|Chemotherapy and targeted therapy|
|All-trans retinoic acid (ATRA) and arsenic trioxide (ATO)||Differentiating agents||Acute promyelocytic leukemia|
- Life-threatening hyperleukocytosis and the differentiation syndrome, marked by weight gain and edema, progressing to dyspnea, interstitial pulmonary infiltrates, pleural and/or pericardial effusions, unexplained fevers, and acute renal insufficiency.
- Other toxicities unique to differentiating agents include pseudotumor cerebri with ATRA and dangerously prolonged QT intervals and hyperglycemia with ATO. If a patient on ATO presents with syncope or palpitations and the absolute QT interval is > 500 msec, ATO should be withheld, electrolytes repleted, and QT-prolonging drugs stopped.
|Dexamethasone 10 mg IV twice a day should be started at the earliest sign of differentiation syndrome, even if other etiologies like sepsis or primary CHF are possible. In patients with acute renal failure or requiring ICU admission for respiratory distress, ATRA or ATO should be temporarily held.|
|Anagrelide||A prostaglandin synthetase inhibitor, specifically inhibits platelet production but occasionally causes mild anemia||Myeloproliferative neoplasms||Palpitations, CHF, noncardiac edema, diarrhea, abdominal pain, headache, bleeding, anemia||In the MRC PT-1 trial, aspirin + hydroxyurea were compared to aspirin + anagrelide treatment for ET. There were more arterial events and fewer venous thromboses in the anagrelide arm. Anagrelide increased progression to marrow fibrosis and conferred a higher risk of serious hemorrhage. More patients withdrew from the anagrelide arm due to adverse effects. A starting dose of 0.5 mg twice a day is appropriate.|
|Anthracyclines (daunorubicin, doxorubicin, idarubicin, epirubicin)|
- Inhibit DNA synthesis by intercalating between DNA base pairs, causing single-strand and double-strand breaks;
- Generate free radicals that cause oxidative damage to DNA and cellular proteins.
|Acute leukemias (eg, daunorubicin in “3 + 7”), lymphomas (eg, doxorubicin is the H in “CHOP”).||Myelosuppression. Early cardiotoxicity may manifest as transient asymptomatic sinus tachycardia or ECG abnormalities and does not predict late cardiotoxicty. Late cardiotoxicity is dose-dependent. Extravasation may cause tissue necrosis days to weeks later. Radiation recall, high emetogenicity, reversible alopecia, and secondary leukemia are other considerations.||Baseline assessment of ejection fraction is advised. Anthracyclines are contraindicated if the EF is < 45%, if the patient suffered an MI in the past three months, or in the presence of severe arrhythmias. Cumulative lifetime doses are limited to 450–550 mg/m2 doxorubicin, 800 mg/m2 daunorubicin, 150 mg/m2 idarubicin.|
|5-Azacitidine and decitabine||At low doses, they act as demethylating agents (inhibit DNA methyltransferase)||Myelodysplastic syndromes||Both drugs cause nausea, diarrhea, constipation, and cytopenias. SC injection site reactions, neuropathy, hepatotoxicity, rash, hypokalemia, and renal failure have occurred with 5-aza.||Profound cytopenias may herald an eventual response to treatment rather than progressive disease.|
|Bleomycin||A glycopeptide antibiotic, it causes scission of single-and double-stranded DNA and interferes with DNA repair||Hodgkin lymphoma, uncommonly used today in NHL||Fever and chills occur in half of patients within hours of treatment. Anaphylactoid reactions may occur. Interstitial pneumonitis and pulmonary fibrosis may be life threatening. The presentation may be subtle: nonproductive cough, dyspnea, unexplained fever. CXR usually shows bilateral reticular or nodual opacities without pleural effusions, but may be normal, and reduced DLCO is the first PFT abnormality. Flagellate erythema is a rare but distinctive rash that may appear from one day to several months following bleomycin administration. Bleomycin enhances radiation injury. Alopecia.||Bleomycin should be withheld if the DLCO falls to 30–35% of the initial value, if the FVC falls significantly, or if there are clinical or radiographic features suggesting pulmonary toxicity. Prednisone 1 mg/kg should be employed in patients with pneumonitis. Since oxygen may synergize with bleomycin to produce fibrosis, supplemental oxygen administered during operative procedures and critical illnesses should be minimized.|
