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Chemoimmunotherapy for hairy cell leukemia
Best Practice & Research Clinical Haematology xxx (2015) 1e6
Contents lists available at ScienceDirect
Best Practice & Research Clinical Haematology journal homepage: www.elsevier.com/locate/beha
Chemoimmunotherapy for hairy cell leukemia Farhad Ravandi* Department of Leukemia, The University of Texas, MD Anderson Cancer Center, USA
a b s t r a c t Keywords: Hairy cell leukemia Nucleoside analogs Rituximab Chemoimmunotherapy
Success in the treatment of patients with hairy cell leukemia (HCL) over the last several decades is largely due to the high efficacy of the nucleoside analogs, cladribine and pentostatin. However, the relapse-free survival curves have not shown a plateau and many patients treated with these agents will eventually relapse. Although better understanding of the pathogenic mechanisms in HCL have led to effective and novel options for the treatment of relapse, long term durability of the responses obtained with these agents still remains unclear. Combination of nucleoside analogs with monoclonal antibodies such as rituximab has been shown to be safe and effective and has the potential to supersede the nucleoside analogs as the frontline strategy. Such chemoimmunotherapy approaches are under further investigation and will have to be assessed with socioeconomic considerations in mind. Other novel monoclonal antibodies, approved for the treatment of other lymphoid neoplasms, may also be considered for future studies of chemo-immunotherapy. © 2015 Elsevier Ltd. All rights reserved.
Historical aspects of therapy in hairy cell leukemia Treatment of patients with hairy cell leukemia (HCL) has evolved significantly over the past several decades [1]. Initially, splenectomy with its associated risks and complications was considered as the standard option for most patients. With the observation of activity of interferon alfa in a cohort of patients, use of interferon became universally accepted as the initial therapeutic strategy for most
* Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel.: þ1 713 745 0394; fax: þ1 713 563 5774. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.beha.2015.09.005 1521-6926/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ravandi F, Chemoimmunotherapy for hairy cell leukemia, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.09.005
2
F. Ravandi / Best Practice & Research Clinical Haematology xxx (2015) 1e6
patients [2]. However, responses with both of these strategies were mostly partial and not durable in the majority of the patients treated [1]. The introduction of the nucleoside analogs, cladribine and pentostatin was another milestone in the treatment of HCL as both of these agents were associated with very high rates of complete remission (CR) which were highly durable in the majority of patients [3e7]. Furthermore, a randomized trial clearly demonstrated the superiority of pentostain over interferon [8]. Thus, cladribine and pentostatin have remained as the standard of care options for frontline therapy of patients with HCL since their introduction in the 1990s. Is there a need for improvement? Despite the near universal response to the nucleoside analogs, many patients with HCL relapse within the first several years and the relapse-free survival curves do not appear to have a plateau [9]. The likelihood of relapse after first line therapy is dependent on the quality of the initial response and, as expected, patients with responses less than a CR are more likely to relapse [9]. Availability of longterm data from a number of large studies and databases has shown that a proportion of patients continue to relapse and require further therapy even later in the course of follow-up. Although, in most cases second line therapy with the same or the alternative nucleoside analog can result in second remissions, this is by no means universal and several reports have shown that the percentage of patients achieving second and subsequent CRs declines with subsequent lines of therapy with nucleoside analogs [7,10]. Furthermore, the duration of second and subsequent remissions is progressively shorter [7,10]. Patients diagnosed with HCL are relatively young with the median age in the 50s in most series. Therefore, the general life expectancy of the average patient is several decades in the industrialized world. Clearly, this is an important consideration for most patients first diagnosed with this disease as there is a definite potential for relapse later in life. This is somewhat reminiscent of the situation with other indolent lymphoid neoplasms such as follicular lymphoma which historically were considered as incurable despite being indolent and not imminently fatal. HCL has been more effectively treated with nucleoside analogs compared to follicular lymphomas to the extent that few if any patients die from HCL with modern management strategies. A recent study of patients with HCL younger than 40 who received initial therapy with cladribine reported an 88% CR rate with a median response duration of 57 months [11]. With 58% of patients relapsing, the median time to first relapse was 54 months [11]. The median overall survival from diagnosis and following first cladribine course were 251 months and 231 months, respectively [11]. Therefore, the primary goal of therapy in HCL appears to be shifting from solely improving survival of the