Justin Taylor, MD
Assistant Professor, Division of Hematology
Sylvester Comprehensive Cancer Center
University of Miami Miller School of Medicine
Justin Watts, MD
Associate Professor, Division of Hematology
Section Chief, Leukemia
Sylvester Comprehensive Cancer Center
University of Miami Miller School of Medicine
I have a 38-year-old male patient with newly diagnosed hairy cell leukemia (HCL). Prior to diagnosis, he experienced intermittent night sweats for several months but had no other symptoms. His primary care physician detected an abdominal mass on physical exam. His blood counts at the time were the following:
- White blood cell (WBC) count: 40.8 ×109/L
- Absolute lymphocyte count (ALC): 38.8 ×109/L
- Absolute neutrophil count (ANC): 0.8 ×109/L
- Hemoglobin (Hb): 9.2 g/dL
- Mean corpuscular volume (MCV): 89 fL
- Platelets: 50 ×109/L
An abdominal and pelvic CT scan revealed 32.2 cm spleen with nodular mass effect on adjacent organs. On review of the slides from a biopsy of the mass, hairy cells were identified. On peripheral blood flow cytometry, an abnormal population of cells consistent with HCL expressing CD5, CD11c, and CD103 (93% of the events) was found. The bone marrow was hypercellular, and 80% to 90% replaced with monoclonal atypical B-cell proliferation expressing the same markers as seen in peripheral blood. He had 2.03% mutated immunoglobulin heavy chain (IGHV) gene, which is considered borderline positive, and BRAFV600E mutation was present.
I told the patient that cladribine was the standard of care. However, there has been some investigation of adding rituximab, which seems to produce deeper remissions that could translate to longer first remission, but there is no evidence of cure. This may be at the expense of additional immunosuppression and the risk of infusion reactions, among other concerns. I have been trying to avoid rituximab since the advent of the COVID-19 pandemic, but he is interested in exploring the possibility of lengthier remission. Is there anything about this patient and his disease that calls for the addition of rituximab?
HCL is an uncommon B-cell neoplasm classified into the splenic B-cell lymphoma and leukemia family in the fifth edition of the World Health Organization’s classification.1 It must be differentiated from other mimics, including the HCL variant, which has been replaced by the term “splenic B-cell lymphoma/leukemia with prominent nucleoli.” Diagnosis is made by bone marrow aspirate and biopsy with adequate immunophenotyping for CD19, CD20, CD5, CD10, CD11c, CD22, CD25, CD103, CD123, cyclin D1, and CD200. Molecular analysis for IGHV4-34 rearrangement and BRAFV600E mutation can aid in the diagnosis.
In this case, the elevated white blood cell (WBC) count and CD5 positivity are atypical for classical HCL; however, this has been reported before, and the BRAFV600E mutation is also present in this case, whereas other splenic small B-cell lymphomas almost always lack BRAF mutations.2 After the diagnosis of classical HCL is confirmed, the next step is to determine whether treatment is warranted. This patient has multiple indications for treatment, including neutropenia and thrombocytopenia. While there is no cure for HCL, the majority of patients can achieve durable remissions with long treatment- and symptom-free intervals. With recent improvements in the therapy for relapsed HCL, the long-term survival is near normal lifespan.
Purine analog-based therapy is the preferred initial treatment for most patients with symptomatic HCL. While the BRAF inhibitor vemurafenib in combination with an anti-CD20 monoclonal antibody is currently being studied in the frontline setting, National Comprehensive Cancer Network guidelines list them as frontline options only in certain circumstances, such as active infection or frail patients. Of the purine analogs used in HCL, cladribine has an easier administration, requiring a single cycle of five daily infusions. Several publications have evaluated the addition of rituximab to cladribine in relapsed HCL, with one single-arm phase II trial also including 59 patients with untreated HCL.3 In this initial study, rituximab was delivered in eight weekly doses (375 mg/m2) four weeks after the initiation of cladribine. With a median follow-up of five years, the failure-free survival was 95%, and overall survival was 97%. Since this trial was not randomized, we don’t know how these patients would have done with cladribine alone; however, the results appeared superior to what might be expected from historical studies.
