Published Research in Hairy Cell Leukemia

We fund promising research to strengthen our shared understanding of hairy cell leukemia and improve outcomes for patients with this disease. Many HCLF research grantees have published their findings in leading journals, advancing knowledge of HCL and bringing us closer to a cure.

HCL Treatment

Long Term Outcomes in Patients with Relapsed or Refractory Hairy Cell Leukemia Treated with Vemurafenib Monotherapy

Journal: Blood, December, 2022

Authors: Shivani Handa, Jeong-Ok Lee, Andriy Derkach, Richard M. Stone, Alan Saven, Jessica K. Altman, Michael Rhodes Grever, Kanti R. Rai, Madhulika Shukla, Shreya Vemuri, Skye Montoya, Justin Taylor, Omar Abdel-Wahab, Martin S. Tallman, Jae H. Park

Key Points:

• Relapses are frequent after vemurafenib monotherapy but retreatment with vemurafenib can induce high response rates in HCL.

• Vemurafenib retreatment is safe with no additional observed adverse events.

We conducted a multicenter phase 2 clinical trial in the U.S. evaluating the efficacy and safety of vemurafenib, an oral BRAF inhibitor, in patients with relapsed/refractory (R/R) HCL. We previously published the initial outcome of 26 U.S. patients together with the Italian study conducted by Tiacci et al. Vemurafenib monotherapy induced 96-100% ORR and 35-42% CR rates in both studies. With a median follow-up duration of 11.7 months, we observed relapses in 29% of the patients but the long-term clinical outcome and response or acquired resistance to vemurafenib retreatment have not been previously reported. Herein, we report the long-term follow-up data of the entire patient cohort in the completed U.S. clinical trial (NCT01711632) including the ORR, relapse free survival, clinical factors associated with improved survival as well as outcomes after retreatment with vemurafenib or alternative agents.

This article is not currently available to the general public. Only Blood subscribers can access the article.

How I Treat Refractory/Relapsed Hairy Cell Leukemia with BRAF Inhibitors

Journal: Blood, April 14, 2022

Authors: Brunangelo Falini, Luca De Carolis, Enrico Tiacci

Abstract: Hairy cell leukemia (HCL) responds very well to frontline chemotherapy with purine analogs (cladribine and pentostatine). However, approximately half of patients experience 1 or more relapses, which become progressively resistant to these myelotoxic and immunosuppressive agents. At progression, standard therapeutic options include a second course of purine analogs alone or in combination with rituximab and, upon second relapse, therapy with the anti-CD22 immunotoxin moxetumomab pasudotox. Furthermore, blockade of the mutant BRAF-V600E kinase (the pathogenetic hallmark of HCL) through orally available specific inhibitors (vemurafenib or dabrafenib) effaces the peculiar morphologic, phenotypic, and molecular identity of this disease and its typical antiapoptotic behavior and is emerging as an attractive chemotherapy-free strategy in various clinical scenarios. These include patients with, or at risk of, severe infections and, in a highly effective combination with rituximab, patients with relapsed or refractory HCL. Other treatments explored in clinical trials are BTK inhibition with ibrutinib and co-inhibition of BRAF (through dabrafenib or vemurafenib) and its downstream target MEK (through trametinib or cobimetinib). Here, we focus on our experience with BRAF inhibitors in clinical trials and as off-label use in routine practice by presenting 3 challenging clinical cases to illustrate their management in the context of all available treatment options.

New Therapeutic Options for Hairy Cell Leukemia

Journal: Acta Haematologica Polonica, October 2021 (published online)

Authors: Anna Janowska, Agnieszka Janus, Konrad Kociszewski, Tadeusz Robak

Abstract: Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder characterized by pancytopenia, splenomegaly and increased susceptibility to infections. In 2011, BRAF gene mutation was identified in almost all the patients with the classical type of HCL. The purine analogs cladribine and pentostatin induce long-term remission in the majority of patients, and they remain the standard treatment for this type of leukemia. However, more than half of patients in complete response relapse over the long term, with a quarter of them relapsing within the first five years. Recently, new drugs have been developed and have demonstrated efficacy in refractory or relapsed HCL. The immunotoxin Moxetumomab pasudotox was registered for HCL in 2018. The BRAF kinase inhibitors vemurafenib and dabrafenib, as well as the Bruton kinase inhibitor ibrutinib, are also proven highly effective in clinical trials.

This is a review article.

