You Make the Call: How would you treat a frail patient with relapsed hairy cell leukemia variant?

Martin S. Tallman, MD
ASH President; Chief of the Leukemia Service at Memorial Sloan Kettering Cancer Center in New York

This month, Marty Tallman, MD, discusses treatment of early-relapsing hairy cell leukemia variant.

And don’t forget to check out next month’s clinical dilemma – send in your responses for a chance to win an ASH Clinical News-themed prize!


I have a frail 84-year-old male patient who presented with an elevated white blood cell count (70,000/mm3), anemia, and a low platelet count in May 2019. The results of his bone marrow biopsy were consistent with hairy cell leukemia variant (HCLV). A BRAF genetic test was negative. He experienced a good response with standard-dose cladribine, but because this was HCLV rather than classical HCL, we expected the remission to be short lived. He has now relapsed approximately 5.5 months after completion of cladribine. I am reluctant to use cladribine again after such a short disease-free period. My plan was to start with rituximab to get a response and then consider low-dose bendamustine. Are there any other drugs I should consider for relapsed HCLV with remission within 6 months?


Treatment of HCLV is frequently difficult. HCLV represents a small proportion of an already very rare hematologic malignancy. HCLV accounts for only approximately 10% of patients with HCL or less than 100 new cases per year in the U.S. While there is a 4 to 5 times higher incidence of classical HCL in men compared with women (the reason is unknown), it is not clear if this imbalance holds true for patients with HCLV. HCLV is more aggressive than classical HCL.

Given the rarity of HCLV, few studies have been published and none with large patient numbers. Most information guiding therapeutic strategies necessarily is derived from anecdotal reports. Even the diagnosis can be difficult. The differential diagnosis includes not only classical HCL, but also splenic marginal zone lymphoma, splenic diffuse red pulp B-cell lymphoma, and B-cell prolymphocytic leukemia. The hairy cells from patients with HCLV can be distinguished from classical HCL by the absence of expression of CD25, CD123, CD200, annexin-A1, and, importantly, BRAF mutation. Therefore, the oral BRAF inhibitor vemurafenib, which would otherwise be attractive particularly in an 84-year-old man with relapsed or refractory classical HCL, is not an option for patients with HCLV.1

Given the excellent activity of vemurafenib in relapsed or refractory classical HCL, it is under investigation in previously untreated patients. In a small pilot trial, vemurafenib is being combined with the anti-CD20 antibody obinutuzumab in patients with previously untreated classical HCL.2 Purine analogs remain the treatment of choice for patients with classical as well as HCLV. While both cladribine and pentostatin are effective, cladribine is often preferred because of its schedule of administration as a short, single, continuous infusion of 7 days or 5-day, 2-hour bolus. Cladribine has been combined with rituximab and appears quite effective in patients with both classical HCL and HCLV.3

In the patient presented here, I agree that another cycle of cladribine so close to the last exposure would be not advisable, since this may incur a risk of prolonged myelosuppression and marrow stem cell injury and is also likely to be ineffective. Therapy-related myeloid malignancies is a well-recognized, albeit uncommon, complication observed in some patients with exposure to multiple cycles of purine analogs such as fludarabine, perhaps particularly when combined with alkylating agents. For the same reason, I would not be particularly enthusiastic about pentostatin in this patient who relapsed approximately 6 months after a first cycle of cladribine.

Moxetumomab pasudotox is an anti-CD22 immunotoxin that is highly effective in classical HCL. However, in a recent publication, 3 patients with HCLV were included and the responses were not robust; none of the 3 achieved complete remission [CR], although they all had a high disease burden.4 This agent has been FDA approved for the treatment of relapsed or refractory HCL in patients who have received at least 2 prior systemic therapies, including a purine analog.

Rituximab is a reasonable choice for relapsed HCLV, particularly in light of this patient’s age. Bendamustine can be considered either alone or combined with rituximab, although one might be concerned about prolonged myelosuppression again if administered so close in time following cladribine. In a report of 3 patients with previously untreated HCLV treated with bendamustine plus rituximab, all 3 achieved clinical CR without evidence of minimal residual disease in the bone marrow by flow cytometry.5 After a median follow-up of 19 months, all 3 patients remain in CR.

Another important treatment consideration would be ibrutinib or another Bruton tyrosine kinase (BTK) inhibitor. BTK inhibitors are oral agents and are active in a variety of chronic lymphoproliferative disorders, including classical HCL and HCLV and can be given with very acceptable toxicity, including in older adults.6 This would be my choice for this 84-year-old man with relapsed HCLV.


  1. Tiacci E, Park JH, De Carolis L, et al. Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med. 2015;373:1733-1747.
  2. Park JH, Shukla M, Salcedo JM, et al. First line chemo-free therapy with the BRAF inhibitor vemurafenib combined with obinutuzumab is effective in patients with HCL. Blood. 2019;134 (Supplement 1):3998.
  3. Ravandi F, Obrien S, Jorgensen J, et al. Phase 2 study of cladribine followed by rituximab in patients with hairy cell leukemia. Blood. 2011;118:3818-3823.
  4. Kretiman RJ, Dearden C, Zinzani PL, et al. Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia. Leukemia 2018;32:1768-1777.
  5. Visentin A, Imbergamo S, Frezzato F, et al. Bendamustine plus rituximab is an effective first-line treatment in hairy cell leukemia variant: report of three cases. Oncotarget. 2017;8:110727-110731.
  6. Bohn JP, Wanner D, Steurer M, et al. Ibrutinib for relapsed refractory hairy cell leukemia variant. Leuk Lymphoma. 2017;58:1224-1226.

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I have a 57-year-old male patient with Coombs-positive hemolytic anemia (with no underlying lymphoproliferative disease) who requires 5-10 mg of prednisone daily to keep his hemoglobin level above 7 g/dL. He refuses splenectomy. He has received treatment with rituximab once with no apparent benefit. Is there any evidence that a second treatment with rituximab might be beneficial?

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