702 but many centers use age 60 or 65 years for transplantations following ablation of hematopoiesis and 70 to 75 years for transplantations not preceded by ablation of hematopoiesis (nonmyeloablative or reduced-intensity transplants). Decisions to proceed to allogeneic transplantation should be individualized, and feasibility depends on (1) the availability of a suitable donor, (2) the recipient’s age and health status, and (3) whether AML is in remission.
For full-intensity transplantations, the patient is prepared with a regimen that includes total-body irradiation and/or high-dose chemotherapy, after which the donor stem cells are infused by vein. Patients given allogeneic blood stem cells have more rapid hematopoietic reconstitution than patients given marrow stem cells, but they may have more chronic GVHD and comparable risk of relapse.703,704 Chapter 23 describes the indications, procedure, and preparative regimens for allogeneic stem cell transplantation. In general, no single preparative regimen is superior for patients with AML in first remission.705 In one study, cyclophosphamide and total-body irradiation lowered relapse risk, but overall results were comparable to conditioning with chemotherapy alone.706 Another retrospective study showed outcomes with intravenous busulfan and cyclophosphamide were not different from those with cyclophosphamide and total-body irradiation in AML in remisison.707 A retrospective registry analysis showed that leukemia-free and overall survivals were better with busulfan and cyclophosphamide, as compared with total body irradiation in AML in first remission.708 Postremission consolidation with cytarabine before allogeneic transplantation for AML in first remission does not improve outcome compared with immediate transplant after successful induction.709 It is unclear that this result will also hold in the setting of reduced-intensity transplants or for transplants performed beyond first remission.710
Related Donors When matched-sibling transplantation is performed for AML in first remission, approximately half of patients have a disease-free survival of 4 years. Small series using T-cell depletion have reported 4-year disease-free survival of 65 percent.711 Leukemia relapses occur in approximately 20 percent of patients who receive an allogeneic transplant. Patients who are alive with good performance status 3 years after transplantation have excellent prospects of long-term survival.711 In the posttransplantation period, approximately one-third of patients die of severe GVHD, opportunistic infection, or interstitial pneumonitis. The outlook for long-term survival is improved if (1) the AML is in remission prior to transplantation, (2) grades III to IV acute GVHD does not occur, and (3) chronic GVHD is low grade.712,713 For patients with unfavorable cytogenetics, an allogeneic sibling transplantation in first remission is often recommended.714 Patients with FLT3/ITD-positive AML may also benefit from allogeneic HSC transplantation in first remission.715,716 When AML patients in first remission were compared on a donor versus no donor basis, and more than 80 percent of patients with a donor went on to transplantation, patients with a donor had a significantly better disease-free survival, although treatment-related mortality was higher.717 For patients with intermediate-risk cytogenetics, where the decision is made to delay transplantation until first relapse and second remission, physicians should identify a source of a HSC graft and ensure that careful monitoring of the patient occurs so that transplantation can be instituted as quickly as possible.718
In an attempt to decrease the relapse rate after stem cell transplantation for advanced acute leukemia,202 I-labeled anti-CD45 antibody to deliver radiation to leukemic cells, followed by a standard transplant preparative regimen, has been used. With this regimen, more radiation can be delivered to hematopoietic tissues compared with liver, lung, or kidney, which may improve the efficacy of the transplant.719
Unrelated Donors Approximately 70 percent of all patients with AML are older than 50 years of age, and the current mean family size in the United States is slightly more than two children per family. Thus, only approximately 10 to 15 percent of subjects with AML are within the age-range and have a sibling donor for marrow transplantation. The ability to extend the proportion of patients who can be transplanted has led to histocompatible, unrelated donors or HLA type-mismatched sibling or parent (haploidentical) donor transplants.720 More than 70 percent of patients of European descent can find a suitable unrelated-matched donor in the available donor registries,721 and another study showed that the majority of patients with AML in first remission for whom transplantation is recommended are able to undergo the procedure; the main barriers to transplantation are relapse of disease while awaiting a donor and poor performance status.722 Molecular matching of classes I and II HLA alleles adds to the clinical success of unrelated donor transplantations, but makes finding a donor more difficult.723 Using such typing, studies have demonstrated that use of matched-unrelated donors as compared with matched-related donors result in similar survival times in AML.724 Transplantation benefits younger adults in first remission, but no difference in outcome between matched-related donors and matched unrelated donors.725 HLA-matched or HLA-mismatched cord blood stem cells can be used in adults with acute leukemia but generally not for patients in first remission.726,727 In adults, the numbers of stem cells available in a single cord product may not result in engraftment, which has led to the use of two-cord blood units for grafting (Chap. 23).728
Reduced-Intensity and Nonmyeloablative Transplantation Patients who, based upon comorbidities or performance status, are deemed too old or too ill to undergo a full-intensity (myeloablative) allogeneic stem cell transplantation may be offered a reduced-intensity transplantation procedure or a nonmyeloablative conditioning regimen, provided a suitable donor is available. Reduced-intensity transplant results in some degree of myeloablation but in non-ablative transplants, autologous stem cell recovery would occur in the case of graft failure.729,730 This type of transplantation for AML and closely related hematologic malignancies relies upon the graft-versus-leukemia effect as primary therapy.731,732,733 These regimens have moderate hematologic and nonhematologic toxicity, and often can be performed on an outpatient basis. Engraftment and establishment of complete donor chimerism are successful in most patients. GVHD rates have been variable, and the ultimate risk of acute and chronic GVHD with these regimens is unclear. A variety of low-intensity regimens have been proposed.734 In AML in first remission, the 1-year progression-free survival is approximately 55 percent.735,736 The role of this approach in the treatment of AML remains to be defined, and comparative trials with longer followup are needed. Nonmyeloablative conditioning with unrelated donors has been used successfully.737,738 Although randomized trials of ablative versus reduced dose-intensity conditioning regimens for transplantation of AML patients in first remission have not been done, there is evidence that reduced dose intensity is an inferior option for disease control, but that disadvantage is offset by the decreased treatment-related mortality.739 One study found that reduced-intensity conditioning compared with myeloablative conditioning using unrelated donors in AML gave similar rates of leukemia-free survival.740 In a multivariate analysis, active disease at transplant and development of grades II to IV GVHD after transplantation had a negative impact on survival in reduced-dose-intensity transplantations.741 Reduced-intensity transplantations are feasible in elderly patients with both fludarabine and low-dose total-body irradiation742 and with fludarabine and IV busulfan743 but donor availability and coexisting medical problems often limit its use.744
Use of Transplantation in Relapsed Patients Some form of allograft usually is recommended for patients in early first relapse or second remission, because long-term survival with chemotherapy alone is improbable, whereas histocompatible sibling transplants in these situations have a 25 percent survival rate. For patients who lack a sibling donor, matched-unrelated donor transplantations can be effective, but treatment-related mortality is high, suggesting that patients with unfavorable cytogenetics should undergo a matched-unrelated donor transplantation in first complete remission, if an acceptable donor can be found.745 However, when transplantation was compared to chemotherapy for AML in second remission, the 3-year probability of event-free survival was 17 percent with chemotherapy and 16 percent with transplantation. Patients younger than 30 years of age who were in remission for at least 1 year fared best.746 Development of chronic GVHD, an unrelated donor, a young age of donor, and blast cell count less than 30 percent at transplantation were found in another series to be favorable predictors of survival for transplantations performed in leukemia relapse.747 Another study found that those with a remission duration of less than 6 months, circulating blasts, donor other than an HLA-matched sibling, poor-performance status, and poor-risk cytogenetics were adverse pretransplantation variables for those in relapse or primary induction failure.748 Patients with extramedullary sites of leukemia are more likely to relapse after allogeneic transplantation.749
Patients with AML who relapse after allogeneic stem cell transplantation can have a long-term remission, if they undergo retransplantation.750 A second stem cell transplantation can induce 2-year overall survival in approximately 25 percent of patients and is effective after either related or unrelated donor transplantations. A clear advantage of changing the donor for the second transplantation has not been demonstrated.751
The mechanism of benefit of allogeneic stem cell transplantation was thought to result from high-dose ablative chemoradiotherapy followed by marrow “rescue.” The increased relapse rate of AML in patients transplanted with marrow from identical twins, compared to nonidentical siblings, or transplanted with T-lymphocyte–depleted marrow has indicated that an immunologic effect of donor lymphocytes may determine the results of transplantation. This immunologic response, referred to as graft-versus-leukemia effect, may play a role in preventing leukemia relapses.752
Donor Leukocyte Infusion In an attempt to enhance graft-versus-leukemia effects, adoptive immunotherapy with donor mononuclear cell infusions is sometimes used to treat relapse of leukemia after allografting.753,754 These infusions have been successful in only a minority of patients with AML, but given the high mortality associated with alternative procedures such as a second transplantation, the infusions are a reasonable approach for patients who relapse after allogeneic transplantation.755 GVHD and marrow aplasia are the major complications of this form of treatment.756 The graft-versus-leukemia reaction is thought to be directed against minor histocompatibility antigens on the cell surface of hematopoietic cells, but reactions against leukemia-specific antigens are possible. Relapses after donor leukocyte infusions for recurring acute leukemia have a higher probability of being extramedullary.757 Donor lymphocyte infusions are most effective in early relapses and in the absence of extensive of chronic GVHD.758 Some patients also enter a new remission upon withdrawal of immune suppression. Patients who enter remission by donor lymphocyte infusion or cessation of immunosuppressive agents have a better survival than those who entered remission with chemotherapy alone or after a second transplantation.759 Unrelated donor-leukocyte infusions can be used to treat relapsed leukemia after unrelated donor stem cell transplantation.760 Approximately 40 percent of AML patients enter remission with this treatment. G-CSF has been used as an alternative to donor leukocyte infusions after AML relapse posttransplantation.761 Donor blood stem cells can be combined with chemotherapy for early relapse of AML after allogeneic stem cell transplantation.762 Strategies with donor leukocyte infusions are anticipated to become more effective once the effector cells are identified and the tumor target antigens better understood.763
Other Modalities to Decrease or Treat Relapse after Transplant Killer-cell immunoglobulin-like receptor (KIR) genes among HLA-matched potential donors can point to donors with donor KIR genotype that are associated with enhanced disease-free survival.764 Early cytomegalovirus replication after transplantation is also associated with decreased relapse risk, possibly because of a virus-versus-leukemia effect in AML.765 Hypomethylating agents have been used for the treatment of relapse after allogeneic transplantation with some success and with induction of T-regulatory cells.766,767 Extramedullary sites of relapse are more common after transplant.767
Recurrent Leukemia in Donor Cells or New Leukemia in Recipient Cells Recurrence of AML in donor cells has been reported in patients who received transplants from healthy siblings. These recurrences in donor cells occurred in approximately one in 18 relapsed patients who received marrow from a donor of the opposite sex.768 A similar frequency of relapsed AML is observed in recipient cells but with a different clonal cytogenetic abnormality, suggesting a “new” leukemia.768 The frequencies are dependent on the sensitivity and specificity of cytogenetic techniques, which have been challenged. AML developing in a stem cell recipient but of donor cell origin long after transplantation has been documented in rare cases.768,769
Summary of Postremission Therapy In younger patients with favorable cytogenetics (CBF with no mutation of KIT) or with NPM1 or double CEBPα mutations in the absence of a FLT3 mutation, there is no advantage to do an allograft in first remission and four cycles of high-dose cytarabine is appropriate treatment. Another option would be two cycles of high-dose cytarabine followed by autografting, an approach often favored in Europe. In those with intermediate-risk cytogenetics, an allograft should be considered as consolidation, and three to four cycles of high-dose cytarabine could be offered if a transplant donor cannot be found. Those with poor-risk cytogenetics or a FLT3-ITD mutation should be considered for an allograft in first complete remission. These recommendations may change as transplant mortality improves and subclasses of the “normal” cytogenetics group are better defined such that targeted agents might have an impact on relapse rates. After patients complete consolidation therapy, they are generally followed with blood counts every 3 months for 2 years, and then every 3 to 6 months for 5 years. Marrow examination is done to confirm continued remission after consolidation is completed but is rarely pursued regularly thereafter unless blood counts change.