Vemurafenib plus Rituximab in Refractory or Relapsed Hairy-Cell Leukemia

Journal: The New England Journal of Medicine, May 13, 2021

Authors: Enrico Tiacci, Luca De Carolis, Edoardo Simonetti, Monia Capponi, Achille Ambrosetti, Eugenio Lucia, Agostino Antolino, Alessandro Pulsoni, Samantha Ferrari, Pier L. Zinzani, Stefano Ascani, Vincenzo M. Perriello, Luigi Rigacci, Gianluca Gaidano, Roberta Della Seta, Natalia Frattarelli, Paolo Falcucci, Robin Foà, Giuseppe Visani, Francesco Zaja, and Brunangelo Falini, et al.

Conclusion: In this small study, a short, chemotherapy-free, nonmyelotoxic regimen of vemurafenib plus rituximab was associated with a durable complete response in most patients with refractory or relapsed HCL.

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Phase 2 Study of Ibrutinib in Classic and Variant Hairy Cell Leukemia

Journal: Blood, March 22, 2021

Authors: Kerry A. Rogers, Leslie Ann Andritsos, Lai Wei, Eric McLaughlin, Amy S Ruppert, Mirela Anghelina, James S. Blachly, Timothy G. Call, Dai Chihara, Anees M Dauki, Ling Guo, S Percy Ivy, Lacey James, Dan Jones, Robert J Kreitman, Gerard Lozanski, David M Lucas, Apollinaire Ngankeu, Mitch A. Phelps, Farhad Ravandi, Charles Schiffer, William E. Carson III, Jeffrey A. Jones, Michael Rhodes Grever

Key Points:

• Ibrutinib can result in durable disease control in hairy cell leukemia patients who are not expected to benefit from purine analogues.

• The safety profile of ibrutinib in hairy cell leukemia is similar to other diseases with cytopenias and risk of frequent infections.

Moxetumomab Pasudotox in Heavily Pre-treated Patients with Relapsed/Refractory Hairy Cell Leukemia (HCL): Long-term Follow-up from the Pivotal Trial

Journal: Journal of Hematology & Oncology 14, Article number: 35 (2021)

Authors: Robert J. Kreitman, Claire Dearden, Pier Luigi Zinzani, Julio Delgado, Tadeusz Robak, Philipp D. le Coutre, Bjørn T. Gjertsen, Xavier Troussard, Gail J. Roboz, Lionel Karlin, Douglas E. Gladstone, Nataliya Kuptsova-Clarkson, Shiyao Liu, Priti Patel, Federico Rotolo, Emmanuel Mitry, Ira Pastan, Francis Giles on behalf of the Study 1053 investigators

Background: Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin. Here, we present the long-term follow-up analysis of the pivotal, multicenter, open-label trial (NCT01829711) of moxetumomab pasudotox in patients with relapsed/refractory (R/R) hairy cell leukemia (HCL).

Results: Eighty adult patients were treated with moxetumomab pasudotox and 63% completed six cycles. Patients had received a median of three lines of prior systemic therapy; 49% were PNA-refractory, and 38% were unfit for PNA retreatment. At a median follow-up of 24.6 months, the durable CR rate (CR with HR > 180 days) was 36% (29 patients; 95% confidence interval: 26–48%); CR with HR ≥ 360 days was 33%, and overall CR was 41%. Twenty-seven complete responders (82%) were MRD-negative (34% of all patients). CR lasting ≥ 60 months was 61%, and the median progression-free survival without the loss of HR was 71.7 months. Hemolytic uremic and capillary leak syndromes were each reported in ≤ 10% of patients, and ≤ 5% had grade 3–4 events; these events were generally reversible. No treatment-related deaths were reported.

Conclusions: Moxetumomab pasudotox resulted in a high rate of durable responses and MRD negativity in heavily pre-treated patients with HCL, with a manageable safety profile. Thus, it represents a new and viable treatment option for patients with R/R HCL, who currently lack adequate therapy.

Targeted Therapy for Treatment of Patients with Classical HCL

Journal: Leukemia Research (March 2021)

Authors: Jeremiah E. Moore, Kendra Delibert, Andrea M. Baran, Andrew G. Evans, Jane L. Liesveld, Clive S. Zent

Highlights:

• cHCL patients with cytopenia, severe infection or purine analogue refractory disease could benefit from targeted therapy.

• Combination of vemurafenib with rituximab was tolerable and effective.

• All patients responded with rapid blood count recovery.

• Median progression free and overall survival was not reached at 18.1 months.

