Chapter 93: Hairy Cell Leukemia

Cases of malignant diseases involving marrow that probably represented examples of hairy cell leukemia (HCL) were reported through the first half of the 20th century and designated by such terms as “lymphoid fibrosis.” They had features characteristic of HCL including marrow replacement by mononuclear cells, marrow fibrosis, splenomegaly and anemia and thrombocytopenia. In 1958, Bouruncle, Wiseman, and Doan described this constellation of findings in a group of patients.¹ At that time there was no means to characterize the immunophenotype of malignant lymphoid cells and they called the disease “leukemic reticuloendotheliosis.” In 1966, Schrek and Donnelly, described the distinctive feature of cytoplasmic projections that were evident on the blood cells in two cases of this disorder. They called these “hairy” cells.^1A The designation HCL has become universally accepted as the name of this lymphocytic neoplasm, characterized by infiltration of the marrow by malignant B-lymphocytes of a specific immunophenotype (see “Laboratory Features” below), often accompanied by reticular fibrosis, splenomegaly, anemia, thrombocytopenia, neutropenia, monocytopenia, and usually pancytopenia. Occasionally, there is an elevated total white cell count because of the abundance of malignant B-lymphocytes in the blood. Splenectomy was the sole therapeutic approach until the early observations of responses secondary to α-interferon and the purine analogues.^2,3 Whereas splenectomy improved the blood counts, the impact of this intervention was temporary, resulting in improvement of symptoms related to splenic sequestration. Most standard chemotherapy was ineffective and poorly tolerated. In 1984, Quesada described the benefits of daily α-interferon in achieving responses in seven patients with progressive HCL.² Three patients achieved a complete response, with the remaining four having partial responses. Extensive description of the effects of α-interferon on marrow showed improvement in granulopoiesis associated with increases in the number of both circulating granulocytes and platelets. While this approach was heralded as a major achievement in treating this disease, other opportunities emerged in the same time frame.

Grever and colleagues demonstrated that low-dose pentostatin was effective in achieving responses in patients with far-advanced low-grade B-cell malignancy.^4,5 Spiers reported the initial response of HCL to pentostatin in a limited number of patients,³ which was followed by a larger study with a complete remission rate of 59 percent.⁶ Kraut and colleagues subsequently showed that low-dose, less-intense, intermittent pentostatin produced a higher complete remission rate (approximately 89 percent) in patients with HCL.⁷ Others confirmed these findings,⁸ and a large prospective randomized trial of pentostatin versus α-interferon solidified that frontline therapy should be based upon a purine analogue.⁹ Piro and colleagues reported that cladribine produced complete responses in 11 of 12 patients with this disease.¹⁰ Numerous trials with cladribine confirmed that a single course of therapy was equally capable of inducing a high percentage of long-term complete responses.^11,12 However, the initial trials with cladribine excluded patients with an active infection.^10,11 Several studies using cladribine aimed at optimizing the remission rate and attempting to reduce myelosuppression showed that either 5 to 7 days of intravenous administration or subcutaneous injection produced responses, but these alternate approaches did not consistently reduce the risks for febrile neutropenia.^13,14,15 In contrast, the reported frequency of febrile neutropenia was less in a study using intermittent administration of pentostatin⁹ compared to those reported with cladribine.¹⁰ Consequently, either purine nucleoside analogue is now used to induce remission.

In patients with an active infection, it is advisable to control the infection before initiating immunosuppressive chemotherapy. However, if this is not possible then administration of either pentostatin alone or following α-interferon may be effective in controlling the underlying disease.^9,16 If α-interferon is initially used to improve the neutrophil count and control the leukemia, the subsequent use of pentostatin to achieve a complete remission is not compromised. Therefore, some investigators have initially treated patients with HCL complicated by infection with α-interferon, which was followed by pentostatin in an effort to reduce infectious complications.¹⁶ While the use of filgrastim does reduce the degree and the duration of neutropenia, it does not reduce the number of febrile episodes in patients being treated with cladribine, in comparison to historical controls.¹⁷ However, it may be helpful in treating serious infections in neutropenic patients with HCL who are in a precarious medical condition. The optimal management of actively infected patients with HCL requiring treatment is still challenging.