TREATMENT OF RELAPSED OR REFRACTORY PATIENTS
Patients who relapse after remission-induction and postinduction therapy have a decreased probability of entering a subsequent remission, and the duration of any remission that occurs is usually shorter. In patients who relapse more than 1 year after the first remission, the original remission-induction regimen can be readministered or a combination salvage chemotherapy regimen can be administered. At relapse, cell lineage trees suggest that the leukemic cell sustaining the relapse resembles the leukemic stem cell of origin.770 When primary tumor and relapse genomes are compared, two primary patterns of relapse are discerned: gain of mutations in a founding clone that evolved into the relapse clone or a subclone of the founding clone that survived induction, gained mutations, and gained ascendancy to become the dominant clone at relapse.771
Refractory leukemia is defined as leukemia that does not respond to initial induction chemotherapy with cytarabine and an anthracycline antibiotic or anthraquinone. Patients with refractory disease are more likely to have disease with adverse cytogenetic findings, a history of antecedent clonal myeloid disease, adverse immunophenotypic features, and expression of MDR.772
Relapsed leukemia is leukemia that recurs following a remission. The duration of remission greatly affects the patient’s prognosis and response to additional treatment. The wide range of response rates may not only reflect the regimen used but may also reflect variability in patient selection, age, and other prognostic factors.772,773
Chemotherapy regimens can be divided into cytarabine-based, noncytarabine-based, and timed sequential therapy with growth factors and cytotoxic drugs. Table 88–6 lists regimens and their response rates; the duration of response usually is measured in months, and, therefore, clinical trials are also recommended for this patient group. The duration of response is difficult to define because many patients go on to other therapies, including allogeneic stem cell transplantation.
In a large patient cohort treated on successive Medical Research Council trials, of those patients who relapsed after first remission, 55 percent entered a second remission. For those with favorable cytogenetics, 5-year survival was 32 percent; for those with intermediate cytogenetics, 5-year survival was 17 percent; and for those with adverse cytogenetic patterns, 5-year survival was 7 percent. In those in a second remission who underwent transplant, 42 as compared to 16 percent survived 5 years.774 Results from therapy were better in younger patients, and in those with longer first remissions, longer durations since last chemotherapy, and better general health. The probability of a second remission is approximately 40 percent in younger (ages 15 to 60 years) and approximately 25 percent in older (ages 60 to 80 years) patients, but the duration of remission is nearly always much shorter than the first remission. An eventual fatal outcome is nearly certain unless allogeneic HSC transplantation can be performed. Rare patients may have a third (or more) relapse followed by a remission when treated with cytotoxic drugs, but each remission is shorter than the preceding one and usually is measured in weeks. For those who have favorable or normal karyotype, long second remission, and no previous stem cell transplantation, intensive chemotherapy can be useful.775 In one study, 21 (approximately 17 percent) of 124 patients had a second remission duration at least 2 months longer than the first remission.776 In patients in relapse treated with the sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) regimen, the duration of the first remission was the only factor associated with a successful outcome, and unfavorable karyotype was the only factor related to duration of survival.777 Patients who relapse less than 1 year from remission should be treated with investigational agents, whereas patients who relapse more than 1 year later may benefit from standard reinduction therapy.778 No standard chemotherapy regimen provides a durable remission of AML patients who relapse (Table 88–7),779-789 and all such patients should be considered for clinical trials if available. For patients not fit for intensive salvage regimens, low-dose cytarabine, hypomethylating agents, or supportive or palliative care can be offered.
Table 88–7.Examples of Chemotherapy Regimens Used for Relapsed or Refractory Patients ||Download (.pdf) Table 88–7. Examples of Chemotherapy Regimens Used for Relapsed or Refractory Patients
|Regimen ||No. of Patients ||Percent of Patients Entering a Complete Remission (Median Duration) ||Year ||Reference |
|Clofarabine 40 mg/m2, IV, days 1–5 ||163 ||35.2 (6.6 months) ||2012 ||789 |
|Cytarabine 1 g/m2, IV, days 1-5 ||163 ||17.8 (6.3 months) ||2012 ||789 |
Clofarabine 25 mg/m2, IV, daily for 5 days
Cytarabine 2 g/m2, IV, daily for 5 days
G-CSF 5 mcg/kg per day subcutaneously daily until ANC ≥2,000/μL
|50 ||46 (9 months) ||2011 ||787 |
Gemtuzumab ozogamicin 6 mg/m2, IV, days 1 and 13
Idarubicin 12 mg/m2, IV, days 2–4
Cytarabine 1.5 g/m2, IV, days 2–5
|15 ||21 (27 weeks) ||2003 ||780 |
Mitoxantrone 12 mg/m2, IV, days 1–3
Cytarabine 500 mg/m2, IV, days 1–3
Followed (at blood count recovery) by:
Etoposide 200 mg/m2, IV, days 1–3
Cytarabine 500 mg/m2, IV, days 1–3
|66 ||36 (5 months) ||2003 ||781 |
Cladribine 5 mg/m2, IV, days 1–5
Cytarabine 2 g/m2, IV, days 1–5, 2 h after cladribine
G-CSF 10 mcg/kg subcutaneously, each day, days 1–5
|58 ||50 (29% disease-free at 1 year) ||2003 ||782 |
Fludarabine 30 mg/m2, IV, days 1–5
Cytarabine 2 g/m2, IV, days 1–5
Idarubicin 10/m2, IV, days 1–3
G-CSF 5 mcg/kg subcutaneously each day, up to 6 doses until neutrophil recovery
|46 ||52 (13 months) ||2003 ||783 |
|Gemtuzumab ozogamicin 9 mg/m2, IV, days 1 and 15 ||43 ||9 ||2002 ||784 |
Mitoxantrone 4 mg/m2, IV, days 1–3
Etoposide 40 mg/m2, IV, days 1–3
Cytarabine 1 g/m2, IV, days 1–3, ± valspodar (PSC-833)
|37 ||32 ||1999 ||785 |
Fludarabine 30 mg/m2, IV, days 1–5
Cytarabine 2 g/m2, IV, days 1–5±
Idarubicin 12 mg/m2, IV, days 1–3
G-CSF 400 mcg/m2, subcutaneously, daily until complete remission
|85 ||66 ||1995 ||786 |
Allogeneic Hematopoietic Stem Cell Transplantation
Allogeneic stem cell transplantation may be the only means to induce a sustained remission in patients with AML who do not enter remission with cytotoxic drug therapy or who relapse after a first remission. Approximately 25 percent of patients with refractory or relapsed AML have a sustained remission of at least 3 years.790 Transplant-related mortality at 3 years is approximately 50 percent. Relapse rates are higher after sibling than matched-unrelated transplantation.791,792 If a histocompatible donor is available and the patient is younger than age 50 years, allogeneic stem cell transplantation can be as successful, if it is performed when the patient is in early relapse compared with in second remission, but this is often done in the context of a clinical trial.793
Relapse after Stem Cell Transplantation For patients who relapse after allogeneic stem cell transplantation, the prognosis is extremely poor and available chemotherapy, donor leukocyte infusions, or second transplants do not result in consistent durable remissions.794 For patients who relapse after reduced-intensity allogeneic transplantations, median overall survival after relapse was found to be 6 months, and no advantage was found for donor leukocyte infusions or second transplantations as compared with chemotherapy.795 Patients who relapse after autologous stem cell transplantation can sometimes be salvaged with reduced-intensity allogeneic transplantation or with full-intensity allogeneic transplantations with high treatment-related mortality rates even in younger patients.