Abstract: Most patients with treatment naïve classical hairy cell leukemia (cHCL) have durable responses with purine nucleoside analogues. In contrast, options are limited for cHCL patients with co-morbidities, purine analogue intolerance, or resistant disease. We report the utility of targeted therapy for nine cHCL patients presenting with treatment naïve cHCL and severe neutropenia and infection (n = 3), purine analogue intolerance (n = 2), or purine analogue resistant disease (n = 4). BRAF inhibitor vemurafenib was started at 240−480 mg twice daily (planned 90-day treatment) and combined with rituximab in seven patients. Therapy was tolerable with no severe adverse events. All patients responded with rapid blood count recovery (median time 1.52 months, range 0.43–4.33). Median progression free and overall survival was not reached at a median follow up of 18.1 months (range 3.2–68.9). These data suggest targeted therapy could be an option for patients unable to be treated with purine analogues.

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Randomized Phase II Study of First-Line Cladribine with Concurrent or Delayed Rituximab in Patients with HCL

Journal: Journal of Clinical Oncology (May 2020)

Authors: Dai Chihara, Evgeny Arons, Maryalice Stetler-Stevenson, Constance M. Yuan, Hao-Wei Wang, Hong Zhou, Mark Raffeld, Liqiang Xi, Seth M. Steinberg, Julie Feurtado, Lacey James, Wyndham Wilson, Raul C. Braylan, Katherine R. Calvo, Irina Maric, Alina Dulau-Florea, Robert J. Kreitman

Purpose: Single-agent purine analog, usually cladribine, has been the standard first-line therapy of hairy cell leukemia (HCL) for 30 years. High complete remission (CR) rates often include minimal residual disease (MRD), leading to relapse and repeated treatments. Rituximab can clear MRD, but long-term results are unknown and optimal timing of rituximab undefined.

Conclusion: Achieving MRD-free CR of HCL after first-line cladribine is greatly enhanced by concurrent rituximab and less so by delayed rituximab. Longer follow-up will determine if MRD-free survival leads to less need for additional therapy or cure of HCL.

Classic Hairy Cell Leukemia Complicated by Pancytopenia and Severe Infection: A Report of 3 Cases Treated with Vemurafenib

Journal: Blood Advances (January 22, 2019)

Authors: Daniel P. Shenoi, Leslie A. Andritsos, James S. Blachly, Kerry A. Rogers, Mollie E. Moran, Mirela Anghelina, Jeffrey A. Jones and Michael R. Grever

Key Points

• Infections are a major cause of morbidity and mortality in HCL patients, and myelosuppressive therapies increase the risk of poor outcomes.

• Vemurafenib achieves rapid hematologic improvement in HCL and may facilitate management during life-threatening infection.

Consensus Guidelines for the Diagnosis and Management of Patients with Classic Hairy Cell Leukemia

Journal: Blood (February 2, 2017)

Authors: Michael R. Grever, Omar Abdel-Wahab, Leslie A. Andritsos, Versha Banerji, Jacqueline Barrientos, James S. Blachly, Timothy G. Call, Daniel Catovsky, Claire Dearden, Judit Demeter, Monica Else, Francesco Forconi, Alessandro Gozzetti, Anthony D. Ho, James B. Johnston, Jeffrey Jones, Gunnar Juliusson, Eric Kraut, Robert J. Kreitman, Loree Larratt, Francesco Lauria, Gerard Lozanski, Emili Montserrat, Sameer A. Parikh, Jae H. Park, Aaron Polliack, Graeme R. Quest, Kanti R. Rai, Farhad Ravandi, Tadeusz Robak, Alan Saven, John F. Seymour, Tamar Tadmor, Martin S. Tallman, Constantine Tam, Enrico Tiacci, Xavier Troussard, Clive S. Zent, Thorsten Zenz, Pier Luigi Zinzani and Brunangelo Falini

Abstract: Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.

Proceedings and Papers from the International Hairy Cell Leukemia Consortium Meeting: “Treatment of Hairy Cell Leukemia in its Second Half Century”, held at the NIH, Bethesda, Maryland, USA, 2010

Journal: Leukemia & Lymphoma (June 2011)

Guest Editors: Robert Kreitman, Aaron Polliack & Michael Grever

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Hairy Cell Leukemia: A 50 Year Report on Clinical Research

Leukemia & Lymphoma (October 2009)

Guest Editor: Michael Grever

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HCL Variant

Long term Follow-up of a Phase II Study of Cladribine with Concurrent Rituximab with Hairy Cell Leukemia Variant

Journal: Blood Advances (December 2021)

Authors:

