Clinical Review

Hairy Cell Leukemia

2017 November;12(6):23-34

References

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18. Shao H, Calvo KR, Gronborg M, et al. Distinguishing hairy cell leukemia variant from hairy cell leukemia: development and validation of diagnostic criteria. Leuk Res 2013;37:401–9.

19. Xi L, Arons E, Navarro W, et al. Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation. Blood 2012;119:3330–2.

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21. Sivina M, Kreitman RJ, Arons E, et al. The bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) blocks hairy cell leukaemia survival, proliferation and B cell receptor signalling: a new therapeutic approach. Br J Haematol 2014;166:177–88.

22. Jaglowski SM, Jones JA, Nagar V, et al. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood 2015;126:842–50.

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25. Mhawech-Fauceglia P, Oberholzer M, Aschenafi S, et al. Potential predictive patterns of minimal residual disease detected by immunohistochemistry on bone marrow biopsy specimens during a long-term follow-up in patients treated with cladribine for hairy cell leukemia. Arch Pathol Lab Med 2006;130:374–7.

26. Ortiz-Maldonado V, Villamor N, Baumann T, et al., Is there a role for minimal residual disease monitoring in the management of patients with hairy-cell leukaemia? Br J Haematol 2017 Aug 18.

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29. Ravandi F, O’Brien S, Jorgensen J, et al. Phase 2 study of cladribine followed by rituximab in patients with hairy cell leukemia. Blood 2011;118:3818–23.

30. Grever M, Kopecky K, Foucar MK, et al. Randomized comparison of pentostatin versus interferon alfa-2a in previously untreated patients with hairy cell leukemia: an intergroup study. J Clin Oncol 1995;13:974–82.

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33. Randomized phase II trial of rituximab with either pentostatin or bendamustine for multiply relapsed or refractory hairy cell leukemia. 2017 [cited 2017 Oct 26]; NCT01059786. https://clinicaltrials.gov/ct2/show/NCT01059786.

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First-Line Therapy

Despite advances in targeted therapies for HCL, because no treatment has been shown to extend the treatment-free interval longer than chemotherapy, treatment with a purine nucleoside analog is usually the recommended first-line therapy. This includes either cladribine or pentostatin. Both agents appear to be equally effective, and the choice of therapy is determined by the treating physician based on his or her experience. Cladribine administration has been studied using a number of different schedules and routes: intravenous continuous infusion (0.1 mg/kg) for 7 days, intravenous infusion (0.14 mg/kg/day) over 2 hours on a 5-day regimen, or alternatively subcutaneously (0.1–0.14 mg/kg/day) on a once-per-day or once-per-week regimen (Table 2).^28,29

Pentostatin is administered intravenously (4 mg/m²) in an outpatient setting once every other week.³⁰ Patients should be followed closely for evidence of fever or active infection, and routine blood counts should be obtained weekly until recovery. Both drugs cause myelosuppression, and titration of both dose and frequency of administration may be required if complications such as life-threatening infection or renal insufficiency arise (Table 2).³⁰ Note that chemotherapy is not recommended for patients with active infections, and an alternative agent may need to be selected in these cases.

Unlike cHCL, vHCL remains difficult to treat and early disease progression is common. The best outcomes have been seen in patients who have received combination chemo-immunotherapy such as purine nucleoside analog therapy plus rituximab or bendamustine plus rituximab.³¹ One pilot study of bendamustine plus rituximab in 12 patients found an overall response rate of 100%, with the majority of patients achieving a complete response.³¹ For patients who achieved a complete response, the median duration of response had not been reached, but patients achieving only a partial response had a median duration of response of only 20 months, indicating there is a subgroup of patients who will require a different treatment approach.³² A randomized phase 2 trial of rituximab with either pentostatin or bendamustine is ongoing.³³

Assessment of Response

Response assessment involves physical examination for estimation of spleen size, assessment of hematologic parameters, and a bone marrow biopsy for evaluation of marrow response. It is recommended that the bone marrow biopsy be performed 4 to 6 months following cladribine administration, or after completion of 12 doses of pentostatin. Detailed response assessment criteria are shown in Table 3.

Second-Line Therapy

Although the majority of patients treated with purine analogs will achieve durable remissions, approximately 40% of patients will eventually require second-line therapy. Criteria for treatment at relapse are the same as the criteria for initial therapy, including symptomatic disease or progressive anemia, thrombocytopenia, or neutropenia. The choice of treatment is based on clinical parameters and the duration of the previous remission. If the initial remission was longer than 65 months and the patient is eligible to receive chemotherapy, re-treatment with initial therapy is recommended. For a remission between 24 and 65 months, re-treatment with a purine analog combined with an anti-CD20 monoclonal antibody may be considered.³⁴ If the first remission is shorter than 24 months, confirmation of the original diagnosis as well as consideration for testing for additional mutations with therapeutic targets (BRAF V600E, MAP2K1) should be considered before a treatment decision is made. For these patients, alternative therapies, including investigational agents, should be considered.²⁴

Monoclonal antibody therapy has been studied in both the up-front setting and in relapsed or refractory HCL.³⁵ An initial study of 15 patients with relapsed HCL found an overall response rate of 80%, with 8 patients achieving a complete response. A subsequent study of 26 patients who relapsed after cladribine therapy found an overall response rate of 80%, with a complete response rate of 32%. Median relapse-free survival was 27 months.³⁶ Ravandi and others studied rituximab in the up-front setting in combination with cladribine, and found an overall response rate of 100%, including in patients with vHCL. At the time of publication of the study results, the median survival had not been reached.³⁷ As has been seen with other lymphoid malignancies, concurrent therapy with rituximab appears to enhance the activity of the agent with which it is combined. While its use in the up-front setting remains an area of active investigation, there is a clear role for chemo-immunotherapy in the relapsed setting.