|Bortezomib||A proteosome inhibitor||Multiple myeloma. Investigational and salvage use in certain lymphomas.||Peripheral neuropathy that is sometimes painful, orthostatic hypotension, gastrointestinal upset, constipation, ileus, thrombocytopenia, herpes zoster, tumor lysis syndrome.||Zoster prophylaxis is advisable in VZV+ patients. The neuropathy may require dose reductions and usually improves or resolves within two years of discontinuing treatment.|
|Busulfan||An alkylating agent, it forms DNA intrastrand and interstrand crosslinks.||Conditioning for allogeneic stem cell transplant. At lower doses, it may be used for palliation in myeloproliferative neoplasms and CML.||Myelosuppression may be prolonged. An Addisonian-like syndrome with skin hyperpigmentation and weakness but normal adrenal function may occur. Alveolar and interstitial pneumonitis are well described. Seizures may occur in the setting of transplant conditioning and busulfan may potentiate cyclophosphamide in causing sinusoidal obstruction syndrome.||In the transplant conditioning setting, drug level monitoring with dose adjustment to achieve 800–1000 ng/mL reduces serious toxicity and phenytoin or, less commonly, lorazepam seizure prophylaxis is employed. Pulmonary toxicity is treated with steroids (eg, prednisone 50–100 mg/day) and minimizing inspired oxygen.|
|Chorambucil||An alkylating agent||CLL, low-grade lymphoma||Generally well-tolerated. Myelosuppression is the usual dose-limiting toxicity. Pulmonary toxicity, rash, and toxic epidermal necrolysis are rare occurrences.||CBCs should be monitored closely, especially with continuous administration.|
|Cyclophosphamide||An alkylating agent, it interferes with DNA replication and transcription of RNA||Lymphoma, transplant conditioning||Myelosuppresion is the major dose-limiting toxicity. Hemorrhagic cystitis is common (10%, up to 40% with high doses). Tumor lysis syndrome may occur. Nasal stuffiness and facial discomfort are common complaints with rapid infusions. Pulmonary toxicity occasionally occurs and has a high fatality rate. SIADH is seen. In the transplant setting, Cy is the main drug responsible for sinusoidal obstruction syndrome and cardiac necrosis can occur at high doses. Alopecia, radiation recall, and secondary leukemia and other cancers are other considerations.||Patients should be well hydrated and prophylactic mesna is used to minimize the occurrence of hemorrhagic cystitis. When this complication does supervene, treatment includes aggressive hydration (to ensure a diuresis of 3 L/24 h) and maintaining platelets > 50 × 109/L. If the urine does not clear, pain is severe, or renal insufficiency develops, then obtain a renal ultrasound and start continuous bladder irrigation adding 300 mg of hydrocortisone to each 3 L bag of irrigation fluid. Additional measures include cystoscopic evacuation of clots and fulguration, and intravesical carboprost.|
|Cytarabine||An analogue of cytidine, AraC inhibits DNA polymerase, thus stopping DNA elongation. It is also incorporated into DNA leading to errors in replication and transcription.||AML induction and consolidation, MDS, high-grade lymphomas||Myelosuppression. Cytarabine sometimes provokes a generalized rash, fever, and myalgia 6–12 hours after administration of high doses. Palmar–plantar erythrodysesthesia manifests as painful paresthesias and edematous erythema of the palms and soles, followed weeks later by desquamation. Rash is due to build up of the drug in areas that lack sweat glands, not an allergic reaction, and further treatment with this agent is permissible. Chemical conjunctivitis is common with high doses and prophylactic steroid eye drops are required. Cerebellar degeneration can occur and may be irreversible. Hepatotoxicity and pulmonary toxicity may occur.||Test for cerebellar dysfunction (include handwriting) before each high dose infusion used in consolidation therapy. Cerebellar toxicity mandates cessation of this therapy. Steroids may be used to treat pulmonary toxicity, which may present as a capillary leak syndrome 2–21 days after the first dose.|