patients to increasing relapse-free interval and reducing the likelihood of relapse. Available therapeutic options for relapse Understanding the biology of HCL and, in particular, the discovery of near universal incidence of BRAF V600E mutations in patients with HCL has provided us with new and highly effective tools for therapy [12]. BRAF kinase inhibitors, commercially available for the treatment of other cancers, have been shown to be effective agents for treating patients with relapsed HCL [13]. Other novel agents such as immunotoxins and B-cell receptor inhibitors are also under investigation with promising early reports from the ongoing trials. Potentially more active anti-CD20 monoclonal antibodies have also been developed and approved for the treatment of other lymphoid neoplasms but have not been evaluated in HCL. Therefore, several novel potential therapeutic strategies are now available for patients with relapsed disease. However, the durability of responses to these agents is unclear due to limited available long-term data from these trials. Role of chemo-immunotherapy Another approach to improving the outcome of patients with HCL may be to improve upon the initial therapy, increasing the proportion of patients who achieve CR with their initial treatment and ensuring that these responses are universally long-lasting. Addition of rituximab to established Please cite this article in press as: Ravandi F, Chemoimmunotherapy for hairy cell leukemia, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.09.005
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regimens for a number of lymphoid neoplasms has been associated with significant improvements in the response rate, relapse-free and overall survival [14e16]. The exact mechanisms by which rituximab is associated with these benefits is not completely understood. Furthermore, in some diseases, such as chronic lymphocytic leukemia, the addition of rituximab is beneficial despite its limited single agent activity [17]. CD20, the surface membrane target of rituximab is highly expressed on HCL cells and small phase II studies have demonstrated moderate activity of rituximab in this disease [18,19]. In a phase II study conducted by our group, using 8 weekly doses of rituximab in patients with relapsed HCL, a 53% response rate was reported [20]. Furthermore, single agent activity in previously untreated patients with HCL, had been reported in these small phase II studies [21]. We have previously reported the early results of a phase II clinical trial with sequential therapy with cladribine followed by rituximab in patients with newly diagnosed HCL [22]. This is a well-tolerated regimen without significant increase in toxicity compared to treatment with cladribine. The premise behind this study was to improve the response rate and durability of responses to cladribine by the addition of eight weekly doses of rituximab after recovery of counts from the cladribine induced pancytopenia (approximately one month after the initiation of cladribine therapy). We also sought to determine the ability of this regimen to eradicate minimal residual disease determined by multiparameter flow cytometry in bone marrow specimen obtained after the completion of rituximab therapy [23]. Clearly, this appears to be an effective strategy with universal achievement of complete remission (CR) in patients with classical HCL [22]. Longer follow-up of the study with 59 patients with classical HCL enrolled, further confirms the universal ability of this regimen to produce CRs in previously untreated patients. More importantly, with a median follow-up of 50 months (range, 3e128 months), only one patient with classical HCL has relapsed. Another patient died in CR from an unrelated other malignancy. We also treated a cohort of 14 patients with classical HCL in first relapse with the same regimen; all achieved CR. Among them, 6 patients have had sufficient follow-up to determine whether the duration of their second CR is longer than their first. In all, the second CR has been more durable than the first (Table 1). Other groups have also combined rituximab with nucleoside analogs or other cytotoxic agents for the treatment of patients with relapsed as well as untreated HCL. Else and colleagues treated 8 patients with multiply relapsed HCL with rituximab given either concomitantly (n ¼ 6) or sequentially (n ¼ 2) with either cladribine or pentostatin and reported a remarkable 87.5% CR rate (7of the 8 patients) [24]. With a median follow-up of 29 months, only one patient had relapsed. The investigators at the National Institute of Health have also recently reported the results of a study combining bendamustine with rituximab in patients with relapsed and refractory HCL [25]. They reported a high
Table 1 Chemo-immunotherapy for HCL in first relapse. Patient
CR1 duration (years)
CR2 duration (years)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
9 1 5.5 9 2.6 1 6.4 (DCF) 4.5 5.5 6 6.5 0 (Rituximab) 1 8.3
9.7 7.9 4.1 8.6 5.1 6.2 4.8 3.0 2.5 2.4 1.9 1.6 1.6 0.8
Patients treated in first relapse with cladribine followed by 8 weekly doses of rituximab. Underlined values refer to patients with sufficient follow-up to compare CR2 with CR1 duration. All CR2 values are ongoing with no relapses. All patients were treated with cladribine for their first line therapy except for patient 7 (treated with pentostatin) and patient 12 (treated with rituximab alone).