Dai Chihara, Evgeny Arons, Maryalice Stetler-Stevenson, Constance Yuan, Hao-Wei Wang, Hong Zhou, Mark Raffeld, Liqiang Xi, Seth M. Steinberg, Julie Feurtado, Lacey James-Echenique, Chin-Hsien Tai, Keyur P. Patel, Raul C. Braylan, Katherine R. Calvo, Irina Maric, Alina Dulau-Florea, and Robert J. Kreitman

Abstract: Hairy cell leukemia variant (HCLv) responds poorly to purine analogue monotherapy. Rituximab concurrent with cladribine (CDAR) improves response rates, but long-term outcomes are unknown. We report final results of a phase 2 study of CDAR for patients with HCLv. Twenty patients with 0 to 1 prior courses of cladribine and/or rituximab, including 8 who were previously untreated, received cladribine 0.15 mg/kg on days 1 to 5 with 8 weekly rituximab doses of 375 mg/m2 beginning day 1. Patients received a second rituximab course ≥6 months after cladribine, if and when minimal residual disease (MRD) was detected in blood. The complete remission (CR) rate from CDAR was 95% (95% confidence interval, 75-100). Sixteen (80%) of 20 patients (95% confidence interval, 56-94) became MRD negative according to bone marrow at 6 months. The median duration of MRD-negative CR was 70.1 months, and 7 of 16 are still MRD negative up to 120 months. With a median follow-up of 69.7 months, 11 patients received delayed rituximab, and the 5-year progression-free survival (PFS) and overall survival (OS) were 63.3% and 73.9%, respectively. Five patients with TP53 mutations had shorter PFS (median, 36.4 months vs unreached; P = .0024) and OS (median, 52.4 months vs unreached; P = .032). MRD-negative CR at 6 months was significantly associated with longer PFS (unreached vs 17.4 months; P < .0001) and OS (unreached vs 38.2 months; P < .0001). Lack of MRD in blood at 6 months was also predictive of longer PFS and OS (P < .0001). After progression following CDAR, median OS was 29.7 months. CDAR is effective in HCLv, with better outcomes in patients who achieve MRD-negative CR.

Cladribine with Immediate Rituximab for the Treatment of Patients with Variant Hairy Cell Leukemia

Journal: Clinical Cancer Research (December 2013)

Authors: Robert J. Kreitman, Wyndham Wilson, Katherine R. Calvo, et al.

Abstract:

In contrast with the classic form, variant hairy cell leukemia (HCLv) responds poorly to single-agent purine analogs, expresses unmutated BRAF, has shorter overall survival, and lacks effective standard therapy. No treatment has achieved a high complete remission (CR) rate even in small series, and of 39 reported cases from six studies, overall response rate after cladribine was 44% with 8% CRs. Rituximab has been found to increase the sensitivity of malignant cells to cladribine, suggesting that combination with cladribine might improve response in HCLv. To test this hypothesis, patients with HCLv were treated with simultaneous cladribine and rituximab.

Conclusion: Although cladribine alone lacks effectiveness for early or relapsed HCLv, cladribine with immediate rituximab achieves complete remission without minimal residual disease and is feasible to administer.

BRAF Mutation

Hairy Cell Leukemia Masquerading as CD5+ Lymphoproliferative Disease: The Importance of BRAF V600E Testing in Diagnosis and Treatment

Journal: JCO Precision Oncology (June 2021)

Authors: Deborah Soong, Priyadarshini Kumar, Karan Jatwani, Jae Park, Ahmet Dogan and Justin Taylor

Summary: Diagnosis of HCL has traditionally depended upon morphologic phenotyping and immunophenotyping, which allow for distinction from HCL-like disorders. A correct diagnosis is vital because purine analogs, such as cladribine or pentostatin, are very effective in HCL, but generally less effective in other lymphomas. Given the high sensitivity and specificity of BRAF V600E testing for genetics-based diagnosis of HCL, early testing for BRAF V600E will allow both diagnostic accuracy and appropriate treatment regimens.

Herein, we describe a 68-year-old female with HCL who was treated for a CD5+ B-cell lymphoproliferative disorder prior to definitive diagnosis because of phenotypically aberrant findings. We provide evidence of true classical HCL diagnosis as well as BRAF V600E mutational status and treatment implications.

Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia

Journal: The New England Journal of Medicine (October 29, 2015)

Authors: Enrico Tiacci, M.D., Jae H. Park, M.D., Luca De Carolis, M.D., Stephen S. Chung, M.D., Alessandro Broccoli, M.D., Sasinya Scott, M.P.H., Francesco Zaja, M.D., Sean Devlin, Ph.D., Alessandro Pulsoni, M.D., Young R. Chung, M.S., Michele Cimminiello, M.D., Eunhee Kim, Ph.D., et al.