The remarkable advances in diagnosis and therapeutics with purine analogues over the past 25 years have clearly changed the natural history of this disease.¹⁸ Patients may now lead a near-normal life, despite the likelihood of intermittent relapses requiring retreatment.^19,20 Although the risk for serious bacterial infection is greatest during initial therapy, there are some delayed risks associated with impaired recovery of T-lymphocyte cell numbers and function following administration of purine analogues.^19,21

In patients who achieve a complete morphologic remission, the presence of minimal residual disease (MRD) has been repeatedly shown by immunohistochemical staining of the marrow.¹⁹ Some patients in hematologic remission with MRD may live normal lives, and do not require retreatment unless there is deterioration in their blood counts.^22,23 Consequently, further research to define the optimal therapeutic approach and timing for evaluation of response is needed.

The excellent results achieved with purine nucleoside induction associated with high percentages of complete remission have contributed to the improvement in overall survival for patients with this disease.²⁰ Using Surveillance, Epidemiology, and End Results Program (SEER) data after 1984, extensive analysis over the past 3 decades shows a progressive improvement in patient survival with HCL. Despite these truly remarkable results, at least 40 percent of patients will relapse.¹⁹ Many of these patients will be successfully retreated, but the failure of the disease-free survival curve to flatten attests to the fact that this disease has been controlled but not cured. Strategies to predict who will be prone to relapse will enable new treatments to be risk-stratified. Furthermore, new agents are being developed to successfully treat patients who have developed resistant disease.^19,24,25

HCL is a rare chronic B-cell lymphoid malignancy accounting for approximately 2 percent of adult leukemias. The estimated annual incidence in the United States is approximately 3.3 persons per million person-years in the United States.²⁴ The mean age at diagnosis is 55 years, but there is a wide range in age of onset.²⁰ Patients may present in their 20s and 30s, and a report on 88 patients who were diagnosed at age 40 or younger showed that these patients do well long-term.²⁶ Younger patients respond better to therapy, but may relapse and require retreatment in order to experience long-term survival benefits.^9,19 There is an unexplained male predominance with this disease with a ratio of 4:1 males to females. There is also an unexplained racial difference with more than 90 percent of patients being white.²⁰

There is a bimodal presentation in age raising the possibility of different etiologies in the younger and older patient groups.²⁷ The search for causative relationships in the older subset of patients has included extensive investigation of environmental and occupational exposures.²⁸ There is a suggestion of increased cases associated with farming and in jobs with extensive exposure to insecticides. Extensive investigation of the risk for secondary malignancies identified an increased overall risk (standardized incidence ratio [SIR] 1.24) in a large population-based study according to SEER data from 1973 through 2000.²⁹ In this study of more than 3000 patients with HCL, three separate malignancies were identified as being of particular concern (SIR 6.61 Hodgkin lymphoma; SIR 5.03 non-Hodgkin lymphoma; and SIR 3.56 thyroid cancer). Whether or not these second malignancies are related to an immune deficit from the leukemia or a result of the therapy for the leukemia is unknown.

HCL represents a clonal population of leukemic cells predominantly infiltrating the marrow, the spleen, and the liver. These cells are characterized as mature activated memory B cells based upon their immunophenotypic profile.³⁰ The neoplastic cells in classic HCL (HCL-c) have hypermutated immunoglobulin genes in approximately 90 percent of the cases.³¹ In those patients who have unmutated immunoglobulin genes, the disease appears to be more aggressive, as is the case in chronic lymphocytic leukemia. Leukemic cells use a variety of VH gene families. In those patients showing a VH4–34 gene, the clinical course has also been noted to be less favorable.^32,33 Molecular parameters may have prognostic value. For example, patients with a mutation in p53 have been less responsive to purine analogue therapy. Therefore, characterization of the molecular and genetic profile of the leukemic cells may elucidate the cell of origin and have prognostic value with respect to clinical outcome and responsiveness to standard therapy.

