Purine analogs provide first-line defense against HCL
A 32-year-old man with chronic low back pain presented with acute worsening of back pain to his medical doctor. He was referred to an orthopedic surgeon who requested an MRI of his spine revealing disc disease at L5/S1 and splenomegaly.
When he presented to us, he had no complaints other than his back pain. He was afebrile, without lymphadenopathy or hepatomegaly but with marked splenomegaly crossing the midline filling up most of his right abdomen and pelvis. Laboratory workup revealed leucopenia (wbc 1.7 x 103K); anemia (hgb 13g/dl); and thrombocytopenia (platelet count 25 x 103) with mild disseminated intravascular coagulopathy.
Photos courtesy of M. Ghesani
A bone marrow aspirate was dry and a biopsy showed diffuse interstitial lymphoid infiltrate with flow cytometry positive for CD19, CD20, CD22 and CD103, and negative for CD5 and CD10. This was consistent with hairy cell leukemia. Staging CT scan of the chest, abdomen and pelvis revealed a 26 x 24 x 12 cm massive splenomegaly with diffuse lytic lesions. There was no lymphadenopathy or hepatomegaly.
Patient was treated with the standard 7-day infusion of cladribine. He developed febrile neutropenia treated with broad spectrum intravenous antibiotics. He is currently awaiting hematologic recovery. Clinically, his spleen size has shrunk more than 50%.
Bouroncle was the first to describe leukemic reticuloendotheliosis in 1958, better known now as hairy cell leukemia (HCL). This is an uncommon malignancy of B-cell origin which usually presents with peripheral blood pancytopenia, splenomegaly and bone marrow involvement. Patients can manifest with symptoms of anemia as fatigability, weakness or with neutropenia as infections. They can also present with autoimmune complications, vasculitis, hemolysis and lytic bone disease. In the modern era, patients now present with incidental findings of cytopenias from routine blood work.
The differential diagnoses for cytopenia and splenomegaly are broad, which includes other B-cell neoplasms such as chronic lymphocytic leukemia, splenic marginal zone lymphoma and hairy cell variant. Distinction between HCL and these other B-cell neoplasms is important as the response of HCL to purine analog monotherapy is significant.
On peripheral blood smears, the villous projections on the hairy cell are circumferential compared to that of marginal zone lymphomas which tend to be polar or noncircumferential. Accurate diagnosis relies on bone marrow biopsy and flow cytometry, which will reveal the amount of bone marrow involvement with or without fibrosis and monoclonality of the B-cell neoplasm
Treatment used to be splenectomy with progressive disease being treated with chemotherapy. Recent advances in systemic therapy has now made splenectomy a rare consideration.
Interferon alfa administered at a dose of 2 million units/m2 subcutaneously three times a week for a year has been shown to produce a partial remission in a majority of patients, defined as normalization of peripheral blood counts. However, true complete remission is rare, and careful review of marrow cells often reveal persistence of disease. The toxicities from IFN alpha range from flu-like symptoms to nausea, vomiting, diarrhea and CNS dysfunction.
Purine analogs are currently the standard of care for first-line treatment of hairy cell leukemia. Pentostatin was the first purine analog found to have utility in HCL after Spiers and colleagues documented 59% complete remission and 37% partial remission in a study of 37 patients. Pentostatin appeared to be effective both in treatment naive and after splenectomy and interferon alpha.
A study by Chadha and colleagues of 86 hairy cell leukemia patients showed that cladribine at a dose of 0.1mg/kg/d given as continuous infusion for 7 days can achieve an 80% complete remission rate and 20% partial remission rate. After a median follow-up of 9.7 years, 36% of the patients relapsed. Twenty-three of these relapsed patients received a second course of cladribine. Twelve (52%) achieved complete remission and seven (30%) achieved partial remission. The overall survival rate after 12 years was 87%.
Pentostatin and cladribine have been shown to be equivalent; however, cladribine has been used more often due to the ease of administration.
Rituximab, a humanized monoclonal antibody to CD20 has been evaluated in relapsed or refractory HCL. A phase 2 study of 24 patients with relapsed disease after cladribine treatment showed OR rates of 24%. Rituximab is undergoing clinical trials as upfront or delayed treatment.
Irene Dy, MD, is a hematology oncology fellow, St. Lukes Roosevelt Hospital.
Munir Ghesani, MD is an associate clinical professor of radiology at Columbia University College of Physicians and Surgeons and attending radiologist at St. Lukes-Roosevelt Hospital Center, and Beth Israel Medical Center. He is a HemOnc Today section editor.
Rosna Mirtcheva, MD, is a radiology attending, St. Lukes Roosevelt Hospital.
Gabriel Sara, MD, is an oncology attending, St. Lukes Roosevelt Hospital.
For more information:
- Bouroncle BA. Leukemic reticuloendotheliosis. Blood. 1958;13(7):609.
- Chadha P. Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine: long-term follow-up of the Northwestern University experience. Blood. 2005; 106(1): 241.
- Golomb HM. Hairy cell leukemia: Treatment successes in the past 25 years. J Clin Oncol. 2008;26(16): 2607-09.
- Grever MR. Modern Strategies for hairy cell leukemia. J Clin Oncol. 2011;29(5):583-89.
- Nieva J. Phase 2 study of rituximab in the treatment of cladribine failed patients with hairy cell leukemia. Blood. 2003; 102(3):810.
- Spiers AS. Remissions in hairy-cell leukemia with pentostatin. NEJM. 1987; 316(14):825.
My personal experience with this disease suggests rituximab is an excellent salvage therapy if, and when, purine analogs cease to provide benefit.
Harry S. Jacob, MD, FRCPath(Hon)
HemOnc Today Chief Medical Editor