Fludarabine/Rituximab for Relapsed Hairy Cell Leukemia: Canadian Experience

Abstract & Commentary

By William B. Ershler, MD

Synopsis: Response rates for patients with hairy cell leukemia are high and typically of long duration, yet one-third or more will relapse. The use of oral fludarabine in combination with rituximab in four monthly cycles was shown to be highly effective in reinducing durable remissions.

Source: Gerrie AS, et al. Fludarabine and rituximab for relapsed or refractory hairy cell leukemia. Blood 2012;119:1988-1991.

Hairy cell leukemia (HCL) was first described in 1958 and was characterized by its refractoriness to treatment and poor prognosis.1 It is now known to be a rare adult B-cell lymphoid leukemia characterized by pancytopenia, splenomegaly, and absolute monocytopenia. Morphologically, HCL is characterized by circumferential cytoplasmic projections. Bone marrow biopsy is typically hypercellular, with an infiltration of cells having nuclei widely separated by abundant cytoplasm, giving a "fried-egg" appearance. Early hematopathologists relied on staining with tartrate-resistant acid phosphatase to confirm the diagnosis.2 More recently, the demonstration of B-cell antigens CD19, CD20, and CD22 coupled with the characteristic appearance serves the same purpose.

Whereas initial clinical experience was typically not effective, outlook was better with the introduction of interferon3 and improved beyond that with purine analogues (pentostatin and cladribine),4,5 which have become the existing standard of care for newly diagnosed HCL.6 Currently, the great majority of patients enjoy long-term remission. Nevertheless, despite the high rate of response and lengthy duration of remission, approximately 30-40% of patients relapse.7

The current report deals with treatment of HCL patients with recurrent or refractory disease with a combination of fludarabine and rituximab. The authors identified 15 patients treated in British Columbia with fludarabine and rituximab from 2004 to 2010 for relapsed/refractory HCL after first-line cladribine (n = 3) or after multiple lines of therapy (n = 12). The regimen consisted of fludarabine 40 mg/m2 per day orally on days 1 to 5 (adjusted in some on the basis of renal function) and rituximab 375 mg/m2 on day 1 of 28-day cycle. Four cycles of treatment were administered. With median follow-up of 35 months, 14 patients were progression-free, whereas one patient developed progressive leukemia and died. Five-year progression-free and overall survivals were 89% and 83%, respectively.

Commentary

For patients with relapsed HCL, cladribine is known to produce a high rate of second remissions, albeit of shorter duration. For example, Jehn and colleagues in Munich reported their experience with single-agent cladribine in which 44 patients were followed for a median of 8.5 years.8 All but one achieved a complete remission (CR). Of these, 17 (39%) relapsed with a median duration of remission of 48 months (range, 8-131 months). Nine patients received a second course of cladribine and eight of the nine achieved a second CR for a median duration of second remission of 2.5 years. Thus, this approach is commonly used, particularly for those who have experienced lengthy periods of progression-free survival. In a recent review from the Mayo Clinic, the recommendation was forwarded that cladaribine (or pentostatin) be readministered for those with initial remissions of 18 months or more.6

Rituximab has been studied as a single agent for those with relapsed disease. In a Phase 2 trial in 24 patients who relapsed after cladribine initial therapy, three patients achieved a CR and three had a partial remission.9 In that trial, febrile reactions and one death resulted from ruptured diverticular abscess during treatment. Somewhat more favorable responses were reported by the Swiss Group for Clinical Cancer Research.10 They evaluated rituximab in 25 patients relapsing after prior cladribine treatment. In that trial, the overall response rate was 80%, with a 32% CR rate. Still, the median remission duration was just less than 3 years.

Fludarabine, another purine analogue, has not been extensively examined in patients with HCL, but has proven efficacious in the initial treatment of chronic lymphocytic leukemia and indolent lymphoma.11 Its use in combination with rituximab is logical for patients with relapsed HCL and the current data would suggest a high likelihood of durable second remissions, comparable, if not superior to repeating initial cladribine (or pentostatin) and certainly superior to rituximab alone. The dose, schedule (monthly x 4), and route of administration (oral) of the fludarabine was shown to be both safe and effective, and certainly should be considered an effective therapeutic option for relapsed/refractory HCL.

References

1. Bouroncle BA, et al. Leukemic reticuloendotheliosis. Blood 1958;13:609-630.

2. Yam LT, et al. Tartrate-resistant acid phosphatase isoenzyme in the reticulum cells of leukemic reticuloendotheliosis. N Engl J Med 1971;284:357-360.

3. Ratain MJ, et al. Treatment of hairy cell leukemia with recombinant alpha 2 interferon. Blood 1985;65:644-668.

4. Piro LD, et al. Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl J Med 1990;322:1117-1121.

5. Spiers AS, et al. Hairy-cell leukemia: Induction of complete remission with pentostatin (2'-deoxycoformycin). J Clin Oncol 1984;2:1336-1342.

6. Naik RR, Saven A. My treatment approach to hairy cell leukemia. Mayo Clinic Proc 2012;87:67-76.

7. Else M, et al. Long remissions in hairy cell leukemia with purine analogs: A report of 219 patients with a median follow-up of 12.5 years. Cancer 2005;104:2442-2448.

8. Jehn U, et al. An update: 12-year follow-up of patients with hairy cell leukemia following treatment with 2-chlorodeoxyadenosine. Leukemia 2004;18:1476-1481.

9. Nieva J, et al. Phase 2 study of rituximab in the treatment of cladribine-failed patients with hairy cell leukemia. Blood 2003;102:810-813.

10. Zenhausern R, et al. Rituximab in patients with hairy cell leukemia relapsing after treatment with 2-chlorodeoxyadenosine (SAKK 31/98). Haematologica 2008;93:1426-1428.

11. Byrd JC, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: Results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 2003;101:6-14.