The identification of a mutation in BRAF V600E in almost 100 percent of patients with HCL-c has had a major impact on classification of the previously defined subsets of this disease.³⁴ The leukemic cells from patients with the variant of HCL (HCL-v) express BRAF wild-type. This genetic difference confirms that these two entities are clearly unrelated with a completely separate clinical course and therapeutic responsiveness. It is interesting that the small subset of patients with an immunophenotype consistent with HCL-c, yet using VH4–34 rearrangement, appear to be BRAF wild-type, further suggesting that there are multiple unique clonal patterns with distinct clinical courses.³⁵ Despite immunophenotypic features consistent with HCL-c, the lack of expression of BRAF V600E identifies a clinical course unlike the highly responsive form of the leukemia.

The presence of BRAF V600E mutation appears to activate the MEK-ERK signaling pathway responsible for leukemic cell survival and proliferation. Downstream activation of pERK correlates with presence of this mutational pathway.³⁶ Hematopoietic stem cells expressing this mutation have been identified in the marrow of murine models of the disease,³⁷ as well as in the marrow of patients with HCL.³⁷ BRAF V600E in marrow stem cells may explain the impairment in normal hematopoiesis that occurs in HCL-c. Furthermore, cytokines secreted by the leukemic cells may be responsible for the areas of hypocellularity observed in some patients with HCL-c.^38,39 Alternatively, impaired hematopoiesis may result from inadequate growth factor production.⁴⁰ Pancytopenia may also result either from extensive marrow infiltration with leukemia or fibrosis induced by the overproduction of transforming growth factor (TGF)-β by leukemic cells.⁴¹

The most common presenting symptoms are weakness and fatigue, which occur in 50 percent of patients with HCL.⁴² Although many patients also have an enlarged spleen, the gradual onset of symptoms is described as fullness in left abdomen, early satiety, and discomfort. Initially, Bouroncle reported that splenomegaly was found in 96 percent of patients.¹ However, more recently the percentage with a markedly enlarged spleen may be less at diagnosis because of earlier detection of the disease. Patients may present with a history of increased infections, and approximately 17 percent have an active infection at the time of diagnosis.¹ Bleeding manifestations are also noted in patients with severe thrombocytopenia. Patients may present with few symptoms, but an abnormal laboratory report suggesting a hematologic disorder may emerge during a routine health examination.

Infection has been the leading cause of death in patients with HCL, and accounted for 55 percent of the fatalities in a large longitudinal review of 725 patients in an Italian series.⁴³ In general, the infections occur as a result of granulocytopenia, monocytopenia, and impaired function of immune effector cells. Approximately 30 percent of patients are found to have a documented source of infection, but an equal number of suspected infections cannot be documented microbiologically.⁴⁴ Fever in this patient population should prompt a search for infection. It has been estimated that 48 percent of infections are caused by pyogenic organisms including Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumonia, and Legionella pneumophilia.²¹ Multiple other organisms have been identified as a source of infection including Aspergillus, Candida, Blastomyces, Histoplasma, Cryptococcus, Toxoplasmosis, Pneumocystis jiroveci, and atypical mycobacteria.