Please cite this article in press as: Ravandi F, Chemoimmunotherapy for hairy cell leukemia, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.09.005
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response rate with eradication of minimal residual disease (MRD) in those achieving CR and with the responses being durable [25]. A high response rate has also been reported for the combination of cladribine and rituximab in treating patients with variant HCL, a group traditionally resistant to therapy with nucleoside analogs alone [22,26]. Whether the best strategy for combining rituximab with nucleoside analogs is to administer them concurrently or sequentially has not been reported although an ongoing study being conducted at the NIH may be able to shed further light on this aspect of chemo-immunotherapy in HCL. Analysis of data from trials of chemo-immunotherapy in other lymphoproliferative neoplasms would suggest that concurrent therapy may be the more effective strategy both in relapse and frontline settings. For example, Byrd and colleagues from the Cancer and Leukemia Group B (CALGB) reported superior efficacy when fludarabine and rituximab were administered concurrently to patients with chronic lymphocytic leukemia rather than when they were given sequentially [27]. Another potential question is whether subsequent courses of rituximab given during remission (perhaps guided by the presence of MRD) could be beneficial in preventing some relapses. Unfortunately, the available data have not conclusively established the significance of persistence of MRD detected by various techniques such as immunohistochemistry or multi-parameter flow cytometry in bone marrow specimens obtained at CR. Although some studies have suggested that detection of MRD may be associated with a higher likelihood of relapse, others have demonstrated persistence of hairy cells in bone marrow samples obtained in morphological/clinical CR many years after achieving CR, thereby casting doubt about the relevance of detection of MRD [28,29].
Socioeconomic considerations Clearly, the potential role of chemo-immunotherapy with the addition of rituximab (and perhaps other monoclonal antibodies such as ofatumomab or obinutuzumab) in the initial treatment of patients with HCL will have to be determined with economic considerations in mind. Although, a subgroup of patients treated with the nucleoside analogs never relapse and therefore do not necessarily require the combination strategy in the frontline setting, the continued potential for relapse, the lack of plateau in the relapse-free survival curves and the relatively young median age of patients with HCL, would favor strategies that would eliminate or at least minimize the risk of relapse. Prospective, randomized trials with built-in quality of life and cost-of-care assessments can further clarify the overall cost-benefit considerations of such strategy but require a multi-national cooperative effort due to the relative rarity of the disorder. Identification of disease or patient characteristics that predispose to inferior responses to the nucleoside analogs and higher likelihood or relapse may help guide the selection of patients for combined therapy. Few clinical characteristics have been associated with inferior outcome to the nucleoside analogs [7]. However, subgroups of patients such as those with unmutated IGHV and those with the VH4-34þ classical HCL have been clearly associated with decreased response to cladribine and are clear candidates for chemoimmunotherapy [30,31].
Practice points and research agenda
Addition of rituximab to nucleoside analogs for treating HCL is feasible Chemo-immunotherapy may prolong duration of remission without significant toxicity Potential superiority of this strategy should be examined in a randomized trial Socio-economic considerations are important before implementing this strategy Patients likely to fail cladribine monotherapy may benefit from chemo-immunotherapy
Please cite this article in press as: Ravandi F, Chemoimmunotherapy for hairy cell leukemia, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.09.005
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Conflict of interest The author reports no relevant disclosures. Acknowledgements Supported in part by the MD Anderson Cancer Center Support Grant CA016672 and by a generous grant from the Hairy Cell Leukemia Foundation. References [1] Grever MR, Lozanski G. Modern strategies for hairy cell leukemia. J Clin Oncol 2011;29:583e90. [2] Quesada JR, Reuben J, Manning JT, Gutterman JU. Alpha interferon for induction of remission in hairy-cell leukemia. N Engl J Med 1984;310:15e8. [3] Piro LD, Carrera CJ, Carson DA, Beutler E. Lasting remissions in hairy-cell leukemia induced by a single infusion of 2chlorodeoxyadenosine. N Engl J Med 1990;322:1117e21. [4] Spiers AS, Parekh SJ, Bishop MB. Hairy-cell leukemia: induction of complete remission with pentostatin (2'-deoxycoformycin). J Clin Oncol 