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Is Early Hematopoietic Stem-Cell Transplantation Necessary in Mantle-Cell Lymphoma? Mitchell R. Smith, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH See accompanying article on page 273
The unifying concept defining mantle-cell lymphoma (MCL) as a t(11;14)-containing lymphoma driven by cyclin D1 dates to the early 1990s.1 With median survival of 3 to 5 years, MCL was then considered aggressive. Now, however, with overall survival (OS) in the range of 7 years, even without novel agents, and the lack of a plateau in survival, it is reasonable to consider MCL as a low-grade lymphoma. Accepting this concept removes the sense of urgency to begin aggressive therapy that often accompanies this diagnosis. It also affects interpretation of appropriate clinical trial end points. Although curative therapy is our ultimate goal, at present the goal of therapy, including high-dose chemotherapy with autologous hematopoietic stem-cell transplantation (HDC/aHCT), is prolongation of OS. In the absence of data indicating that this is achievable, studies often use progressionfree survival (PFS) as a surrogate end point that is not yet validated as a predictor of long-term outcome. Selecting optimal treatment approaches for MCL is often as much art as science, and there is no single correct approach. An evolving general approach is to offer intensive regimens, now usually including HDC/aHCT, to young, fit patients, whereas older, less fit patients receive less intensive therapy, such as bendamustine-rituximab. However, an OS benefit for HDC/aHCT has not been convincingly demonstrated, and novel agents such as the BTK inhibitor ibrutinib are changing the field. The large Center for International Blood and Marrow Transplant Research (CIBMTR) database of treatment outcomes for HCT in MCL, reported in the article by Fenske et al2 that accompanies this editorial, provides important historical data that support the use of HDC/aHCT and reduced-intensity conditioning allogeneic stem-cell transplantation (RIC-alloHCT) in the subset of patients with chemotherapy-sensitive MCL, and provides lessons regarding the role and timing of autologous and RIC-alloHCT. Analysis of this large cohort with mature follow-up confirms good outcomes for chemotherapysensitive patients undergoing HCT early in their course and the expected balance of better disease control, possibly curative, but with higher toxicity, for RIC-alloSCT. Patients in this database were selected as having chemotherapy-sensitive disease and proceeding to HCT. Because the data cutoff was 2007, definition of complete remission (CR) likely varied with time and may not have been uniform, and most patients were treated before newer effective agents were available. Few patients received rituximab after HCT. Use of multivariable analysis from time of diagnosis as a better outcome indicator than the commonly reported time from HCT is helpful and should be adopted in other settings. Although it is common, as in the study by Fenske at Journal of Clinical Oncology, Vol 32, No 4 (February 1), 2014: pp 265-267
al,2 to analyze autologous and allogeneic HCT outcomes together, it is important to bear in mind the quite different theoretical mechanisms of benefit for these two procedures which, although obvious, are often obscured by our semantics of referring to both as transplantation. HDC/aHCT supports higher doses of myelosuppressive chemotherapy, and has not been curative in MCL or other indolent lymphomas; RIC-alloHCT is an immunologic attack that may be curative, but at a cost of significant short- and long-term toxicities. Lack of demonstrable benefit in OS for RIC-alloHCT is an important finding. I agree with the placement of RIC-alloHCT in the authors’ algorithm and will not discuss RIC-alloHCT further. Once we accept that HDC/aHCT is not curative in MCL and that OS is improving with other therapies, it is worth stepping back to consider the goals of therapy in MCL. Fenske et al2 conclude that so-called early HCT provides excellent outcomes and improves OS compared with so-called late HCT; however, the latter finding may reflect a biologic selection, and the outcomes may in fact be similar to non-HCT approaches. In prognostically favorable groups, such as MCL with a low MCL International Prognostic Index (MIPI) score3 or low proliferative rates by gene expression4 or Ki67,5 OS is already quite long. Patient selection of a younger population with low MIPI scores for HDC/aHCT may make results seem favorable. The important question of whether intensive therapies overcome poor prognostic features, which would support the authors’ algorithm recommending that all patients in first or second complete remission (CR1 or CR2) undergo HCT, remains unknown. In fact, analysis of patients with high MIPI scores in two studies showed poor outcomes despite HDC/aHCT.6,7 The National Comprehensive Cancer Network data showed similar outcomes with intensive therapy with or without HCT.8 The Nordic Lymphoma Group demonstrated marked improvement with inclusion of rituximab and high-dose cytarabine; HCT was already included in their historical control data.7 The only randomized comparison of HDC/aHCT and non-HCT consolidation with interferon failed to show a survival benefit, and antedated use of rituximab and high-dose cytarabine.9 In the CIBMTR data, OS is not much longer than PFS, raising concern about efficacy of subsequent therapy after HDC/aHCT. Treatment strategies using non-HDC/ aHCT consolidation or maintenance can provide comparable OS; for example, in unselected patients, the estimated 5-year OS rate is 73% with radioimmunotherapy,10 the 3-year OS rate is 91% with rituximab,11 and in patients older than age 60 years who respond to rituximab plus cyclophosphamide, doxorubicin, vincristine, and © 2013 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
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prednisone, the median OS is 67 months.12 In other indolent B-cell lymphomas for which HDC/aHCT is not curative, it is not generally used in CR1 but is reserved for those patients with more aggressive clinical behavior documented by early relapse. The CIBMTR data suggest benefit of HDC/aHCT later in the disease course if patients remain chemotherapy sensitive. Although this differs from current practice in many centers, it provides support for a potential study testing HDC/aHCT consolidation in CR1 versus CR2. Thus, although having all responding patients undergo early HDC/aHCT has become generally accepted, whether this strategy is optimal remains uncertain, especially as new active agents become available. Too often we assess HDC/aHCT results as an isolated procedure, and this is a necessary limitation of registry studies. We know that dose-intense and dose-dense approaches can affect overall treatment efficacy, but we do not always incorporate that into treatment strategies. The importance of considering HDC/aHCT as part of a comprehensive strategy is illustrated by observations that outcomes are influenced by inclusion of high-dose cytarabine induction regimens7,13 and use of rituximab pre- or peri-HCT,9,14,15 and that patients in molecular remission at the time of HDC/aHCT have better outcomes.7,13,16 Mathematical models of cell killing (eg, NortonSimon hypothesis17) predict that applying HDC/aHCT at a time of minimal residual disease is important, so timing of HDC/aHCT relative to the last treatment, rituximab purging, and whether induction and pre-HCT conditioning regimens are non– cross resistant may all factor into efficacy outcomes for HDC/aHCT. These provide the potential to improve outcomes of regimens that include HDC/aHCT without altering the basic procedure. Other ways to improve HDC/ aHCT outcomes may include better definition of patients who will benefit, perhaps on the basis of pretreatment risk stratification, but also response-adapted approaches that might include achieving CR before HDC/aHCT. CR was a marker of improved outcome in the CIBMTR data,2 even with the caveat that CR was not uniformly defined. Strict definition of CR, such as by positron emission tomography scanning or molecular monitoring of minimal residual disease, needs further exploration, but molecular monitoring to define CR before HDC/aHCT and to allow early intervention after HDC/aHCT does seem useful.7 I foresee use of HDC/aHCT in MCL more closely following its use in myeloma, where, with only modestly active chemotherapy and a median survival of 3 to 5 years, prolongation of PFS by HDC/aHCT was deemed to be a favorable outcome and HDC/aHCT became standard consolidation treatment in first remission. Over the last decade, the advent of effective, well-tolerated, biologically targeted novel agents in myeloma in induction and maintenance treatment has markedly improved outcomes and brought the benefit of HDC/aHCT into question, with appropriate clinical trials underway. We can see novel agents in MCL changing treatment paradigms in a similar fashion. Rituximab maintenance markedly prolonged PFS in patients with MCL responding to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.12 Novel classes of agents with activity in heavily pretreated patients with relapsed MCL include the proteasome inhibitor bortezomib, the immune modulator lenalidomide, and the mammalian target of rapamycin inhibitor temsirolimus, each having modest single-agent activity but with higher response rates when combined with rituximab.18,19 More exciting are agents that target B-cell receptor signal pathways, in particular B-cell receptor signaling through BTK. The BTK inhibitor ibrutinib yields response rates of 266