A subsequent randomized trial was performed with cladribine plus concurrent or delayed rituximab.4 In this trial, purine analog-naïve patients were randomly assigned to cladribine with eight weekly doses of rituximab concurrently (starting on day one) or at least six months later (delayed) after detection of measurable residual disease (MRD) in the blood. The primary endpoint was MRD-free complete remission (CR) at six months (before delayed rituximab was given). Each arm enrolled 34 patients, with the concurrent cladribine and rituximab group achieving 97% MRD-free CR versus 24% of patients treated with cladribine only. The 76% of patients in the delayed arm who did not achieve MRD at six months were then treated with rituximab, and 67% of them became MRD-free. The median follow-up was eight years, and at last follow-up, 94% of the concurrently treated group remained MRD-free versus 47% in the delayed treatment group. However, nearly equal numbers of patients remained in CR in both groups.
Whether being MRD-free results in longer remissions in upfront HCL treatment remains unknown and will require longer follow-up of the above-mentioned study. However, we must also consider the toxicity. There was significantly more thrombocytopenia and platelet transfusions given in the concurrent treatment arm. A potential limitation of this study was the long duration before starting delayed rituximab, with some experts advocating for starting rituximab just four to six weeks after initial treatment with cladribine and limiting to four weekly doses. This could decrease the length of immunosuppression and alleviate some potential concerns related to COVID-19; however, there is a lack of randomized data on using this sequential approach in the frontline setting.5
In a younger, fit patient with HCL that has high disease burden and some atypical features, I would consider giving rituximab concurrently with cladribine, given the high rates and longer duration of MRD-negativity with one eight-week treatment cycle, with the use of prophylactic anti-infectious agents, appropriate infectious precautions, and close monitoring for thrombocytopenia. While we do not yet know if MRD-negativity correlates with longer duration of CR, it stands to reason it may delay time to relapse, thereby limiting lifelong exposure to purine analogs and other therapies.
- Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia. 2022;36(7):1720-1748.
- Soong D, Kumar P, Jatwani K, et al. Hairy cell leukemia masquerading as CD5+ lymphoproliferative disease: the importance of BRAF V600E testing in diagnosis and treatment. JCO Precis Oncol. 2021;5:1035-1039.
- Chihara D, Kantarjian H, O’Brien S, et al. Long-term durable remission by cladribine followed by rituximab in patients with hairy cell leukaemia: update of a phase II trial. Br J Haematol. 2016;174(5):760-766.
- Chihara D, Arons E, Stetler-Stevenson M, et al. Randomized phase II study of first-line cladribine with concurrent or delayed rituximab in patients with hairy cell leukemia. J Clin Oncol. 2020;38(14):1527-1538.
- Lamure S, Salmanton-García J, Robin-Marieton E, et al. COVID-19 and hairy-cell leukemia: an EPICOVIDEHA survey. Blood Adv. 2022;6(13):3870-3874.
NEXT MONTH'S CLINICAL DILEMMA
I have been referred a 41-year-old male patient who had a native aortic valve thrombus that caused a non-ST elevation myocardial infarction (NSTEMI) and a cerebrovascular accident. The thrombus was surgically removed, and he was started on warfarin. His primary care physician switched him to aspirin and clopidogrel after one year of treatment because of a labile international normalized ratio. The patient couldn’t afford apixaban.
He is negative for antiphospholipid syndrome, factor V Leiden, prothrombin gene mutation, and paroxysmal nocturnal hemoglobinuria, but his antithrombin was slightly low at 65%. There is no family history of thrombosis. He is obese and was on an oral body building supplement containing 25 mg dehydroepiandrosterone (DHEA) and androsterone at the time of the clot.
I feel he needs extended anticoagulation, but his surgeon thinks six months has been good enough. I am unaware of a strong association between the DHEA and thrombosis, so should this be considered unprovoked?
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