1984;2:1336e42. [5] Goodman GR, Burian C, Koziol JA, Saven A. Extended follow-up of patients with hairy cell leukemia after treatment with cladribine. J Clin Oncol 2003;21:891e6. [6] Kraut EH, Bouroncle BA, Grever MR. Pentostatin in the treatment of advanced hairy cell leukemia. J Clin Oncol 1989;7:168e72. [7] Else M, Dearden CE, Matutes E, Garcia-Talavera J, Rohatiner AZ, Johnson SA, et al. Long-term follow-up of 233 patients with hairy cell leukaemia, treated initially with pentostatin or cladribine, at a median of 16 years from diagnosis. Br J Haematol 2009;145:733e40. [8] Grever M, Kopecky K, Foucar MK, Head D, Bennett JM, Hutchison RE, et al. Randomized comparison of pentostatin versus interferon alfa-2a in previously untreated patients with hairy cell leukemia: an intergroup study. J Clin Oncol 1995;13: 974e82. [9] Dearden CE, Else M, Catovsky D. Long-term results for pentostatin and cladribine treatment of hairy cell leukemia. Leuk Lymphoma 2011;52(Suppl. 2):21e4. [10] Zinzani PL, Pellegrini C, Stefoni V, Derenzini E, Gandolfi L, Broccoli A, et al. Hairy cell leukemia: evaluation of the long-term outcome in 121 patients. Cancer 2010;116:4788e92. [11] Rosenberg JD, Burian C, Waalen J, Saven A. Clinical characteristics and long-term outcome of young hairy cell leukemia patients treated with cladribine: a single-institution series. Blood 2014;123:177e83. [12] Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med 2011;364:2305e15. [13] Pettirossi V, Santi A, Imperi E, Russo G, Pucciarini A, Bigerna B, et al. BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity. Blood 2015;125:1207e16. [14] Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 2010;116:2040e5. [15] Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376:1164e74. € hner H, Viardot A, Hiddemann W, Spiekermann K, et al. Improved outcome of adult Burkitt [16] Hoelzer D, Walewski J, Do lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial. Blood 2014;124: 3870e9. [17] Tam CS, O'Brien S, Wierda W, Kantarjian H, Wen S, Do KA, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 2008;112:975e80. [18] Lauria F, Lenoci M, Annino L, Raspadori D, Marotta G, Bocchia M, et al. Efficacy of anti-CD20 monoclonal antibodies (Mabthera) in patients with progressed hairy cell leukemia. Haematologica 2001;86:1046e50. [19] Ginaldi L, De Martinis M, Matutes E, Farahat N, Morilla R, Catovsky D. Levels of expression of CD19 and CD20 in chronic B cell leukaemias. J Clin Pathol 1998;51:364e9. [20] Thomas DA, O'Brien S, Bueso-Ramos C, Faderl S, Keating MJ, Giles FJ, et al. Rituximab in relapsed or refractory hairy cell leukemia. Blood 2003;102:3906e11. [21] Hagberg H, Lundholm L. Rituximab, a chimaeric anti-CD20 monoclonal antibody, in the treatment of hairy cell leukaemia. Br J Haematol 2001;115:609e11. [22] Ravandi F, O'Brien S, Jorgensen J, Pierce S, Faderl S, Ferrajoli A, et al. Phase 2 study of cladribine followed by rituximab in patients with hairy cell leukemia. Blood 2011;118:3818e23. [23] Ravandi F, Jorgensen JL, Thomas DA, O'Brien S, Garris R, Faderl S, et al. Eradication of minimal residual disease in hairy cell leukemia. Blood 2006;107:4658e62. [24] Else M, Osuji N, Forconi F, Dearden C, Del Giudice I, Matutes E, et al. The role of rituximab in combination with pentostatin or cladribine for the treatment of recurrent/refractory hairy cell leukemia. Cancer 2007;110:2240e7. [25] Burotto M, Stetler-Stevenson M, Arons E, Zhou H, Wilson W, Kreitman RJ. Bendamustine and rituximab in relapsed and refractory hairy cell leukemia. Clin Cancer Res 2013;19:6313e21. [26] Kreitman RJ, Wilson W, Calvo KR, Arons E, Roth L, Sapolsky J, et al. Cladribine with immediate rituximab for the treatment of patients with variant hairy cell leukemia. Clin Cancer Res 2013;19:6873e81.
Please cite this article in press as: Ravandi F, Chemoimmunotherapy for hairy cell leukemia, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.09.005
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[27] Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, 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;101:6e14. [28] Tallman MS, Hakimian D, Kopecky KJ, Wheaton S, Wollins E, Foucar K, et al. Minimal residual disease in patients with hairy cell leukemia in complete remission treated with 2-chlorodeoxyadenosine or 2-deoxycoformycin and prediction of early relapse. Clin Cancer Res 1999;5:1665e70. [29] Sigal DS, Sharpe R, Burian C, Saven A. Very long-term eradication of minimal residual disease in patients with hairy cell leukemia after a single course of cladribine. Blood 2010;115:1893e6. [30] Arons E, Suntum T, Stetler-Stevenson M, Kreitman RJ. VH4-34þ hairy cell leukemia, a new variant with poor prognosis despite standard therapy. Blood 2009;114:4687e95. [31] Forconi F, Sozzi E, Cencini E, Zaja F, Intermesoli T, Stelitano C, et al. Hairy cell leukemias with unmutated IGHV genes define the minor subset refractory to single-agent cladribine and with more aggressive behavior. Blood 2009;114:4696e702.