While the majority of infections occur before effective treatment has been initiated, the additional risk of infection as a complication of treatment exists both immediately following therapy and for many months thereafter.²¹ The purine nucleoside analogues that are used as a backbone of induction therapy can produce profound and prolonged myelosuppression. Because of the extensive marrow involvement with leukemia, the myeloid reserve is severely compromised at the initiation of therapy. Following effective therapy, the granulocytes gradually recover, but the purine nucleoside analogues usually induce a prolonged period of reduction in lymphoid cells, thus opportunistic infections resulting from compromised lymphocyte function may also emerge in the posttreatment period.⁴⁵ Once the patient has achieved a complete remission, the risks for infection become progressively less as the hematologic parameters improve. Full recovery of lymphocyte function following purine analogue therapy, however, may require several years.^46,47

Unusual symptoms related to HCL may include bone pain and autoimmune complications.^48,49 Bone pain may be the result of lytic disease that can involve the spine, the femur, and other skeletal sites. Lytic bone disease can occur at any time during the course of the disease. Both magnetic resonance imaging (MRI) and computed tomography (CT) scans have been helpful in identifying these lesions even when plain films of involved areas are normal. Biopsies of bone lesions have confirmed the presence of hairy cells, and these manifestations may respond to effective treatment of the leukemia. Many of the patients with bone lesions respond to systemic treatment of the disease, but others require additional localized irradiation.

Diverse autoimmune findings in patients represent other unusual complications.^49,50 Patients may complain of migratory inflammatory episodes involving the joints and tenosynovial tissues. These painful inflammatory episodes are usually self-limited and resolve spontaneously but may be recurrent. Vasculitic skin lesions and erythema nodosum have been reported.⁵¹ Autoimmune hemolytic anemia and thrombocytopenia have also been observed.^52,53,54 The autoimmune phenomena are not related to tumor burden, and may be present at initial diagnosis or occur anytime throughout the course of the disease. Finally, patients have also presented with paraneoplastic neurological syndromes.⁵⁵

Patients with HCL reviewed in a large Italian series had pancytopenia (77 percent) reflecting impaired hematopoiesis due to marrow infiltration and splenic sequestration.^21,43 Approximately 28.4 percent of patients had a hemoglobin less than 8.5 g/dL with 14.9 percent requiring a blood transfusion, 39 percent of patients had an absolute neutropenia (neutrophils <500/μL), and 72.6 percent had a platelet count less than 100,000. Jansen earlier developed prognostic criteria for HCL relating the degree of anemia and splenomegaly to survival.⁵⁶ The Jansen staging system was developed before the age of effective therapy. Nevertheless, a later study also showed that the degree of anemia in younger patients correlated with overall survival following therapy with pentostatin.⁹ Most patients have monocytopenia. Many patients have morphologic evidence of “hairy cells” on blood films characterized by pale blue or gray cytoplasm with a serrated/ruffled border (Fig. 93–1). The nucleus is oval and often reniform in shape with spongy chromatin and indistinct nucleoli. In the past, cytochemical staining with tartrate-resistant acid phosphatase (TRAP) was routinely performed since hairy cells are positive for this enzyme. However, this stain is technically difficult and was therefore replaced by immunohistochemical stains (IHC) for this enzyme. Moreover, a more definitive diagnosis can be made by flow cytometry identifying the characteristic immunophenotypic profile. HCL cells are strongly positive for CD20, and are positive for CD11c+, CD25+, CD103+, and CD123+. The leukemic cells are usually negative for CD5−, CD10−, CD27−, and CD43−. Consequently, it is essential to secure a comprehensive immunophenotypic profile of the leukemic cells, as even small monoclonal populations can be identified by multichannel flow cytometry in the blood (see Fig. 93–1).

MARROW BIOPSY

In establishing the diagnosis, a marrow biopsy should be obtained to evaluate the degree of marrow cellularity and the percentage of leukemic cell infiltration (Fig. 93–2).⁵⁷ In addition, marrow fibrosis is characteristic of this disease. The marrow cellularity can be quite variable. Some patients with this diagnosis have a severely hypocellular marrow, and this pattern could be misread as hypocellular or aplastic anemia.⁵⁷ More often, there is either infiltrative disease or diffuse marrow replacement with the characteristic mononuclear cells with nonoverlapping cellular borders. These cells have resembled a “fried egg–like” appearance. Immunohistochemical stains can be used to definitively identify the leukemic cells within the biopsy. Immunohistochemical staining of the marrow with anti-CD20 is most useful, followed by staining with annexin and DBA.44 monoclonal antibody to further narrow the differential diagnosis. The demonstration that the mutation BRAF V600E is found in the overwhelming majority of cells from patients with HCL-c has provided yet another confirmatory stain for this disease.⁵⁸