OTHER TREATMENT MODALITIES
Several newer chemotherapeutic agents are being examined for treatment of AML. For example, liposomal preparations of fixed ratios of daunorubicin and cytarabine have entered trials.796 CPX-351 produced a higher response rate than did cytarabine and daunorubicin chemotherapy (67 percent vs. 51 percent), but event-free survival and overall survival were not significantly different. In those patients who had secondary AML, however, a statistically significant prolongation of event-free (4.5 vs. 1.3 months) and overall survival (12.1 vs. 6.1 months) was noted. Cytopenias were more prolonged with CPX-351, but this did not translate into an increase in infection-related deaths.796 When this agent was used in adults with first relapse of AML and was compared with various standard intensive salvage chemotherapy regimens, 1-year survival was not improved in the CPX-351 group as a whole, but in predefined poor-risk patients there was suggestion of improved response rates, event-free survival, and overall survival.796a This agent was given priority review by the FDA in June 2017.
Methylation of DNA at critical sites can cause transcriptional inactivation of genes or chromosomal instability. In AML, aberrant methylation, especially preferential methylation of chromosome 11, has been described.797 Epigenetic gene silencing caused by DNA methylation is a target for presumptive demethylating agents such as 5-azacytidine or decitabine, and silencing mediated by histone deacetylation is a target for histone deacetylases.798 Decitabine, a potent agent, can cause maturation and growth arrest of AML cells.799,800,801 5-Azacytidine also has activity in AML, and it is being studied in an oral formulation.802 These agents, singly or in combination, have resulted in response rates of 25 to 60 percent.803 Methylome analysis may be useful as a pharmacodynamic end point in those treated with decitabine,804 and higher levels of miR-29b are associated with responses to decitabine.805 Histone deacetylase inhibitors can restore retinoic acid-dependent transcriptional activation and maturation in AML blasts.806 Depsipeptide can promote histone acetylation and gene transcription in RUNX1/ETO-positive leukemic cells.807 Depsipeptide (romidepsin),808 LBH589,809 vorinostat (suberoylanilide hydroxamic acid [SAHA]),810 and MGCD0103811 have each been studied in early phase trials in leukemia. Combination therapy of these agents with other targeted therapies is being explored,812 and combination therapy with hypomethylating agents and histone deacetylase inhibitors has been reported.813
Inhibitors of DOT1L and MDM2
The histone methyltransferase DOT1L is necessary for sustaining MLL-rearranged, AML. EPZ-5676, an aminonucleoside inhibitor of DOT1L histone methyltransferase activity is under clinical investigation in MLL-rearranged leukemias.814 Other DOLT1L inhibitors are being explored in IDH1/2 mutated AML.815 AGI-6780 has been identified as an IDH2 R140Q inhibitor with potential for differentiation.816 Inhibitors of MDM2, a regulator of p53 and p53-specific E3 ubiquitin ligase have also entered trials.817
Inhibitors of Isocitric Dehydrogenase 1 and 2
In the ~12 percent of patients who have mutations of IDH2, increased 2-hydroxyglutarate is produced, leading to DNA and histone hypermethylation. Inhibitors of mutant IDH2, such as enasidenib, can induce cell differentiation, although with no correlation with a reduction in 2-hydroxyglutarate levels in either R140 or R172 mutant subtypes.817a The neutrophils that emerged were functional but retained mutant IDH2 expression. Mutations in NRAS and MAPK pathway mediators were higher in nonresponding patients. In a phase 1/2 study of enasidenib, those patients with relapsed or refractory AML (n = 176) had an overall response rate of 40.3 percent with a median duration of response of 5.8 months. Nineteen percent of patients had a complete response, and their median survival was 19.7 months. The treatment was well tolerated, but 7 percent had a differentiation syndrome akin to that seen with ATRA or arsenic trioxide in promyelocytic leukemia patients. Furthermore, 12 percent had elevated indirect bilirubin levels.817b Trials are underway to compare this agent to standard care regimens in older patients with relapsed/refractory AML (NCT02577406). Other trials in previously untreated patients in combination with chemotherapy (NCT02677922) or azacitidine (NCT02632708) are also underway. Mutant IDH1 inhibitors are under development,817c and these agents also result in differentiation and reversal of hypermethylation patterns. Ivosidenib (AG-120) is an oral IDH1 inhibitor that is furthest along in clinical trials, but others are being examined.817d In preliminary results from 78 patients treated with AG-120, 38.5 percent of cases had responses, 17.9 percent of which were complete.817e Other IDH1 inhibitors that have entered trials are AG-881 and IDH305.817d
The CD33 antigen is expressed on approximately 90 percent of AML blasts and is a target for antibody-mediated destruction. Gemtuzumab ozogamicin is a recombinant humanized anti-CD33 monoclonal immunoglobulin G4 antibody conjugated to the cytotoxin calicheamicin.818 The conjugated antibody is rapidly internalized and causes subsequent cell apoptosis.819 Hyperbilirubinemia and transaminase elevations can occur. Although it results in similar survival rates as standard chemotherapy reinduction, its use was associated with fewer days of hospitalization.820 In patients who relapsed between 3 and 11 months, gemtuzumab ozogamicin resulted in higher remission rates compared to regimens containing high-dose cytarabine in different trials. However, in patients who had prolonged first remissions of greater than 19 months, cytarabine resulted in superior remission rates.821 Prior gemtuzumab ozogamicin exposure may increase the risk of venoocclusive disease in patients who later undergo myeloablative allogeneic HSC transplantation procedures.822 Gemtuzumab ozogamicin was approved by the FDA in 2000, but withdrawn from the market in 2010. Studies in Europe are examining its role in induction treatment coupled with standard chemotherapy, in postremission therapy, and in the treatment of APL.823,824,825 In those studies, it did not alter remission rates but appeared to decrease relapse rate or improve relapse-free survival. These and other studies have led to gemtuzumab ozogamicin’s reconsideration for FDA approval.825a Other CD33 antibody conjugates such as SGN-CD33A (vadastuximab talirine) also are in clinical trials. This compound is a humanized CD33 antibody linked to a pyrrolobenzodiazepine dimer. Some trials with this agent have been suspended or stopped because of concern regarding sinusoidal obstructive syndrome or prolonged cytopenias.825b Other bi-specific T-cell engaging (BiTE) antibodies and diabodies directed to CD33 also are under development.825c,825d
Therapies Targeted to Signal Transduction Mediators
Tyrosine Kinase Inhibitors: FLT3 Inhibitors Constitutively activating FLT3 receptor mutations have been found in approximately 30 percent of patients with AML. Several small-molecule FLT3 tyrosine kinase inhibitors have been formulated, and midostaurin has now received regulatory approval.826,827,828,829,830,831 Myeloblast differentiation may occur, including a syndrome with neutrophilic dermatosis wherein the neutrophils are FLT3-positive.832 FLT3-mutant allelic burden may predict response to such inhibitors.833 These agents are in phase I and phase II trials, in which they have induced a decline in blood blast cells, but rarely result in complete remissions.834,835 Newer-generation FLT3 inhibitors have been developed in an attempt to improve their effects.836 Crenolanib may inhibit both ITD and TKD mutations.837 Quizartinib (previously AC220) showed activity in a phase I study in relapsed/refractory AML, especially in patients with FLT3-ITD mutations.838 Gilteritinib is another specific FLT3 inhibitor that has entered clinical trials. It also inhibits AXL and has been found to have sufficient activity to warrant phase 3 trials. It is inhibitory to both the FLT3 ITD and TKD mutations.839 Whereas use of sorafenib840 and midostaurin588a have resulted in improved outcomes in combination with cytostatic drugs in de novo AML, other kinase inhibitors such as lestaurtinib have not resulted in improved outcomes in younger patients with newly diagnosed FLT3-mutated AML.840a
Kit Tyrosine Kinase Inhibitors: Imatinib Mesylate Activation of the KIT tyrosine kinase by somatic mutation has been documented in a small minority of AML cases. Paracrine or autocrine activation of KIT may occur in AML cells.841 Imatinib mesylate has induced a complete remission in refractory secondary AML,842 but this is a very uncommon result of its use.843 Dasatinib has been studied in CBF leukemias with a KIT mutation in conjunction with chemotherapy, but final results of studies are awaited.844
Nuclear Factor-Kappa B Inhibitors AML leukemia stem cells have activated NF-κB, unlike normal HSCs.845 Proteasome inhibitors such as bortezomib inhibit NF-κB and have been examined in AML. They have been found to increase sensitivity to chemotherapy agents in NPM1-mutated AML.846 Bortezomib is also being combined with chemotherapy agents in AML patients.847 Other inhibitors more specific to the NF-κB family have been proposed for study in AML.848
Other Signal Transduction and Tyrosine Kinase Inhibitors Numerous inhibitors of activated tyrosine kinases have been examined for AML therapy.849,850 These include mammalian target of rapamycin (mTOR) inhibitors,851,852 phosphoinositol 3′-kinase inhibitors,853,854 AKT inhibitors, such as perifosine,855 small-molecule mitogen-activated protein kinase (MEK) kinase inhibitors,856 Aurora kinase inhibitors,857 and heat-shock protein inhibitors.858 None of these agents have had an impact on AML survival as single agents, but using a combination of agents that target multiple pathways or using multitargeted tyrosine kinase inhibitors may hold promise for incremental improvements in AML therapy.859 There is some indication that extramedullary disease may increase in incidence in cases treated with signal transduction agents alone.860