Please cite this article in press as: Ravandi F, Chemoimmunotherapy for hairy cell leukemia, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.09.005
Contents lists available at ScienceDirect
Best Practice & Research Clinical Haematology journal homepage: www.elsevier.com/locate/beha
Chemoimmunotherapy for hairy cell leukemia Farhad Ravandi* Department of Leukemia, The University of Texas, MD Anderson Cancer Center, USA
a b s t r a c t Keywords: Hairy cell leukemia Nucleoside analogs Rituximab Chemoimmunotherapy
Success in the treatment of patients with hairy cell leukemia (HCL) over the last several decades is largely due to the high efficacy of the nucleoside analogs, cladribine and pentostatin. However, the relapse-free survival curves have not shown a plateau and many patients treated with these agents will eventually relapse. Although better understanding of the pathogenic mechanisms in HCL have led to effective and novel options for the treatment of relapse, long term durability of the responses obtained with these agents still remains unclear. Combination of nucleoside analogs with monoclonal antibodies such as rituximab has been shown to be safe and effective and has the potential to supersede the nucleoside analogs as the frontline strategy. Such chemoimmunotherapy approaches are under further investigation and will have to be assessed with socioeconomic considerations in mind. Other novel monoclonal antibodies, approved for the treatment of other lymphoid neoplasms, may also be considered for future studies of chemo-immunotherapy. © 2015 Elsevier Ltd. All rights reserved.
Historical aspects of therapy in hairy cell leukemia Treatment of patients with hairy cell leukemia (HCL) has evolved significantly over the past several decades [1]. Initially, splenectomy with its associated risks and complications was considered as the standard option for most patients. With the observation of activity of interferon alfa in a cohort of patients, use of interferon became universally accepted as the initial therapeutic strategy for most
* Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel.: þ1 713 745 0394; fax: þ1 713 563 5774. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.beha.2015.09.005 1521-6926/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ravandi F, Chemoimmunotherapy for hairy cell leukemia, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.09.005
2
F. Ravandi / Best Practice & Research Clinical Haematology xxx (2015) 1e6
patients [2]. However, responses with both of these strategies were mostly partial and not durable in the majority of the patients treated [1]. The introduction of the nucleoside analogs, cladribine and pentostatin was another milestone in the treatment of HCL as both of these agents were associated with very high rates of complete remission (CR) which were highly durable in the majority of patients [3e7]. Furthermore, a randomized trial clearly demonstrated the superiority of pentostain over interferon [8]. Thus, cladribine and pentostatin have remained as the standard of care options for frontline therapy of patients with HCL since their introduction in the 1990s. Is there a need for improvement? Despite the near universal response to the nucleoside analogs, many patients with HCL relapse within the first several years and the relapse-free survival curves do not appear to have a plateau [9]. The likelihood of relapse after first line therapy is dependent on the quality of the initial response and, as expected, patients with responses less than a CR are more likely to relapse [9]. Availability of longterm data from a number of large studies and databases has shown that a proportion of patients continue to relapse and require further therapy even later in the course of follow-up. Although, in most cases second line therapy with the same or the alternative nucleoside analog can result in second remissions, this is by no means universal and several reports have shown that the percentage of patients achieving second and subsequent CRs declines with subsequent lines of therapy with nucleoside analogs [7,10]. Furthermore, the duration of second and subsequent remissions is progressively shorter [7,10]. Patients diagnosed with HCL are relatively young with the median age in the 50s in most series. Therefore, the general life expectancy of the average patient is several decades in the industrialized world. Clearly, this is an important consideration for most patients first diagnosed with this disease as there is a definite potential for relapse later in life. This is somewhat reminiscent of the situation with other indolent lymphoid neoplasms such as follicular lymphoma which historically were considered as incurable despite being indolent and not imminently fatal. HCL has been more effectively treated with nucleoside analogs compared to follicular lymphomas to the extent that few if any patients die from HCL with modern management strategies. A recent study of patients with HCL younger than 40 who received initial therapy with cladribine reported an 88% CR rate with a median response duration of 57 months [11]. With 58% of patients relapsing, the median time to first relapse was 54 months [11]. The median overall survival from diagnosis and following first cladribine course were 251 months and 231 months, respectively [11]. Therefore, the primary goal of therapy in HCL appears to be shifting from solely improving survival of the patients to increasing relapse-free