Additional baseline laboratory tests to obtain before treatment include an assessment of renal function as both of the commonly used purine nucleoside analogues are excreted by a renal route. It is important to screen for evidence of previous hepatitis B as serious complications including acute liver injury have resulted from the use of immunosuppressive agents (e.g., rituximab).⁵⁹

LABORATORY VALUES USEFUL IN PATIENT MONITORING

Serial complete blood count monitoring with attention to the absolute neutrophil count, the platelet count, and the hemoglobin is the most useful approach to follow the progress of HCL patients. As the expression of soluble interleukin-2 (IL-2) receptor correlates with tumor burden a baseline determination of the soluble IL-2 receptor may be important for following the course of the disease and its response to treatment.⁶⁰ Soluble CD22 also can be followed in a similar manner as a correlate of leukemic cell burden.^61,62

Several B-cell clinical entities can be considered when establishing a diagnosis of HCL-c. The World Health Organization (WHO) defined an HCL-v that is completely separate from the classic form of this disease.^19,39,58,64 The frequency of HCL-v is approximately 10 percent of HCL-c.⁶⁴ This rare chronic B-cell lymphoproliferative disorder is characterized by leukocytosis, lack of monocytopenia and neoplastic B cells with nucleoli and convoluted nuclei. The cytoplasm may have a shaggy edge, but the ruffled border is usually not circumferential as in HCL-c. The immunophenotype is characterized as CD25− and CD123− negative, annexin-1 negative, and negative for TRAP, both by cytochemical and by immunohistochemical methods. The BRAF V600E mutation is not present in this entity.³⁴ The clinical course of the disease is initially indolent, but eventually progresses with spleen and liver involvement. Some patients respond to splenectomy with temporary stabilization of the disease. Patients do not achieve durable responses with purine analogues as monotherapy, but may respond to immunotoxin conjugates (e.g., HA-22) or combined therapies with a purine analogue and a monoclonal antibody.^65,66

Another entity that must be distinguished from HCL is splenic marginal zone lymphoma/splenic marginal zone lymphoma with villous lymphocytes.⁶⁴ This entity is a chronic B-cell neoplasm that involves the spleen, splenic hilar nodes, marrow and the blood. Patients may present with splenomegaly, anemia, and thrombocytopenia. The malignant cells in the blood are characterized by cytoplasmic villi/projections that are typically polar in distribution. The immunophenotypic profile is distinctly different than HCL-c. While the cells are positive for CD20, they are negative for CD25, annexin 1, and usually negative for CD103.

Splenic diffuse red pulp small B-cell lymphoma is an uncommon lymphoma that infiltrates the splenic red pulp in a diffuse pattern.⁶⁴ It can also involve the marrow and the blood. The malignant cells resemble those seen in splenic marginal lymphoma with villous lymphocytes. Patients usually have very large spleens, leukopenia, and thrombocytopenia. The immunophenotypic profile shows strong expression of CD20 and negative staining for CD25, CD11c, CD123, and annexin. This indolent lymphoma has been reported to respond to splenectomy.

There are patients with classic appearing HCL who have molecular features suggesting that there may be more than one molecular “variant” of this disease. For example, patients with a classic immunophenotype who are BRAF V600E mutation-negative and use the immunoglobulin VH4–34 have a worse prognosis than those with HCL-c, despite having identical immunophenotypic markers.^19,35 Patients with unmutated immunoglobulin gene rearrangement and those harboring a p53 mutation also have a worse prognosis, indicating that these molecular features potentially define yet another form of this disease.³¹ Further study of the molecular prognostic features will hopefully identify information that will enable improvement in selection of appropriate therapy.¹⁹ Establishing an accurate diagnosis of HCL or one of the clinical entities that mimic this disease by including a complete set of immunophenotypic and molecular markers is essential in selecting the best therapeutic option for each patient (Table 93–1).