Other Inhibitors of Signal Transduction and Apoptosis Pathways Many malignancies overexpress antiapoptotic proteins, such as BCL-2 and BCL-xL.861 Small-molecule BCL-2 homology domain-3 (BH3) mimetics such as ABT-737862 and GX15–070 (obatoclax)863 inhibit BCL-2. CDDO-Me, a triterpenoid, studied in vitro induces apoptosis and differentiation in AML cells through activation of caspase-8 and caspase-3 and induction of mitochondrial cytochrome c release.864
Prenylation Inhibitors: Farnesyltransferase inhibitors (FTIs)865,866,867,868 and geranylgeranyltransferase-1 inhibitors (GTIs), such as statins, have been examined as therapy in AML. Examples of responses of AML to lovastatin have been reported.869 Simvastatin adds to the effect of cytarabine’s inhibition of AML cell lines.870 Other studies suggest that the statins may mediate antileukemic effects independent of Ras/Rho prenylation through blockade of cholesterol responses to cellular injury.871 Effectiveness of either FTIs or GTIs as single agents has been minimal in untreated AML patients.865,866,867,868
Maturation Therapies Several analogues of vitamin D inhibit AML cells by inducing inhibition of cyclin-dependent kinases.872 In general, AML cells have not responded to retinoids. Single-strand conformational polymorphism analysis and DNA sequencing of leukemic cells from AML, other than APL, have not found mutations of RAR-α.873 Nevertheless, combinations of retinoids, growth factors, and chemotherapeutic agents are being examined for therapeutic potential in AML.874 Leukemias with 11q, –5, and –7 chromosome abnormalities have high telomerase activity, which can be inhibited by maturation-inducing agents.875 In one study, addition of ATRA to chemotherapy did not improve patient outcome but did result in a 25 percent increase in apoptosis in AML marrow cells in vitro.876 ATRA has induced a complete remission in a patient with acute myelomonocytic leukemia.877,878 Arsenic trioxide induces apoptosis and cytotoxic effects in blasts from patients with AML other than APL, and it is not influenced by permeability glycoprotein (P-gp) expression.879,880
Antiangiogenesis Agents and Agents That Inhibit Microenvironmental Interactions
Targeting the increased vascular density of marrow noted in AML or cytokines secreted by marrow endothelium has been examined as means to inhibit AML cell growth. Amifostine,881 thalidomide,880 sunitinib,881 and other agents that target VEGF and interleukin (IL)-8,882 as well as of the angiopoietin signaling pathway,883 are potential antiangiogenic agents in the treatment of AML. Lenalidomide, which also has antiangiogenic properties, is used to treat deletion 5q– AML.884 Antagonists of the chemokine receptor CXCR4, which plays a role in retention of hematopoietic cells in marrow and of integrins or selectins, have been proposed as therapeutic agents to overcome stromal-mediated resistance and to enhance chemotherapy-induced cell death.885,886
Modulation of Drug Resistance
Numerous mechanisms of drug resistance occur in AML,887 and several attempts to overcome this resistance have been instituted, but none of the agents used, such as cyclosporine or PSC-833, have had a significant impact on AML outcomes to date. P-gp, MDR protein-1 (MRP-1), and breast cancer resistance protein (BCRP) expression all have been found in AML.888
Other Immunotherapy and Antisense DNA Approaches
Culture of AML blasts upregulates costimulatory molecules, and the role of dendritic cells in antileukemia therapy is being examined.889,890,891 Other approaches to generating autologous T-cell antileukemic activity include vaccination with AML-specific peptides, immunization with AML blasts exhibiting dendritic cell phenotype and function,892,893 and pulsing normal dendritic cells with AML-specific peptide sequences.894 Natural killer cells may mediate antileukemia effects.895 Low doses of IL-2 have been used in the maintenance phase of AML, and some patients have remained on this regimen for 10 or more years without significant side effects.896 However, low-dose IL-2 does not improve outcomes when used as maintenance treatment in older AML patients.897 The WT gene WT1 is expressed on AML blasts, and a WT1 vaccine may elicit cytotoxic T-cell responses against this protein.898 Peptides derived from the mutated nucleophosmin I gene can elicit in vitro CD4 and CD8 T-cell responses.129 Other proteins against which such humoral responses have been elicited include minor HLA antigens and proteinase-3.899 Coinhibitory molecule signaling can hamper benefit of immune therapies, so efforts to modulate coinhibitory networks are underway in leukemias.900 Small interfering RNA (siRNA) targeting of transcription factors901 and GTI-2040, an antisense to ribonucleotide reductase, have been used in AML therapy.902 In addition to CD33, CD45, CD66, and CD38 have been examined as targets for immunotherapy of AML.903,904 Immunotoxin conjugates are being examined in AML as well to increase potency of naked monoclonal antibodies.905 Alloreactive haploidentical KIR ligand-mismatched natural killer cells are also being examined in high-risk elderly AML cases.906
The immunomodulatory drug lenalidomide has also been examined in AML and has some activity in high doses in relapsed or refractory AML.907,908
The IL-3 receptor α (CD123) is overexpressed in AML as compared with normal HSCs, so it has been proposed as a target for chimeric antigen receptors (CARS) as a bridge to allogeneic HSC transplantation.909,910
Other antigens that are being examined as targets in AML-directed chimeric-antigen receptor (CAR)-T cell therapy are Lewis Y, CD33, folate receptor-beta, CD44v6, and CLL-1 (C-type lectin-like molecule 1).910a,910b Unlike their success in B-cell malignancies, in AML, no myeloid-directed CAR-T cell has been generated to be compatible with normal hematopoietic recovery. Strategies to deplete CAR-T cells after their anti-AML effects with antibodies or the use of allogeneic stem cell transplant to rescue patients from their deleterious effects on hematopoiesis are being explored.910c
SPECIAL THERAPEUTIC CONSIDERATIONS
Acute Promyelocytic Leukemia
General Consideration in Therapy Because of the early induction mortality in APL, patients who are suspected based on morphology and presence of coagulopathy should begin ATRA without waiting for definitive FISH or molecular confirmation. There is now an International Consortium on APL, the goal is to improve outcomes through education and guidelines formulaton.911 While many trials with variations in the induction, consolidation, and maintenance phases are published, the clinician is urged to consider clinical trials and to follow one protocol plan through all the phases of therapy.
Induction Treatment ATRA has become a standard component of induction therapy for APL. Used alone, ATRA can induce a short-term remission in at least 80 percent of patients.912 However, ATRA should be combined with an anthracycline such as idarubicin or with arsenic trioxide during induction treatment for most benefit and to prevent drug resistance.913 Idarubicin by itself can induce remission in approximately 75 percent of patients.914 A typical induction regimen for APL is ATRA 45 mg/m2 daily in divided doses with idarubicin at standard induction doses (e.g., 12 mg/m2 on days 1 to 3).915,916 Although cytarabine has been largely abandoned as part of induction, some studies show a high degree of efficacy of high-dose cytarabine combined with ATRA.917 There is evidence that in patients who present with a white cell count of 10 × 109/L or greater, the complete remission rate and overall survival may be superior when cytarabine is added to induction or consolidation regimens, especially if arsenic trioxide is not part of the induction regimen.918,919 The addition of arsenic trioxide to ATRA and idarubicin in induction regimens results in approximately 95 percent complete remission rates. This approach allows reduction in anthracycline usage and excellent overall survival (93 percent).920 In low- to intermediate-risk APL (WBC <10 × 109/L), the combination of ATRA and arsenic trioxide was found equal to, or possibly superior to, an ATRA plus chemotherapy regimen.921,922 Also, there was less hematologic toxicity and fewer infections with that combination of drugs. Older patients generally tolerate a combination of ATRA and an anthracycline.923 Combinations that include gemtuzumab ozogamicin are being examined for their effectiveness in APL induction therapy, but this antibody is no longer marketed in the United States.924 The combination of ATRA and arsenic trioxide results in more rapid remissions and lower PML-RAR-α transcript levels than either agent alone.925 Despite the high remission rates and frequency of long-term event-free survival achieved in this disease, controversies remain regarding therapy because of the 5 to 10 percent of patients who die as a result of fatal intracranial hemorrhage.926 This relatively high early death rate (17.3 percent) persisted despite use of ATRA in induction therapy.927 Thus, there are several induction regimens that can be chosen to treat APL based on WBC at diagnosis and, to a lesser extent, patient age and ability to tolerate anthracyclines. For those with low-risk disease, a combination of ATRA plus arsenic trioxide, ATRA plus idarubicin alone, or ATRA plus daunorubicin plus cytarabine can be used. In high-risk patients, ATRA plus daunorubicin and cytarabine, ATRA plus idarubicin, or ATRA and arsenic trioxide with idarubicin (dose-adjusted based on age) can be used.928 Table 88–8 lists APL induction regimens.