interval and reducing the likelihood of relapse. Available therapeutic options for relapse Understanding the biology of HCL and, in particular, the discovery of near universal incidence of BRAF V600E mutations in patients with HCL has provided us with new and highly effective tools for therapy [12]. BRAF kinase inhibitors, commercially available for the treatment of other cancers, have been shown to be effective agents for treating patients with relapsed HCL [13]. Other novel agents such as immunotoxins and B-cell receptor inhibitors are also under investigation with promising early reports from the ongoing trials. Potentially more active anti-CD20 monoclonal antibodies have also been developed and approved for the treatment of other lymphoid neoplasms but have not been evaluated in HCL. Therefore, several novel potential therapeutic strategies are now available for patients with relapsed disease. However, the durability of responses to these agents is unclear due to limited available long-term data from these trials. Role of chemo-immunotherapy Another approach to improving the outcome of patients with HCL may be to improve upon the initial therapy, increasing the proportion of patients who achieve CR with their initial treatment and ensuring that these responses are universally long-lasting. Addition of rituximab to established Please cite this article in press as: Ravandi F, Chemoimmunotherapy for hairy cell leukemia, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.09.005
F. Ravandi / Best Practice & Research Clinical Haematology xxx (2015) 1e6
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regimens for a number of lymphoid neoplasms has been associated with significant improvements in the response rate, relapse-free and overall survival [14e16]. The exact mechanisms by which rituximab is associated with these benefits is not completely understood. Furthermore, in some diseases, such as chronic lymphocytic leukemia, the addition of rituximab is beneficial despite its limited single agent activity [17]. CD20, the surface membrane target of rituximab is highly expressed on HCL cells and small phase II studies have demonstrated moderate activity of rituximab in this disease [18,19]. In a phase II study conducted by our group, using 8 weekly doses of rituximab in patients with relapsed HCL, a 53% response rate was reported [20]. Furthermore, single agent activity in previously untreated patients with HCL, had been reported in these small phase II studies [21]. We have previously reported the early results of a phase II clinical trial with sequential therapy with cladribine followed by rituximab in patients with newly diagnosed HCL [22]. This is a well-tolerated regimen without significant increase in toxicity compared to treatment with cladribine. The premise behind this study was to improve the response rate and durability of responses to cladribine by the addition of eight weekly doses of rituximab after recovery of counts from the cladribine induced pancytopenia (approximately one month after the initiation of cladribine therapy). We also sought to determine the ability of this regimen to eradicate minimal residual disease determined by multiparameter flow cytometry in bone marrow specimen obtained after the completion of rituximab therapy [23]. Clearly, this appears to be an effective strategy with universal achievement of complete remission (CR) in patients with classical HCL [22]. Longer follow-up of the study with 59 patients with classical HCL enrolled, further confirms the universal ability of this regimen to produce CRs in previously untreated patients. More importantly, with a median follow-up of 50 months (range, 3e128 months), only one patient with classical HCL has relapsed. Another patient died in CR from an unrelated other malignancy. We also treated a cohort of 14 patients with classical HCL in first relapse with the same regimen; all achieved CR. Among them, 6 patients have had sufficient follow-up to determine whether the duration of their second CR is longer than their first. In all, the second CR has been more durable than the first (Table 1). Other groups have also combined rituximab with nucleoside analogs or other cytotoxic agents for the treatment of patients with relapsed as well as untreated HCL. Else and colleagues treated 8 patients with multiply relapsed HCL with rituximab given either concomitantly (n ¼ 6) or sequentially (n ¼ 2) with either cladribine or pentostatin and reported a remarkable 87.5% CR rate (7of the 8 patients) [24]. With a median follow-up of 29 months, only one patient had relapsed. The investigators at the National Institute of Health have also recently reported the results of a study combining bendamustine with rituximab in patients with relapsed and refractory HCL [25]. They reported a high
Table 1 Chemo-immunotherapy for HCL in first relapse. Patient
CR1 duration (years)
CR2 duration (years)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
9 1 5.5 9 2.6 1 6.4 (DCF) 4.5 5.5 6 6.5 0 (Rituximab) 1 8.3
9.7 7.9 4.1 8.6 5.1 6.2 4.8 3.0 2.5 2.4 1.9 1.6 1.6 0.8
Patients treated in first relapse with cladribine followed by 8 weekly doses of rituximab. Underlined values refer to patients with sufficient follow-up to compare CR2 with CR1 duration. All CR2 values are ongoing with no relapses. All patients were treated with cladribine for their first line therapy except for patient 7 (treated with pentostatin) and patient 12 (treated with rituximab alone).