CRITERIA FOR INITIATION OF TREATMENT

Patients with HCL should be treated for symptoms related to the disease or for deterioration in blood counts. Patients may have symptoms associated with a markedly enlarged spleen. Excessive fatigue related either to the underlying disease or to the degree of anemia also warrant treatment. If the absolute neutrophil count is documented to be less than 1,000/μL or if the platelet count is confirmed to be less than 100,000/μL, then consideration for treatment should be given rather than waiting until the patient’s blood counts have deteriorated to very low levels. Many patients will have achieved these low hematologic parameters by the time of diagnosis, therefore meriting prompt therapy. Approximately 10 percent of patients with HCL-c may not meet these criteria, and can be followed for an extended period of time without therapy, albeit with close followup.^60,62,63

If patients have had recurrent infections requiring antibiotics, it may be prudent to delay treatment for the HCL until after the infection has been controlled. After the infection is controlled, subsequent treatment with a purine analogue can be administered to secure a consolidated remission of the leukemia. These challenges highlight the importance of starting effective anti-leukemic therapy before the absolute neutrophil count deteriorates to a dangerous level.

STANDARD APPROACH

Patients may either be treated with cladribine or pentostatin (Table 93–2).^62,67,68 Cladribine has been approved for initial therapy, and pentostatin has been approved for second-line therapy. Cladribine has been administered by several routes on differing schedules. This agent is usually administered over 5 to 7 days, and the patient’s blood counts need to be carefully monitored after this initial course. Initial studies administered cladribine as a continuous intravenous infusion for 7 days as a single course.¹⁰ Subsequently, other investigators administered this agent as a daily intravenous infusion over 2 hours each day for 5 days.⁶⁸ Approximately 4 to 6 months after blood count recovery following cladribine, a marrow biopsy should be obtained to determine the quality of the response. The overall complete remission rate with this agent is reported to vary from 75 percent to 91 percent.^67,69,70

Alternatively, if pentostatin is to be used for induction therapy, it is administered once every 2 weeks as a short intravenous injection followed by administration of approximately a liter of fluid.^9,62 Weekly blood counts are monitored, and the second and subsequent doses are administered if the absolute granulocyte count has not decreased to dangerously low levels. Titrating these doses to be given every 2 to 3 weeks may lessen the degree of myelosuppression related to the agent.⁶² After several reduced or delayed doses, the dose and schedule are returned to the standard dose of 4 mg/m² intravenous every 2 weeks in an effort to achieve complete remission. The complete remission rate to pentostatin with this approach approximated 75 percent in a multiinstitutional study.⁹ Patients may require 6 months or more of therapy with this agent. When the blood counts and the spleen have returned to normal, then a marrow biopsy should be performed to see if complete remission has been achieved by morphologic evaluation. This biopsy will serve as a baseline for evaluation of MRD. If there are no visible areas of HCL by morphologic criteria, then two additional doses are administered as consolidation.

MINIMAL RESIDUAL DISEASE

Although a complete remission is based upon recovery of blood counts, there must be no morphologic evidence of leukemic cells either in the blood or the marrow.¹⁹ MRD is defined as evidence of leukemic cells on the marrow biopsy that can be detected using IHC when there is no residual morphologic evidence of disease. IHC directed at markers on the leukemic cells may identify residual disease that is either diffusely infiltrating the marrow or localized. Antibodies directed at CD20, annexin, BRAF V600E (e.g., VE1), or DBA.44 will detect disease that is not identified morphologically.¹⁹ In addition, detailed flow cytometric immunophenotypic analysis of either the blood or the marrow aspirate may be capable of identifying residual leukemia cells (e.g., positive for CD20+, CD11c+, CD103+, CD25+, CD123+ and negative for CD27−). Flow cytometry of the marrow may be negatively impacted by the difficulty in securing an aspirate that is not contaminated by blood. Consequently, identification of the extent of MRD using IHC on a marrow biopsy may be less adversely impacted by sampling error. Eradication of MRD may be achieved by adding additional therapy (e.g., administration of rituximab), but the necessity for this additional therapy must be considered.⁷¹