Table 88–8.Examples of Treatment Protocols for Acute Promyelocytic Leukemia ||Download (.pdf) Table 88–8. Examples of Treatment Protocols for Acute Promyelocytic Leukemia
|Induction ||Consolidation ||Reference |
|HIGH-RISK PATIENT || || |
ATRA 45 mg/m2 PO in divided doses
Daunorubicin 60 mg/m2 IV for 3 days
Cytarabine 200 mg/m2 IV for 7 days
1st Cycle: Daunorubicin 60 mg/m2 IV for 3 days; Cytarabine 200 mg/m2 IV for 7 days
2nd Cycle: Cytarabine 2 g/m2 (or 1.5 g/m2 in older patients) IV, every 12 hours for 5 days plus daunorubicin 45 mg/m2 IV for 3 days
ATRA 45 mg/m2 PO (days 1–36 in divided doses)
Idarubicin (6–12 mg/m2 based on age) IV on days 2, 4, 6, and 8
Arsenic trioxide 0.15 mg/kg IV (days 9–26)
1st Cycle: ATRA 45 mg/m2 PO in divided doses for 28 days; arsenic trioxide 0.15 mg/kg IV per day for 28 days
2nd Cycle: ATRA 45 mg/m2 PO for 7 days every 2 weeks × 3. Arsenic trioxide 0.15 mg/kg per day × 5 days IV for 5 weeks
|LOW-RISK PATIENT || || |
|ATRA 45 mg/m2 PO in divided doses daily until remission; arsenic trioxide 0.15 mg/kg IV daily until remission || |
Arsenic trioxide 0.15 mg/kg IV per day, 5 days per week for 4 weeks every 8 weeks for 4 cycles
ATRA 45 mg/m2 PO per day for 2 weeks every 4 weeks for 7 cycles
|ATRA 45 mg/m2 PO in divided doses until clinical remission; Idarubicin 12 mg/m2 IV on days 2, 4, 6, and 8 || |
1st Cycle: ATRA 45 mg/m2 PO for 15 days; idarubicin 5 mg/m2 IV for 4 days
2nd Cycle: ATRA 45 mg/m2 PO for 15 days; mitoxantrone 10 mg/m2 IV for 5 days
3rd Cycle: ATRA 45 mg/m2 PO for 15 days; idarubicin 12 mg/m2 IV for 1 dose
All-Trans Retinoic Acid: Dose and Mechanism of Action ATRA, an analogue of vitamin A, has been used to initiate the therapy of APL since 1987 in the United States. ATRA induces complete remissions in approximately 80 percent of previously untreated patients.929 In vitro, ATRA is 10 times more potent in inducing maturation of leukemic promyelocytes to neutrophils than 13-cis retinoic acid, the other naturally occurring isomer.930 ATRA induces maturation of the leukemic cells and their apoptosis results in the reappearance of normal polyclonal hematopoiesis and a remission in most cases.931 ATRA may induce synthesis of a protein that selectively degrades PML-RAR-α. ATRA can overcome the recruitment of histone deacetylase activity by the PML-RAR-α fusion gene through interference with a nuclear corepressor.932 STAT1 is induced and activated by ATRA. Promyelocytic leukemia cells with PML-RAR-α break-fusion sites in PML exon 6 have decreased in vitro responsiveness to ATRA.933 The t(11;17) variant of APL, in which the promyelocytic leukemia zinc finger (PLZF) gene is fused to RAR-α, does not respond to ATRA.934 Other nonpromyelocytic leukemia subtypes of AML have not responded to ATRA therapy. ATRA is beneficial in APL during the induction and maintenance phases of disease,935 and improved outcome with ATRA is reflected in the 5-year survival rates of 75 to 80 percent.936 Additional cytogenetic changes do not influence treatment outcomes with ATRA plus an anthracycline.937 ATRA induction therapy can result in favorable results without blood product support.938
Toxic Effects of All-Trans Retinoic Acid ATRA therapy is associated with dryness of the skin and lips, occasionally leading to mild exfoliation, nausea, headache, arthralgia, and bone pain. The white cell count may rise dramatically in the first week or two of therapy. Serum glutamic-pyruvate transaminase and triglyceride concentrations often increase. Leukemic promyelocytes disappear from the blood in 2 to 4 weeks, and a normal marrow aspirate may be obtained in 4 to 10 weeks. Anemia improves gradually. The majority of patients become PML-RAR-α–negative by PCR after the second consolidation therapy in conjunction with ATRA.939 ATRA has been used successfully to treat APL diagnosed during pregnancy.940 ATRA has been used from week 3 of gestation, but may result in fetal malformations when it is used during the first trimester.941
Differentiation Syndrome A rapid increase in the total blood leukocyte count to as high as 80 × 109/L in the first several weeks of therapy, referred to as the differentiation syndrome (previously called the retinoic acid syndrome), is a potential cause of early death during therapy.942,943,944 The median time of onset is 11 days, but the syndrome has occurred up to 47 days after therapy starts.944 Two approaches to treatment of this phenomenon have been suggested: early use of cytotoxic chemotherapy945,946 and glucocorticoid administration.947,948 The syndrome consists of fever, weight gain, dependent edema, pleural or pericardial effusion, and bouts of hypotension. Respiratory distress is the key feature. In fatal cases, pulmonary interstitial infiltration with maturing granulocytes is prominent. Once respiratory distress is evident, the patient should receive dexamethasone 10 mg IV every 12 hours for several days. Because the syndrome may occur at relatively low total white cell counts and its onset is unpredictable, high-dose glucocorticoid therapy should be instituted if respiratory symptoms develop even in the absence of pulmonary infiltrates or an elevated white cell count.942,946 ATRA can be continued or resumed with glucocorticoids or with concurrent cytotoxic chemotherapy, but the syndrome may recur.942 This syndrome is not observed during maintenance therapy. It may also occur with arsenic trioxide therapy, and some recommend prophylactic glucocorticoids in those with a WBC greater than 10 × 109/L or in those receiving both ATRA and arsenic trioxide.943
Treatment of Coagulopathy Reducing the risk of early death from hemorrhage as a result of the coagulopathy accompanying APL requires use of fresh-frozen plasma, platelet replacement, and fibrinogen replacement.489,490,949 Targeted levels for platelet counts are usually 30 to 50 × 109/L928 and for fibrinogen levels 1.5 g/L or higher, but these levels are often difficult to achieve in patients with active hemorrhage.950 Heparin treatment was used during induction chemotherapy in the past to prevent onset of disseminated intravascular coagulopathy during treatment, but rarely is used now.951 ATRA may have some corrective effect on coagulation disorders in APL.952 However, a reduction of 5 to 10 percent of fatal hemorrhages has not been significant with ATRA used early during treatment. Paradoxically, hypercoagulable clotting tendency may occur in patients during the first months of ATRA therapy.931 In the coagulopathy of APL, the blasts overexpress annexin II, and there is evidence that the effects of annexin II can be reversed by l-methionine administration.953
Chemotherapy Induction of remission with ATRA alone is followed by relapse in weeks to months unless intensive chemotherapy is used concomitantly.954 At relapse, cells show high levels of a cytosolic retinoic-acid-binding protein not detected prior to ATRA therapy.932 The mechanism of retinoid resistance in leukemic cells may involve cytochrome P450 and P-gp because of induction of various enzymes that may alter ATRA metabolism.955 ATRA, whether administered as part of induction therapy or as maintenance therapy, confers a disease-free survival advantage. More than 70 percent of patients receiving ATRA at any point were in continuous remission at 2.5 years versus less than 20 percent of patients who never received ATRA.936 The acquired in vivo resistance that occurs rapidly to ATRA as a single agent requires consolidation of ATRA-induced complete remission with intensive chemotherapy using an anthracycline antibiotic. Customary treatment today involves simultaneous administration of ATRA and an anthracycline and/or arsenic trioxide. Some therapists have returned to combining an anthracycline antibiotic with cytarabine in an effort to decrease CNS relapse, especially in patients younger than 60 years of age with white counts greater than 10 × 109/L at presentation.956 Maintenance therapy with ATRA alone or in combination with mercaptopurine or methotrexate has been recommended. This additional therapy has not been examined in a randomized trial of ATRA dosing and scheduling, but ATRA usually is given in an interrupted fashion. Intensified maintenance therapy may have a negative impact on those patients who have become negative for the PML-RAR-α fusion transcript after induction plus consolidation therapy.957 Some therapists have proposed that elderly patients can be treated with ATRA and arsenic trioxide without chemotherapy and with addition of gemtuzumab ozogamicin in the event of an elevated white count at the time of diagnosis.958
Arsenic Trioxide Arsenic trioxide can trigger apoptosis of APL cells at high concentrations and maturation at low concentrations. The presence of PML-RAR-α is important for the response. Apoptosis may occur through induction of activation of caspase-1 and caspase-3 after changes in the mitochondrial membrane potential with increase in H2O2.959,960 It also may function through NF-κB inhibition.961 Death-associated protein 5 also contributes to arsenic trioxide–induced apoptosis in APL.962 Arsenic trioxide given at 0.06 to 0.12 mg/kg body weight per day until leukemic cells were eliminated from the marrow induced remission within 12 to 89 days in 11 of 12 patients.963 Suppression of hematopoiesis did not occur. Rash, light-headedness, fatigue, and musculoskeletal pain were the main side effects. Arsenic trioxide can be combined with idarubicin in relapsed patients; it also has been used with ATRA.921,964,965 A retinoic acid–like syndrome (see “All-Trans-Retinoic Acid: Dose and Mechanism of Action” above) has been described in patients with APL treated with arsenic trioxide.966 Torsade de pointes, an uncommon variant of ventricular tachycardia in which the underlying etiology and management are different from those of the usual variety of ventricular tachycardia, has been described with arsenic trioxide use,967 and monitoring of electrocardiographic QTc intervals and electrolyte levels during therapy is recommended.968
Consolidation Therapy Consolidation therapy is required in APL to achieve a durable molecular remission. Consolidation typically consists of anthracycline plus ATRA, but in high-risk patients, the addition of cytarabine or use of arsenic trioxide can be used to diminish the rate of relapse. Almost every induction regimen described in APL has a distinct consolidation regimen attached to it, dependent on disease stratification. To achieve uniformly good responses, it is recommended that one follow a given protocol’s induction, consolidation, and maintenance regimen. Table 88–8 provides examples of paired induction and consolidation regimens. Excellent results can be achieved with all of these regimens, if treatment plans are executed faithfully.
Maintenance Therapy After consolidation phases of therapy are complete, patients should be in a molecular remission, that is, PCR-negative for PML-RAR-α. ATRA maintenance with chemotherapy is recommended based on the APL 93 trial, which showed that relapse-free survival was superior with ATRA versus no ATRA, and that the best results were achieved when ATRA was combined with 6-mercaptopurine and methotrexate.969 The 10-year cumulative relapse rates were 43 percent with no maintenance, 33 percent with ATRA alone, 23 percent with chemotherapy alone, and 13 percent with ATRA and chemotherapy.970 Maintenance is usually recommended for 2 years, and studies to examine whether maintenance is beneficial in low-risk disease are ongoing.928 During maintenance, PCR monitoring on blood samples is recommended.928 If the PCR is positive in blood, a marrow examination should be done.
