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.
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
Table 93–2.Management of Hairy Cell Leukemia ||Download (.pdf) Table 93–2. Management of Hairy Cell Leukemia
|Determine accurate diagnosis |
|Decision on initiation of therapy |
Approximately 10 percent can be carefully followed on “watch and wait” approach but majority of patients require treatment
Determinants or symptoms prompting treatment: symptomatic splenomegaly or laboratory studies showing: absolute neutrophil count <1000/μL; hemoglobin <10 g/dL; or platelet count <100,000/μL
|Important assessments before therapy for leukemia |
|Decision on frontline therapy |
Cladribine 0.1 mg/kg/day for 7 days continuous intravenous infusion12,69,75
Cladribine 0.12 mg/kg/day for 5 days as 2-hour intravenous infusion vs. weekly infusion for 6 weeks14
Pentostatin 4 mg/m2 intravenous dose every 2 weeks until maximal response or failure9,72,76
|Assessment of response |
Following induction therapy, a marrow biopsy to document quality of response and quantitate minimal residual disease (MRD)
Methods for quantification of MRD with immunohistochemical stains and the optimal timing for MRD assessment are under investigation
In general, response assessment after cladribine is recommended after 3 to 5 months. In contrast, response assessment following pentostatin is made at time of best clinical response
|Clinical investigations for resistant hairy cell leukemia |
Alternate purine analogues alone or combined chemoimmunotherapy (e.g., bendamustine and rituximab)77
Immunotoxin conjugates (e.g., moxetumomab pasudotox [HA22]73)
BRAF V600E inhibitors (e.g., vemurafenib)25,78
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.
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
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.
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