Abstract: Background: BRAF V600E is the genetic lesion underlying hairy cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues.

Conclusions: A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy cell leukemia.

BRAF Mutations in Hairy-Cell Leukemia

Journal: The New England Journal of Medicine (June 16, 2011)

Authors: Enrico Tiacci, M.D., Vladimir Trifonov, Ph.D., Gianluca Schiavoni, Ph.D., Antony Holmes, Ph.D., Wolfgang Kern, M.D., Maria Paola Martelli, M.D., Alessandra Pucciarini, Ph.D., Barbara Bigerna, B.Sc., Roberta Pacini, B.Sc., Victoria A. Wells, B.Sc., Paolo Sportoletti, M.D., Valentina Pettirossi, Ph.D., et al.

Abstract: Background: Hairy cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure. We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL.

Conclusions: The BRAF V600E mutation was present in all patients with HCL who were evaluated. This finding may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL.

Quality of Life

Patient-driven research: Initial results from a prospective health–related quality of life study performed at the request of patients living with hairy cell leukemia

Journal: Leukemia Research, Volume 120, September 2022

Authors: Mirela Anghelina, Michelle J. Naughton, Qiuhong Zhao, Amy S. Ruppert, Jasmine Neal, Kerry A. Rogers, James S. Blachly, Gerard Lozanski, Seema A. Bhata, Eric Kraut, Narendranath Epperla, Puneet Mathur, Clive S. Zent, Versha Banerji, Claire Dearden, Terri Hutchinson, Michael Grever, Leslie A. Andritsos

Abstract: A diagnosis of leukemia can have a profound effect on patients’ health-related quality of life (HRQoL), however this has not been measured prospectively in patients with hairy cell leukemia (HCL). At the request of patients living with HCL who had identified this gap in knowledge about the disease, we conducted a longitudinal study of HRQoL among patients enrolled in the HCL Patient Data Registry (PDR). From September 1, 2018 to September 1, 2020, 165 patients were enrolled in the study and completed the baseline survey. The Functional Assessment of Cancer Therapy – Leukemia (FACT-Leu) was used to measure patients’ HRQoL. Results show that newly diagnosed HCL patients reported the lowest HRQoL, followed by patients in relapse and those on “watch and wait.” Factors associated with higher (better) FACT-Leu total scores in the multivariable analysis included older age, higher social support, and greater physical activity. These same factors were associated with lower levels of fatigue. In rare diseases where it is difficult to perform large prospective studies, patient/researcher collaborations are critical for the identification of studies that are of importance to patients and their families in order to maximize the benefits of the research and improve the lives of patients living with HCL.

Note: A corrigendum was published to modify the acknowledgements section. View it online. >>

Minimal Residual Disease (MRD)

Consensus opinion from an international group of experts on measurable residual disease in HCL

Journal: Blood Cancer Journal, December 2022

Authors: Farhad Ravandi, Robert J. Kreitman, Enrico Tiacci, Leslie Andritsos, Versha Banerji, Jacqueline C. Barrientos, Seema A. Bhat, James S. Blachly, Alessandro Broccoli, Timothy Call, Dai Chihara, Claire Dearden, Judit Demeter, Sasha Dietrich, Monica Else, Narendranath Epperla, Brunangelo Falini, Francesco Forconi, Douglas E. Gladstone, Alessandro Gozzetti, Sunil Iyengar, James B. Johnston, Jeffrey Jorgensen, Gunnar Juliusson, Francesco Lauria, Gerard Lozanski, Sameer A. Parikh, Jae H. Park, Aaron Polliack, Graeme Quest, Tadeusz Robak, Kerry A. Rogers, Alan Saven, John F. Seymour, Tamar Tadmor, Martin S. Tallman, Constantine S. Tam, Philip A. Thompson, Xavier Troussard, Clive S. Zent, Thorsten Zenz, Pier Luigi Zinzani, Bernhard Wörmann, Kanti Rai, and Michael Grever

Abstract: A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the duration of remission. Several assays including immunohistochemical analysis of bone marrow specimens, multi-parameter flow cytometry and molecular assays to detect the mutant BRAF V600E gene or the consensus primer for the immunoglobulin heavy chain gene (IGH) rearrangement have been utilized with few comparative studies. Here we provide a consensus report on the available data, the potential merits of MRD assessment in the front-line and relapse settings and recommendations on future role of MRD assessment in HCL.