FOLLOWUP CARE

The advantages of achieving a complete remission have been stressed.⁷² However, the therapy for this disease is immunosuppressive. Extensive treatment to eradicate MRD may involve continued therapy with its attendant consequences of increased risk for infection or possibly a secondary malignancy. Consequently, clinical judgment must be exercised to achieve the optimal outcome for patients with this disease. An accurate assessment of response to therapy may best be made several months following completion of initial induction therapy.⁷¹ In those who have achieved a complete response, careful followup is indicated. In those who had less than a complete remission, a determination will need to be made regarding salvage therapy versus close observation based upon blood count recovery.

THERAPY AT RELAPSE

The duration of response following initial therapy for HCL is variable. The criteria for retreatment can be based upon recurrence of clinical symptoms and on the status of the blood count.⁶² A decision to restart therapy before progressive severe pancytopenia has returned is important. Considering both the risks and benefits of additional therapy requires clinical judgment.

There are several therapeutic options for treating patients with either resistant disease or disease that had an early relapse following initial response. In general, if the patient achieved an initial response and subsequently relapses within 1 to 2 years, an alternate agent might be selected for retreatment.⁶² Otherwise, retreatment with the initial therapy can be considered if the first remission was durable. Most patients will initially be treated with a purine nucleoside analogue. If there is an early relapse, the alternate purine analogue may be selected for reinduction. If patients initially received cladribine, pentostatin might be chosen for reinduction. In patients who demonstrate resistant disease, the identification of the BRAF V600E target has provided a therapeutic strategy involving an inhibitor (e.g., vemurafenib) as investigational therapy. Although patients have been reported to respond, this agent is not yet FDA-approved for this indication.^24,25 Furthermore, immunotoxin conjugates (e.g., HA22) have also been reported to produce remissions in patients with resistant disease.⁷³ The purine nucleoside analogues (cladribine and pentostatin) have also been effective in producing long-term salvage remissions in patients with HCL in relapse. In patients who have either resistant or relapsed disease, a combination of a purine analogue and a monoclonal antibody have also been used.^62,71

The outlook for patients with HCL has markedly improved since its original description in 1958.⁶⁸ Patients can now anticipate a near normal life expectancy with the caveat that the disease will likely require close observation and retreatment for those who relapse. Survival at the end of 1 year is estimated to be approximately 88 percent with 5-year survival at 77 percent in one longitudinal population-based report.²¹ Other long-term followup studies in the era of purine nucleoside therapy have identified similar results with 5-year survival being 90 percent and estimated 10-year survival at 81 percent.⁷²

Whereas overall survival has improved, there is an increased risk of serious infection during the first year following diagnosis. The overall relative risk of a serious infection compared to a normal population is 2.59. This adjusted relative risk during the first year from diagnosis and treatment is 8.04.²¹ The risk of serious infection is highest during the first year, and then declines toward normal in subsequent years. This indicates that patients should be followed very closely during the initial years following treatment. Full recovery of lymphocyte numbers and function after therapy may require several years. Consequently, physicians should follow their patients closely and document the recovery of these immune effectors cells. Patients should receive vaccinations utilizing dead or attenuated viral vaccines, and avoid “live” viral vaccines while in remission. Prompt attention to early signs of infection is important for health maintenance.

The results of clinical investigations have markedly improved the outcome for this patient population. Clinical relapse will likely occur because the current therapy controls the disease, but does not cure it.⁷⁴ Despite the enormous progress made in managing these patients, continued clinical investigation is warranted in an effort to achieve the best outcome with durable complete remissions and minimal risk of infection.