Treatment for Relapsed Acute Promyelocytic Leukemia Conventional chemotherapy can be effective after relapse. Arsenic trioxide has been used in those who do not achieve molecular remission at completion of consolidation or who subsequently demonstrate molecular relapse and can generate high molecular remission rates in more than 80 percent of patients alone or when combined with chemotherapy.971 It is still uncertain whether ATRA has benefit in patients previously exposed to ATRA. Patients younger than age 70 years should be considered for allogeneic or autologous HSC transplantation after they have achieved a second remission or for allogeneic transplantation if a second remission cannot be induced.972 Other treatments for patients in relapse include the combination of ATRA, arsenic trioxide, and gemtuzumab ozogamicin. This combination has resulted in durable remissions.973 Transplantation generally is not recommended for patients with APL in first remission given the prolonged remissions after standard treatments. Allogeneic stem cell transplant is best used in advanced APL, especially in patients with persistent disease by PCR.974 The outcome of autologous stem cell transplantation in second complete remission is excellent if the stem cells used are negative for PML-RAR-α.941 High-dose cytarabine can be used for stem cell mobilization which will also treat CNS relapse, and when a second molecular remission is followed by an autograft, the 5-year disease-free survival is approximately 75 percent. This result is superior to survival after allografting, but a direct comparison of autologous transplantation, allogeneic transplantation, and arsenic trioxide or ATRA with standard chemotherapy has not been made in patients with APL in a second remission after relapse.975 For patients in a second remission who are not candidates for allogeneic stem cell transplant, up to six cycles of arsenic can be used.
Many cases of extramedullary relapse in APL have been reported.976 Many of the relapses occur in patients who received ATRA and who initially were diagnosed with hyperleukocytosis,977 and many of the patients are in marrow remission. Relapses occurring more than 5 years after diagnosis have been reported, some at extramedullary sites such as in the mastoid bone.978 Early detection of relapse is important as those with molecular relapse before hematologic relapse has occurred fare best.979 Patients should be monitored with PCR every 3 months for 2 years after remission induction, especially those with intermediate- or high-risk disease.928
MDS can occur in patients in remission with APL, usually 24 months or more after diagnosis. The complication results from a second (drug-induced) clonal disease in long-term responders.980-992 Cases of therapy-related APL have been described.983 Patients with APL who are FLT3-ITD–positive generally have worse overall outcomes than do those persons who present with elevated white cell counts and older age.984 There is also evidence that mutations in the ATRA-targeted ligand binding domain of PML-RAR-α and additional chromosome abnormalities may be associated with reduced postrelapse survival in those on ATRA.985 Oral arsenic trioxide and tamibarotene, a synthetic retinoid, are being examined in relapsed APL.986,987 Children older than 4 years and adolescents have outcomes with ATRA-treated APL equivalent to that of adults, but younger children have more frequent relapses.988
SECONDARY ACUTE MYELOGENOUS LEUKEMIA
Secondary leukemias arise after treatment of another malignancy or an autoimmune disease with cytotoxic chemotherapy or radiation. Secondary AML responds more poorly to chemotherapy and allogeneic stem cell transplantation than does de novo AML. Secondary AML accounts for approximately 5 to 10 percent of all AML cases, although this percentage is increasing.980,990 The leukemogenic risk of treatment regimens depends on the agents used. Future development of agents with lower risk of inducing AML is an important goal.991
Effect of Topoisomerase II Inhibitors
Exposure to topoisomerase II inhibitors (e.g., etoposide, mitoxantrone, amsacrine) can lead to AML with MLL gene rearrangements on chromosome 11q32.992 Inversion 16 is an uncommon aberration in secondary AML and, like balanced translocations of chromosome bands 11q32, 21q22, and t(15;17), is associated with prior chemotherapy with topoisomerase II inhibitors when seen in the setting of treatment-induced leukemias. The site of breakpoints within the MYH11 gene involved in inversion 16 may vary between therapy-induced AML and AML occurring de novo.993 The latency period for development of AML after topoisomerase II inhibitors is approximately 2 years. No relationship with higher cumulative dose has been identified. Studies of single nucleotide polymorphisms to ascertain genetic predisposition are ongoing.994 Polymorphisms in detoxification genes and in genes involved in DNA repair pathways might be involved.995 Even the use of low-dose or oral etoposide can be associated with development of secondary AML.
Effect of Alkylating Agents and Cisplatin
Alkylating agents cause secondary AML, often preceded by myelodysplasia. The mean latency period after onset of treatment is approximately 6 years. Deletions of all or part of chromosome 5 or 7 are the most common cytogenetic changes. The risk is related to cumulative alkylating agent dose. Germline aberrancies of NFI and p53 may increase the risk of AML. Cisplatin used for treatment of ovarian cancer also increases the risk of secondary leukemia.996
Other drugs that may increase the risk of secondary leukemias include low-dose weekly methotrexate for rheumatoid arthritis,997 etanercept therapy,998 temozolamide,999 growth hormone administration,1000 and G-CSF given to patients with congenital, but not idiopathic or cyclic neutropenia.1001 In the latter cases, a cause-and-effect relationship between MDS/AML and G-CSF therapy has not been established. Improved survival duration with G-CSF may allow expression of an underlying leukemic predisposition.
Other Settings for Secondary Leukemia
Patients with APL in remission may develop a new MDS (oligoblastic leukemia), presumably secondary to therapy.1002 Series of children with treatment-related myelodysplasia or AML have the same latency period as do adults treated with alkylating agents or topoisomerase II inhibitors for AML.1003 Breast cancer patients receiving doxorubicin and cyclophosphamide regimens of such intensity that they required G-CSF support had increased rates of posttherapy AML. Breast and prostate radiotherapy are associated with an increased risk of AML.1004,1005 In patients with non-Hodgkin lymphoma, up to 10 percent of patients treated with either conventional chemotherapy or high-dose therapy developed secondary AML within 10 years.1006 Secondary leukemia is seen after autologous marrow or blood stem cell transplants involving high-dose chemotherapy and/or radiotherapy. In a study of 83 patients after autografting, 12 had nonclonal cytogenetic abnormalities and 10 had clonal abnormalities, five of whom developed secondary AML. Onset occurred 12 to 48 months after autografting. The relative contribution of the underlying disease and the conditioning therapy is uncertain.1007 Clonality analysis using an X chromosome gene, based on methylation of the human androgen receptor locus in cell samples in patients with lymphoma, found a clonal marrow cell population 6 months after autologous transplantation at a time when no morphologic or clinical evidence of AML was present. AML appeared later in some patients.1008 More than 10 percent of patients with non-Hodgkin lymphoma who underwent stem cell rescue after total body irradiation and cyclophosphamide developed AML at a median followup of 6 years.1009 Using a triple FISH assay to detect loss of chromosomal material from 5q31, 7q22, or 13q14, abnormal cells were detected before high-dose therapy was given to non-Hodgkin lymphoma patients.1010 Thus, some patients are at increased risk for developing secondary AML based on pretreatment chromosome studies.
Treatment of Secondary Leukemia
Secondary leukemia generally is treated similarly to de novo leukemia. However, given the lower response rates and remission durations of secondary leukemia, patients can be treated in clinical trials examining new therapies or treated initially with chemotherapy regimens used for refractory disease.1011 CPX-351, which provides a fixed 5:1 molar ratio of cytarabine to daunorubicin, has demonstrated efficacy in secondary AML but is not yet approved for use.796 Some patients may benefit from early allogeneic HSC transplantation.1012 Autologous transplant can be successful if stem cells are harvested prior to the development of secondary AML.1013 In those who have low blood blast counts, allogeneic stem cell transplantation as initial therapy may be superior to induction chemotherapy followed by transplantation, but this remains an area of controversy.1014 Although patients may have a response rate of approximately 50 percent to standard induction chemotherapy, most soon relapse, and long-term survival is approximately 10 percent.1015 Secondary AML more often has unfavorable cytogenetic features compared to de novo leukemia.1016
TREATMENT OF Ph CHROMOSOME–POSITIVE AML
This cytogenetic variant of acute leukemia is characterized by extraordinary drug resistance. Imatinib mesylate in doses of 600 to 800 mg/day may produce a hematologic remission in a small proportion of patients with Ph chromosome–positive AML, based on the response in patients with CML who go on to a myeloid blast crisis. No formal studies of the response to imatinib mesylate of de novo Ph chromosome–positive AML have been performed. In myeloid blast crisis of CML, the uncommon full hematologic response (blood and marrow) usually is short lived, measured in weeks or a few months. This outcome also seems to be the case when therapy with other drugs (e.g., cytarabine, etoposide, anthracycline antibiotics) is included. Occasional cases in which chemotherapy has induced remission in Ph chromosome–positive AML and imatinib mesylate has appeared to help induce and sustain the remission have been reported.1017 Thus, in Ph chromosome–positive AML, a matched-related or matched-unrelated donor stem cell transplant should be considered if the patient is younger than age 50 years. This approach may have the highest probability of a long-term remission. There is little information about the use of second generation BCR-ABL inhibitors in this setting.