Please cite this article in press as: Ravandi F, Chemoimmunotherapy for hairy cell leukemia, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.09.005
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response rate with eradication of minimal residual disease (MRD) in those achieving CR and with the responses being durable [25]. A high response rate has also been reported for the combination of cladribine and rituximab in treating patients with variant HCL, a group traditionally resistant to therapy with nucleoside analogs alone [22,26]. Whether the best strategy for combining rituximab with nucleoside analogs is to administer them concurrently or sequentially has not been reported although an ongoing study being conducted at the NIH may be able to shed further light on this aspect of chemo-immunotherapy in HCL. Analysis of data from trials of chemo-immunotherapy in other lymphoproliferative neoplasms would suggest that concurrent therapy may be the more effective strategy both in relapse and frontline settings. For example, Byrd and colleagues from the Cancer and Leukemia Group B (CALGB) reported superior efficacy when fludarabine and rituximab were administered concurrently to patients with chronic lymphocytic leukemia rather than when they were given sequentially [27]. Another potential question is whether subsequent courses of rituximab given during remission (perhaps guided by the presence of MRD) could be beneficial in preventing some relapses. Unfortunately, the available data have not conclusively established the significance of persistence of MRD detected by various techniques such as immunohistochemistry or multi-parameter flow cytometry in bone marrow specimens obtained at CR. Although some studies have suggested that detection of MRD may be associated with a higher likelihood of relapse, others have demonstrated persistence of hairy cells in bone marrow samples obtained in morphological/clinical CR many years after achieving CR, thereby casting doubt about the relevance of detection of MRD [28,29].
Socioeconomic considerations Clearly, the potential role of chemo-immunotherapy with the addition of rituximab (and perhaps other monoclonal antibodies such as ofatumomab or obinutuzumab) in the initial treatment of patients with HCL will have to be determined with economic considerations in mind. Although, a subgroup of patients treated with the nucleoside analogs never relapse and therefore do not necessarily require the combination strategy in the frontline setting, the continued potential for relapse, the lack of plateau in the relapse-free survival curves and the relatively young median age of patients with HCL, would favor strategies that would eliminate or at least minimize the risk of relapse. Prospective, randomized trials with built-in quality of life and cost-of-care assessments can further clarify the overall cost-benefit considerations of such strategy but require a multi-national cooperative effort due to the relative rarity of the disorder. Identification of disease or patient characteristics that predispose to inferior responses to the nucleoside analogs and higher likelihood or relapse may help guide the selection of patients for combined therapy. Few clinical characteristics have been associated with inferior outcome to the nucleoside analogs [7]. However, subgroups of patients such as those with unmutated IGHV and those with the VH4-34þ classical HCL have been clearly associated with decreased response to cladribine and are clear candidates for chemoimmunotherapy [30,31].
Practice points and research agenda
Addition of rituximab to nucleoside analogs for treating HCL is feasible Chemo-immunotherapy may prolong duration of remission without significant toxicity Potential superiority of this strategy should be examined in a randomized trial Socio-economic considerations are important before implementing this strategy Patients likely to fail cladribine monotherapy may benefit from chemo-immunotherapy
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Conflict of interest The author reports no relevant disclosures. Acknowledgements Supported in part by the MD Anderson Cancer Center Support Grant CA016672 and by a generous grant from the Hairy Cell Leukemia Foundation. References [1] Grever MR, Lozanski G. Modern strategies for hairy cell leukemia. J Clin Oncol 2011;29:583e90. [2] Quesada JR, Reuben J, Manning JT, Gutterman JU. Alpha interferon for induction of remission in hairy-cell leukemia. N Engl J Med 1984;310:15e8. [3] Piro LD, Carrera CJ, Carson DA, Beutler E. Lasting remissions in hairy-cell leukemia induced by a single infusion of 2chlorodeoxyadenosine. N Engl J Med 1990;322:1117e21. [4] Spiers AS, Parekh SJ, Bishop MB. Hairy-cell leukemia: induction of complete remission with pentostatin (2'-deoxycoformycin). J Clin Oncol 1984;2:1336e42. [5] Goodman GR, Burian C, Koziol JA, Saven A. Extended follow-up of patients with hairy cell leukemia after treatment with cladribine. J Clin