|Fludarabine||A purine analogue, it inhibits DNA and RNA polymerase, DNA primase, DNA ligase and ribonucleotide reductase||CLL, lymphomas, salvage regimens for AML, conditioning regimens in nonmyeloablative stem cell transplantation||Myelosuppression may persist for many months. Profoundly reduces B and T lymphocytes; this degree of immunosuppression can lead to opportunistic infection with intracellular pathogens (PCP, Listeria) and transfusion-related graft-versus-host disease. Interstitial pneumonitis and dose-dependent irreversible neurotoxicity (including confusion, cortical blindness, and necrotizing leukoencephalopathy) rarely occur in current protocols. Autoimmune haemolytic anemia is common when used in DAT+ CLL patients.||Blood banks and patients themselves should be aware of the need to irradiate cellular blood products. PCP prophylaxis is required.|
|Hydroxyurea||Considered an antimetabolite, it inhibits ribonucleotide reductase, which leads to depletion of the deoxynucleoside triphosphate pool.||Myeloproliferative neoplasms, CML, temporary control of AML||Dose-related neutropenia, macrocytic anemia, thrombocytopenia. Vasculitic ulcerations in patients with MPNs. Mouth ulcers. Enhances the toxicity of radiation and may cause radiation recall.||Hydroxyurea will ameliorate splenomegaly and hypercatabolic symptoms. Women on chronic hydroxyurea therapy who are contemplating pregnancy should be switched to interferon-alpha.|
|Imatinib (first generation), nilotinib, dasatinib (second generation)||Tyrosine kinase inhibitors with varying specificity for BCR-ABL and other kinases||CML, Ph+ ALL, and subsets of CMML, chronic eosinophilic leukemia, and systemic mastocytosis|
- Imatinib: Nausea, diarrhea, muscle cramps, fluid retention, periorbital edema, hepatotoxicty, rashes.
- Nilotinib: Indirect hyperbilirubinemia, asymptomatic lipase elevations, hyperglycemia, rashes.
- Dasatinib: Pleural and pericardial effusions, pulmonary edema. Both nilotinib and dasatinib may prolong the QT interval. All TKIs cause neutropenia and thrombocytopenia (often before resumption of nonclonal hematopoiesis).
|The three currently available TKIs have very different drug-drug interactions and side effect profiles. Toxicity from one agent does not preclude switching to another TKI.|
|Glucocorticoids (eg, prednisone, dexamethasone, methylprednisolone)||Upregulate or downregulate gene transcription, and cause apoptosis of lymphocytes.||ALL, CLL, NHL, Hodgkin lymphoma, myeloma||Short-term: Euphoria, psychosis, insomnia, hyperglycemia, appetite stimulation, myopathy, fluid retention, hypertension, hypokalemia. Chronic use: Cushingoid appearance, peptic ulcers, osteoporosis, avascular necrosis, cataracts, impaired cellular immunity.||Side effects should be actively managed. Fungal and PCP prophylaxis may be indicated, depending on dose, duration of use, and prior history of candidal or mold infections. In patients in whom a prolonged (≥ 3 month) course of glucocorticoids is envisioned, primary osteoporosis prevention with a bisphosphonate in addition to calcium and vitamin D should be considered, especially if the baseline T-score is ≤ -1.|
|L-asparaginase||By hydrolyzing asparagine, it deprives lymphoid cells of this required amino acid, impairing protein synthesis.||ALL||Hypersensitivity reactions, acute pancreatitis, hyperglycemia, hepatotoxicity. Thrombosis is frequent but hemorrhage may also occur, as asparagine depletion interferes with liver synthesis of both anticoagulant and procoagulant proteins. Lethargy, confusion, and personality changes resolve within days of drug discontinuation.||For allergic patients, Erwinia-derived asparaginase should be substituted for standard E Coli-derived asparaginase. Asparaginase is poorly tolerated in adults, particularly because of thrombotic complications. Serum amylase should be obtained prior to each cycle, and significant elevations or symptomatic pancreatitis preclude further therapy with this drug.|
|Lenalidomide and thalidomide||Immunomodulators with antiangiogenic activity||Myeloma (both). 5q- syndrome/MDS (lenalidomide). Investigational use in many other hematologic cancers.|
- Thalidomide: Somnolence, constipation, peripheral neuropathy. Lenalidomide: myelosuppression, especially thrombocytopenia, rare pneumonitis.