TREATMENT OF OLDER PATIENTS
Approximately 65 percent of patients with AML are older than age 60 years at the time of diagnosis.1018 The disease in this age group is less responsive to therapy, and this age group has a higher proportion of patients who have oligoblastic myelogenous leukemia (MDS); an antecedent clonal myeloid disease; prior chemotherapy for cancer of another site; and comorbid conditions that decrease the tolerance to intensive chemotherapy programs.1019,1020,1021,1022 The AML cells of elderly patients often have more CD34 expression, suggesting origin from a more primitive multipotential (? stem) cell. This finding is thought to contribute to longer duration of postchemotherapy aplasia and to the increased risk of induction deaths in this age group.1023 Patients older than age 60 years also have a high frequency of unfavorable cytogenetic findings (32 percent) and higher MDR1 expression (71 percent) and functional drug efflux (58 percent).1024,1025
The therapist and patient determine whether a standard regimen, a standard regimen with dose reductions, or a special regimen is used.1026,1027 Decisions based on chronologic age should be supplanted by measurements of cognitive, neurologic, and physical fitness used by geriatricians to evaluate the wisdom of considering intensive treatment.1028 These are often not well-validated in geriatric AML populations, but there is evidence that assessments focused on cognition and objective measures of physical function may predict for overall survival in those older than age 60 years who undergo standard induction chemotherapy.1029 In patients older than age 60 years who are fit and otherwise are considered good candidates, standard two-drug therapy can be used: cytarabine and an anthracycline antibiotic, and on some occasions the addition of a third drug, etoposide. Remission rates of approximately 35 to 45 percent can be achieved. Based on case studies, those who are able to receive induction chemotherapy may have a median survival slightly better than those who receive supportive care alone,1030,1031 but there are no randomized trials that address this issue.1032 Patients older than 70 years (median: 74; range: 70 to 88) may not have much benefit from intensive chemotherapy with an 8-week mortality of greater than 30 percent and a median survival of less than 6 months.1033 Some investigators have proposed waiting for cytogenetic information before therapy decisions are made in older patients. Those with unfavorable cytogenetics and two or more other criteria including age older than 75 years, poor performance status, and WBC greater than 50 × 109/L were found not to benefit from chemotherapy.1034 Chemotherapy has been combined with growth factor support to accelerate neutrophil recovery in older patients.1035 In a study in which patients older than age 55 years were randomized to receive either placebo or G-CSF after induction therapy, no reduction in the duration of hospitalization, survival prolongation, or cost of supportive care was noted.1036 In previously untreated elderly patients with AML, mitoxantrone induction therapy produces a slightly higher remission rate than did daunorubicin, but had no significant effect on remission duration and survival.1037 Oral idarubicin alone has been used with success.1038
Attenuated standard regimens can be used in older patients. An example of an attenuated regimen is cytarabine 100 mg/m2 subcutaneously every 12 hours for 10 doses on days 1 through 5 and daunorubicin 30 mg/m2 IV on days 1 through 3 of treatment. One induction regimen is not superior to another in older patients. Outcomes achieved with cytarabine and daunorubicin are comparable to results with mitoxantrone and etoposide.1039 Other regimens for older patients include lower total doses of idarubicin, etoposide, and cytarabine (DIVA regimen)1040 and a combination of continuous infusion low-dose cytarabine with etoposide and G-CSF.1041 Temozolomide has been used in this age group,1042 and clofarabine is also being tested in patients age 60 years and older.1043 In one study of clofarabine in older patients who were deemed unfit for 7-plus-3 chemotherapy, a 5-day clofarabine regimen resulted in a 48 percent response rate, and 18 percent died within 30 days.1044 Another study in those older than 60 years showed a response rate of 46 percent and an overall median survival of 41 weeks and a 30-day all-cause mortality of approximately 10 percent.1045 Several investigational therapies, including 5-azacytidine, decitabine, cloretazine, and depsipeptide, are also being studied. There are also several reports concerning addition of other agents to standard chemotherapy to improve responses. These include bevacizumab,1046 sorafenib,1047 and gemtuzumab ozogamicin.1048,1049 CPX-351 has been studied in older adults.796 Thus far, none of these drugs have resulted in improvement in overall survival. Apart from selected subsets, in patients with specific mutations, inhibitors directed to those mutations could potentially improve survival. For example, in mutant IDH2-relapsed or refractory AML, enasidenib (AG-221) can induce responses with a median response duration of 5.8 months in a population with a median age of 67 years.817b
Autologous Stem Cell Infusion or Nonmyeloablative Allogeneic Transplantation
Autologous stem cell transplantation has been used in fit patients older than age 60 years.1050 The incidence of relapse is lower when marrow stem cells are used compared to blood stem cells. Some patients older than age 60 years may be eligible for reduced-intensity allogeneic stem cell transplantation from related or unrelated donors, but more data regarding outcomes are needed.1051 In a large registry study, examining reduced-intensity allogeneic HSC transplantation for older patients with AML and MDS in first remission, older age was not found to affect 2-year nonrelapse mortality, disease-free or overall survival.1052
Postremission Therapy in Older Patients
No consensus exists regarding the best regimen or the number of treatment cycles for postremission therapy in older adults. Regardless of the consolidation regimen, the duration of the leukemia-free survival is longer with high-dose cytarabine and autologous stem cell transplantation, just as it is in younger patients,1042 but fewer older patients can tolerate this degree of therapeutic intensity. Higher-dose cytarabine can be used in older adults with AML, but usually at a reduced dose.1053 Older patients treated with attenuated high-dose cytarabine at 750 mg/m2 intravenously for 12 doses and then consolidated with four to six doses had an approximately 50 percent remission rate with a median duration of remission of 326 days.1054 Fifty-one percent of 110 patients older than 60 years of age had a 9-month median remission duration when consolidated with high-dose cytarabine.1055 Older patients are at higher risk for relapse despite successfully completing intensive consolidation therapy, regardless of whether other adverse prognostic features are present. Cytarabine as maintenance therapy may prolong disease-free survival but does not improve overall survival.1056 Decitabine and 5-azacytidine are also being examined for maintenance therapy. In one randomized study, those receiving consolidation therapies had more hospitalizations and more transfusion requirements.1057
Patients older than 80 years of age do not tolerate treatments well. Remission rates are approximately 30 percent, but the median survival of treated patients is approximately 1 month. Less than 10 percent of patients survive for 1 year.1058
Unlike the case in younger patients, the treatment outcomes for older patients have not improved over the last two decades.1059 Treatment options in older patients include (1) no treatment, (2) supportive care, (3) palliative low-dose chemotherapy, (4) attenuated induction chemotherapy, or (5) high-dose chemotherapy regimens. Investigative agents should also be given strong consideration in this population.1060 Comorbidities are independent predictors of complete remission and should be taken into account during decision making,1061 as should performance status.1062 Some argue that the approximately 15 percent rate of death in those older than 60 years of age in the first month after standard induction chemotherapy is unacceptable given the less than 1 year median survival expected.1063 Lower-dose regimens can also be toxic and can lead to severe cytopenias. Use of colony-stimulating factor permits older patients to tolerate full-dose induction therapy. The Medical Research Council of the United Kingdom observed remission rates of 80 percent in children, 70 percent in adults younger than 50 years of age, 68 percent in adults 50 to 59 years old, 53 percent in adults 60 to 69 years old, 39 percent in adults 70 to 75 years old, and 22 percent in adults older than 75 years of age.1064 In one study of patients older than 60 years of age, the 2-, 5-, and 10-year survivals were 22, 11, and 8 percent, respectively.1065,1066 The older patients who remain free of leukemia beyond 1 year have a reasonable quality of life.1067,1068 The National Cancer Institute 5-year relative survival rates for patients with AML are 11 percent for adults ages 65 to 74 years and 1.8 percent for adults ages 75 years and older.1069
Even though t(8;21) and inversion 16 are rare in older AML patients, remission rates are high with these favorable prognostic chromosome changes, so induction chemotherapy is often recommended, although rates of relapse remain high.1070 In parallel, elderly patients with unfavorable cytogenetics have a dismal prognosis, and those who have a monosomal karyotype have low complete remission and overall survival rates; 37 versus 64 percent and 8 versus 28 percent, respectively, in those with and without monosomal karyotype.1071
TREATMENT OF PREGNANT PATIENTS
Leukemia (AML, ALL, CML) is the second most common malignancy of women in the childbearing age group and is expected to occur in approximately 1 in 75,000 to 100,000 pregnancies.1072,1073 No systematic studies of the (1) effects of leukemia on pregnancy or delivery, (2) effects of the leukemia or its treatment on the fetus, or (3) postnatal development of the offspring exposed to maternal chemotherapy in utero have been performed. A recent literature review led to the conclusion that treatment during the second and third trimesters resulted in fewer complications to the fetus, but delaying treatment adversely affected the outcome of mothers. Remission rates were comparable to that of nonpregnant patients.1074 Folic acid inhibitors, purine, pyrimidine, or retinoid analogues given during the first trimester of pregnancy increase the probability of major congenital malformations. In a French study of 37 patients with acute leukemia during pregnancy, 34 patients achieved remission, and disease-free survival appeared equivalent to that of patients who were not treated during pregnancy.1075 In another study from Saudi Arabia, of 21 pregnant patients with acute leukemia, 10 were given chemotherapy with seven livebirths and three spontaneous abortions without any teratogenetic or congenital malformations. In the 11 not given chemotherapy until after 34 weeks of gestation, three had normal births and eight had an abortion before starting chemotherapy.1076
If the pregnancy is not terminated, leukapheresis might be useful in the first trimester, when chemotherapy poses a high risk to the embryo. Intensive chemotherapy given to women in the second and third trimesters of pregnancy does not present an inordinate risk to fetal or neonatal development,1077,1078 although an increased frequency of premature delivery, higher perinatal mortality, and lower birthweight for gestational age are observed, especially if the fetus is exposed to chemotherapy.
Cytarabine is highly teratogenic in animal models and malformations have been described in women who were treated in the first trimester of pregnancy. Doxorubicin is the preferred anthracycline antibiotic to treat pregnant women as it has lower transplacental transfer. Doxorubicin is considered relatively safe when used in pregnant women.1079 Newborn infants may be transiently cytopenic if the mother receives chemotherapy near the time of delivery. Development of the newborn usually is normal after intensive chemotherapy for AML during pregnancy, if therapy is started after the first trimester.1072,1077,1078 Vaginal delivery should be used whenever possible. Pregnant women with AML who enter remission have little difficulty with childbirth or postparturition. The remission rates of AML are approximately the rates expected for the age group, and long-term remissions can occur with current therapy. Leukemic infiltrates can be found on the maternal side of the placenta, but usually not in the villi. One case of maternal-to-fetal transmission of AML has been documented.1080 Transmission of AML from one identical twin to another through a shared placental circulation accounts for the dual occurrence in twins in the first several years of life.177 There are reports of the use of ATRA for APL treatment during pregnancy, but use during the first trimester is discouraged, and data are sparse.941,1081,1082
AML represents approximately 15 percent of the acute leukemias in children (younger than 20 years of age) in the United States. APL is treated as in adults, with ATRA and an anthracycline antibiotic. In other phenotypes of AML, intensive treatment—including initial therapy with cytarabine and daunomycin or doxorubicin and a third drug such as mitoxantrone or 6-thioguanine, followed by intensive multidrug consolidation therapy including additional agents such as etoposide, and intrathecal cytarabine—has resulted in remission in approximately 80 percent of children and 5-year relapse-free remissions in approximately 50 percent of treated children.1083,1084,1085,1086 Most of the children in long-term remission are considered cured.