Oncol 2003;21:891e6. [6] Kraut EH, Bouroncle BA, Grever MR. Pentostatin in the treatment of advanced hairy cell leukemia. J Clin Oncol 1989;7:168e72. [7] Else M, Dearden CE, Matutes E, Garcia-Talavera J, Rohatiner AZ, Johnson SA, et al. Long-term follow-up of 233 patients with hairy cell leukaemia, treated initially with pentostatin or cladribine, at a median of 16 years from diagnosis. Br J Haematol 2009;145:733e40. [8] Grever M, Kopecky K, Foucar MK, Head D, Bennett JM, Hutchison RE, et al. Randomized comparison of pentostatin versus interferon alfa-2a in previously untreated patients with hairy cell leukemia: an intergroup study. J Clin Oncol 1995;13: 974e82. [9] Dearden CE, Else M, Catovsky D. Long-term results for pentostatin and cladribine treatment of hairy cell leukemia. Leuk Lymphoma 2011;52(Suppl. 2):21e4. [10] Zinzani PL, Pellegrini C, Stefoni V, Derenzini E, Gandolfi L, Broccoli A, et al. Hairy cell leukemia: evaluation of the long-term outcome in 121 patients. Cancer 2010;116:4788e92. [11] Rosenberg JD, Burian C, Waalen J, Saven A. Clinical characteristics and long-term outcome of young hairy cell leukemia patients treated with cladribine: a single-institution series. Blood 2014;123:177e83. [12] Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med 2011;364:2305e15. [13] Pettirossi V, Santi A, Imperi E, Russo G, Pucciarini A, Bigerna B, et al. BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity. Blood 2015;125:1207e16. [14] Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 2010;116:2040e5. [15] Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376:1164e74. € hner H, Viardot A, Hiddemann W, Spiekermann K, et al. Improved outcome of adult Burkitt [16] Hoelzer D, Walewski J, Do lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial. Blood 2014;124: 3870e9. [17] Tam CS, O'Brien S, Wierda W, Kantarjian H, Wen S, Do KA, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 2008;112:975e80. [18] Lauria F, Lenoci M, Annino L, Raspadori D, Marotta G, Bocchia M, et al. Efficacy of anti-CD20 monoclonal antibodies (Mabthera) in patients with progressed hairy cell leukemia. Haematologica 2001;86:1046e50. [19] Ginaldi L, De Martinis M, Matutes E, Farahat N, Morilla R, Catovsky D. Levels of expression of CD19 and CD20 in chronic B cell leukaemias. J Clin Pathol 1998;51:364e9. [20] Thomas DA, O'Brien S, Bueso-Ramos C, Faderl S, Keating MJ, Giles FJ, et al. Rituximab in relapsed or refractory hairy cell leukemia. Blood 2003;102:3906e11. [21] Hagberg H, Lundholm L. Rituximab, a chimaeric anti-CD20 monoclonal antibody, in the treatment of hairy cell leukaemia. Br J Haematol 2001;115:609e11. [22] Ravandi F, O'Brien S, Jorgensen J, Pierce S, Faderl S, Ferrajoli A, et al. Phase 2 study of cladribine followed by rituximab in patients with hairy cell leukemia. Blood 2011;118:3818e23. [23] Ravandi F, Jorgensen JL, Thomas DA, O'Brien S, Garris R, Faderl S, et al. Eradication of minimal residual disease in hairy cell leukemia. Blood 2006;107:4658e62. [24] Else M, Osuji N, Forconi F, Dearden C, Del Giudice I, Matutes E, et al. The role of rituximab in combination with pentostatin or cladribine for the treatment of recurrent/refractory hairy cell leukemia. Cancer 2007;110:2240e7. [25] Burotto M, Stetler-Stevenson M, Arons E, Zhou H, Wilson W, Kreitman RJ. Bendamustine and rituximab in relapsed and refractory hairy cell leukemia. Clin Cancer Res 2013;19:6313e21. [26] Kreitman RJ, Wilson W, Calvo KR, Arons E, Roth L, Sapolsky J, et al. Cladribine with immediate rituximab for the treatment of patients with variant hairy cell leukemia. Clin Cancer Res 2013;19:6873e81.
Please cite this article in press as: Ravandi F, Chemoimmunotherapy for hairy cell leukemia, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.09.005
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[27] Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, 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;101:6e14. [28] Tallman MS, Hakimian D, Kopecky KJ, Wheaton S, Wollins E, Foucar K, et al. Minimal residual disease in patients with hairy cell leukemia in complete remission treated with 2-chlorodeoxyadenosine or 2-deoxycoformycin and prediction of early relapse. Clin Cancer Res 1999;5:1665e70. [29] Sigal DS, Sharpe R, Burian C, Saven A. Very long-term eradication of minimal residual disease in patients with hairy cell leukemia after a single course of cladribine. Blood 2010;115:1893e6. [30] Arons E, Suntum T, Stetler-Stevenson M, Kreitman RJ. VH4-34þ hairy cell leukemia, a new variant with poor prognosis despite standard therapy. Blood 2009;114:4687e95. [31] Forconi F, Sozzi E, Cencini E, Zaja F, Intermesoli T, Stelitano C, et al. Hairy cell leukemias with unmutated IGHV genes define the minor subset refractory to single-agent cladribine and with more aggressive behavior. Blood 2009;114:4696e702.
Please cite this article in press as: Ravandi F, Chemoimmunotherapy for hairy cell leukemia, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.09.005