- Both agents are associated with thrombosis. Rashes and rare cases of toxic epidermal necrolysis have been reported. Both agents are teratogenic.
|The risk of thrombosis is augmented by concurrent glucocorticoids or erythropoietin. The optimal VTE prophylaxis is debated.|
|Melphalan||An alkylating agent||Low dose: elderly or unfit patients with myeloma; High-dose: conditioning for autologous stem cell transplant in myeloma, NHL, and HL||Mucositis is the limiting effect of high dose treatment. Pneumonitis and pulmonary fibrosis rarely occur. Tissue necrosis occurs with extravasation.||Prolonged alkylator exposure precludes subsequent autologous stem cell collection, which is why melphalan is avoided as initial therapy in transplant-eligible patients.|
|6-Mercaptopurine||A purine analogue||Maintenance therapy in ALL and APL||Myelosuppression, especially in patients with thiopurine methyltransferase deficiency; hepatotoxicity, immunosuppression, radiation recall.||Allopurinol significantly increases plasma concentrations of 6-MP. When administered together, the 6-MP dose should be reduced by 25–33%. 6-MP should be stopped promptly at the first indication of myelosuppression, since the nadir may be delayed.|
|Methotrexate||As an antifolate, it prevents de novo purine and pyrimidine biosynthesis.||High-grade NHL, ALL, prevention of graft-versus-host disease in the transplant setting||Myelosuppression, stomatitis, mucositis, tumor lysis syndrome, hepatotoxicity, acute renal insufficiency, idiosyncratic pulmonary toxicity, radiation recall, chemical meningitis with intrathecal administration.||Many drugs can reduce renal clearance of MTX or displace MTX from albumin, increasing bioavailability. For example, penicillins should not be administered with high-dose MTX. MTX also accumulates in effusions and edema fluid, which can lead to substantial toxicity. Effusions should be evacuated before MTX is given. Leucovorin rescue, hydration, and urinary alkalinization are the mainstays of treating MTX toxicity. High flux hemodialysis may be tried, and glucaripidase may be available on a compassionate basis.|
|Vinca alkaloids (vincristine and vinblastine)||Antimicrotubule agents||ALL, NHL, Hodgkin lymphoma, myeloma||Vincristine's dose-limiting effect is neurotoxicity. Commonly, this includes peripheral sensory impairment, paresthesias, and loss of deep tendon reflexes. Painful dysesthesia, motor impairment that includes foot drop and difficulty with fine finger movements, ataxia, cranial nerve palsies manifesting as hoarseness, ptosis, facial nerve palsies, or jaw pain, and in extreme cases paralysis can occur. Autonomic toxicity includes constipation and ileus. Vinblastine is less neurotoxic. Both drugs are vesicants.||With vincristine, aggressive bowel regimens are needed to prevent obstipation and ileus. Extravasation may be treated by infiltrating the area with 1–2 mL of hyaluronidase, 150 U/mL, then applying warm compresses for 72 hours.|
|Alemtuzumab||A monoclonal anti-CD52 antibody||CLL, T-cell lymphomas||Infusion reactions, as described for rituximab below, are common during the first week of therapy. Profound cytopenias are very common. Opportunistic infections due to profound lymphopenia are frequent.||Prophylaxis against PCP and herpetic infections, and prophylactic or preemptive therapy for CMV is mandatory. Blood products administered prior to recovery from lymphopenia should be irradiated to avoid transfusion-related graft-versus-host disease.|
|Rituximab||A monoclonal anti-CD20 antibody||CLL, B-cell NHL||Infusion reactions including fevers, rigors, urticaria, bronchospasm and hypotension are common. The incidence of infusion reactions is highest with the first dose (77%) and diminishes with subsequent doses. Anaphylaxis may occur, usually at the second or subsequent infusion. Pulmonary reactions that manifest with dyspnea, bronchospasm, hypoxia, and lung infiltrates may occur acutely (one to two hours after initiation of the first infusion) or be delayed (one to four weeks after infusion). Tumor lysis syndrome is well-recognized (particularly in CLL). Due to immunosuppression, hepatitis reactivation and extremely rarely progressive multifocal leukoencephalopathy may occur; the risk of PML is likely augmented when rituximab is combined with chemotherapy.||Most infusion reactions are mild-to-moderate and can be managed by interrupting or slowing the infusion and supportive care (saline, antihistamines, methylprednisolone, acetaminophen, bronchodilators, ± epinephrine if severe).|