Monocytic leukemia and hyperleukocytic (>100 × 109/L) myelogenous leukemia are unfavorable phenotypes. In children, FLT3-ITD mutations are approximately half as common (15 percent) as in adults (30 percent), but are a very poor prognostic indicator.1087 Therapy can be adjusted for children based on the presence of poor prognostic variables, which include age younger than 2 years or older than 10 years; abnormalities of chromosome 3, 5, or 7, complex karyotypes, FLT3 mutations, elevated white cell count of 50 × 109/L or greater, male gender; and, perhaps, most importantly, because it reflects the effect of all factors, the presence of greater than 15 percent blast cells in the marrow examined 14 days after onset of treatment.1088,1089 The presence of residual blast cells detected by flow cytometry after induction therapy is a very poor prognostic finding.1090 The duration of first remission predicts the subsequent remission rate and long-term survival in children with relapse.
Translocations 8;21, 15;17, or inv16 are good prognostic markers. Loss of a sex chromosome in the t(8;21) group is especially favorable. Monosomy 7 and abnormalities of chromosomes 3 or 5 are poor prognostic features.1091 Pediatric AML with t(8;16)(p11;p13) has been found to be a distinct clinical entity, and in a subset of neonatal cases, spontaneous remissions can occur.1092 In childhood 11p23/MLL AML, there are large differences in outcome based on translocation partners that are independent prognostic markers as assessed in a large international study.1093 When gene mutations were examined in childhood leukemia, FLT3-ITD was most frequent, and 29 percent had more than one gene mutation. Mutated epigenetic regulators were less than in adults, but were often seen with other mutations.1094
In the United Kingdom Medical Research Council Trial 12, completed in 2002, using daunorubicin, mitoxantrone cytarabine, etoposide, and asparaginase in different combinations, approximately 90 percent of children with AML had a remission, 60 percent of children had a 5-year disease-free survival, and most were considered cured.1091 Approximately 4 percent of children are drug resistant with this program and approximately 4 percent die during induction and intensification therapy. Studies are under way to examine the effects of using fludarabine in the regimen (Medical Research Council 15 Trial).
Autologous stem cell transplantation has not improved outcome compared to current intensive chemotherapy treatment regimens.1095 Allogeneic stem cell transplantation from a histocompatible sibling should be considered in children in first remission with a donor and poor prognostic indicators or in children who relapse.1095 Trials have shown good results of allogeneic transplantation in first remission; event-free survival was better in childhood AML with those allografted than with those who underwent autografting.1096 Children younger than age 2 years previously had a very poor prognosis. They tend to present with myelomonocytic or monocytic leukemia with high blast counts and CNS involvement. The t(9;11) abnormality has a more favorable prognosis. Intensive multidrug regimens have resulted in 3-year survivals approaching 70 percent of all infants treated. Thus, most infants can be successfully treated with intensive chemotherapy or allogeneic stem cell transplantation.1097,1098 Cord blood may be a suitable allograft option for children with AML who lack an acceptably matched unrelated marrow donor.1099
Growth failure, neurocognitive abnormalities, endocrine deficiencies, and cardiac abnormalities are found in children treated at a young age.1100 The occurrence of a second malignancy in cured children is approximately 10-fold greater than expected in a matched population by age.1101 Indefinite followup of children in remission or believed to be cured is important to assess developmental and intellectual progress and to evaluate long-term adverse events.
NONHEMATOPOIETIC ADVERSE EFFECTS OF TREATMENT
More than 50 percent of patients with AML develop skin lesions during remission-induction or remission-consolidation therapy. The rash may be on the trunk and extremities. The rash usually is maculopapular initially but can become hemorrhagic in patients who have thrombocytopenia. Allopurinol, trimethoprim-sulfamethoxazole, and other β-lactam antibiotics are commonly implicated causes. Use of multiple drugs enhances the probability of skin reactivity of patients.1102 Cytostatic therapy coupled with the effects of leukemia predisposes patients to an increased frequency of allergic dermatitis.
Alterations in cardiac function, especially left ventricular and intraventricular septal diastolic wall motion abnormalities, occur frequently in patients after they are exposed to the anthracycline antibiotics, daunorubicin, or doxorubicin.1103 The risk of serious cardiac effects is correlated with increasing dose of anthracycline antibiotic, increasing patient age, and presence of underlying heart disease. Adverse effects include electrocardiographic changes, such as prolonged QT interval, myocarditis, pericarditis, myocardial infarction, and congestive heart failure. The incidence of congestive heart failure is dose related and ranges from approximately 5 percent at doses of 550 mg/m2 to greater than 30 percent at doses of 600 mg/m2.1104 The frequency and long-term sequelae increase as anthracycline dose increases. However, even lower doses of these agents exert negative effects on cardiac myocytes. Measurement of heart wall behavior, valvular competence, and ejection fraction by ultrasonography can assist in assessing the risk of proceeding with anthracycline treatment in patients with or without pretreatment heart disease.1105,1106 In younger patients, transient abnormalities, although frequent, often improve after therapy is completed. Increased long-term remissions in children and younger adults have led to an increase in serious ventricular and valvular disturbances years after therapy in some patients. Periodic evaluation of cardiac status by ultrasonography should be undertaken in long-term survivors.1106 Cardiomyopathy and heart failure can occur 10 to 15 years after therapy. Two approaches that may ameliorate the cardiomyopathic effect of anthracycline antibiotics are the use of these agents in liposome encapsulated preparations1107 and the use of dexrazoxane. Either approach may reduce the cardiotoxicity of anthracycline antibiotics.1108
Hepatitis may occur in multiply transfused patients and usually is mild, but persistent hepatitis can develop, although hepatitis viruses A and B infection are not increased above the expected incidence in the general population. Hepatitis caused by type A virus is nearly nonexistent early in the course of AML. Cases of type B hepatitis can occur infrequently in patients who are carriers of the B virus and in whom chemotherapy and transient immunosuppression reactivate the virus.1109,1110,1111 These rare cases of fibrosing cholestatic hepatitis can be fulminant. Screening blood products for hepatitis virus C has markedly decreased the risk of hepatitis C.1112 Reactivation of carriers of the C virus after chemotherapy is unusual.1113 Medication induced chemical hepatitis or cholestasis can occur but is usually reversible. Iron overload in the multiply transfused survival may lead to later liver abnormalities.
Systemic Candidiasis Syndrome
The syndrome is manifested by fever, abdominal pain, and hepatomegaly. Increased serum alkaline phosphatase activity often is noted. Blood cultures are often negative. Abdominal ultrasonography, computed tomography, and MRI show characteristic hepatic lesions: circular areas of decreased attenuation of liver and often spleen, kidney, lung, or paraspinal muscles by imaging.1114 Ultrasonography reveals multiple hypoechogenic areas with a bull’s-eye appearance. Laparoscopic-guided liver biopsy reveals yellow nodules on the liver surface, which on microscopic examination are large granulomas with Candida and pseudohyphae. Cure of this infection is possible with long-term (2 to 10 months) antifungals. Hepatosplenic candidiasis is seen much less frequently when azoles are used for fungal prophylaxis.
Necrotizing inflammation of the cecum with secondary infection can occur in patients with acute leukemia on intensive chemotherapy.233 Bacteremia may occur. Right lower abdominal pain and fever can simulate appendicitis. The diagnosis can be confirmed by sonography or computerized tomographic scanning in which a characteristic mucosal thickening and polypoid appearance are evident.1115,1116 Management includes bowel rest, nasogastric suction, fluids, and antibiotics. Parenteral alimentation is sometimes used but is generally not helpful.1117 Restoration of the neutrophil count after chemotherapy is an important feature of resolution. In the absence of resolution, right hemicolectomy should be considered but is a last resort in neutropenic patients, usually imposed if hemodynamic stability is lost.233
Although bleeding is associated with AML, thrombotic complications can also occur; up to 10 percent in APL and up to 3 percent in other AML subtypes.1118 Management can be difficult because of thrombocytopenia. Central lines may contribute to this incidence.1119 Thrombotic thrombocytopenic purpura has also been reported in patients in remission of AML during consolidation chemotherapy.1120 Patients with AML undergoing allogeneic stem cell transplantation also may develop posttransplantation thrombotic thrombocytopenic purpura, which rarely responds to plasmapheresis.
Fertility and Gonadal Function
Patients treated for AML, especially patients undergoing conditioning for allogeneic stem cell transplantation, have decreased gonadal function.1121,1122,1123 Men may develop oligospermia. Women may develop ovarian dysfunction and very high gonadotropin levels.1124 Men recover gonadal function more often and sooner than do women. Recovery of ovarian function in women is partly dependent on a younger age at the time of treatment. In survivors of childhood AML treated only with chemotherapy and not transplantation, normal pubertal development and fertility are found, but antimüllerian hormone was low in some women.1125 Women in remission following treatment for AML with allogeneic transplantation can become pregnant and deliver healthy infants1126,1127; however, this preservation of fertility is rare.1128 Histologic studies of the testes show marked suppression of spermatogenesis as a function of duration of treatment for AML and not of the specific agents used or the patient’s age. Residual spermatogenesis in intensively treated patients enables recovery of reproductive function in males.1129 Males receiving intensive daunorubicin, cytosine arabinoside, or 6-thioguanine treatment for AML have conceived children during therapy.1130 Banking of sperm should be offered, and cryopreservation of ova can be attempted prior to institution of cytotoxic therapy, but often neither is logistically possible or successful in patients with AML who are acutely ill at presentation and require urgent chemotherapy.1121 Banking of sperm or ova-ovarian tissue should be considered before myeloablative conditioning regimens for transplantation are administered. Many AML survivors report they were not, or not fully, informed about fertility-related issues.1131