© 2013 by American Society of Clinical Oncology
approximately 70%,20 which appear durable in some patients, although more data and longer follow-up, in particular to determine what happens when MCL becomes resistant to BTK inhibition, are needed. Improved efficacy and/or decreased toxicity may come from later generations of agents in these classes, alternative targets in these pathways such as SYK inhibition,21 or targeting related pathways such as phosphatidylinositol 3-kinase. Additional pathways also hold promise. CDK inhibition as a means to attack the pathognomonic cyclin D1 abnormality in MCL has been demonstrated in a proof-ofconcept study with biologic end points.22 Normal as well as malignant mantle cells express BCL2, and BH3 mimetics that overcome this block to apoptosis are active in MCL. Our goal in the next decade will be to optimize the integration of ibrutinib, and soon other agents, into our treatment protocols. Given the number of potential pathways, exponential possible combinations, and potential applications in induction, consolidation, or maintenance therapy, along with the barriers to clinical trial accrual, achieving this goal will be a challenge. We need to accept that we want answers to broad questions, such as whether each class of active drugs is most useful in induction or consolidation/maintenance therapy, rather than which drug in that class might provide a small advantage, and which combinations of pathway inhibition are synergistic. This will require cooperation and careful planning to best use our resources. US Intergroup development of national trials suggests that we can succeed in this endeavor. Meanwhile, given gaps in our knowledge, recommending HDC/aHCT for patients whose MCL is responding to treatment is neither right nor wrong, but if done should be part of an overall strategy, preferably within a clinical trial. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Mitchell R. Smith, Cephalon (Teva) (C), Celgene (C) Stock Ownership: None Honoraria: Mitchell R. Smith, Spectrum, Roche/Genentech Research Funding: None Expert Testimony: None Patents: None Other Remuneration: None REFERENCES 1. Raffeld M, Jaffe ES: Bcl-1, t(11;14), and mantle cell-derived lymphomas. Blood 78:259-263, 1991 2. Fenske TS, Zhang M-J, Carreras J, et al: Autologous or reduced-intensity conditioning for allogeneic hematopoietic cell transplantation for chemotherapysensitive mantle-cell lymphoma: Analysis of transplantation timing and modality. J Clin Oncol 32:273-281, 2014 3. Hoster E, Dreyling M, Klapper W, et al: A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood 111:558-565, 2008 4. Rosenwald A, Wright G, Wiestner A, et al: The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell 3:185-197, 2003 5. Determann O, Hoster E, Ott G, et al: Ki-67 predicts outcome in advancedstage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: Results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group. Blood 111:2385-2387, 2008 6. Budde LE, Guthrie KA, Till BG, et al: Mantle cell lymphoma international prognostic index but not pretransplantation induction regimen predicts survival for patients with mantle-cell lymphoma receiving high-dose therapy and autologous stem-cell transplantation. J Clin Oncol 29:3023-3029, 2011 JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Editorial
7. Geisler CH, Kolstad A, Laurell A, et al: Nordic MCL2 trial update: Six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC ⫹ autologous stem-cell support: Still very long survival but late relapses do occur. Br J Haematol 158:355-362, 2012 8. LaCasce AS, Vandergrift JL, Rodriguez MA, et al: Comparative outcome of initial therapy for younger patients with mantle cell lymphoma: An analysis from the NCCN NHL Database. Blood 119:2093-2099, 2012 9. Dreyling M, Lenz G, Hoster E, et al: Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: Results of a prospective randomized trial of the European MCL Network. Blood 105:2677-2684, 2005 10. Smith MR, Li H, Gordon L, et al: Phase II study of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy followed by yttrium-90-ibritumomab tiuxetan in untreated mantle-cell lymphoma: Eastern Cooperative Oncology Group Study E1499. J Clin Oncol 30:3119-3126, 2012 11. Kahl BS, Li H, Smith MR, et al: Mature results from ECOG study E1405: A phase II study of VcR-CVAD with maintenance rituximab for previously untreated mantle cell lymphoma. 54th American Society of Hematology Annual Meeting and Exposition, Atlanta, GA, December 8-11, 2012 (abstr 153) 12. Kluin-Nelemans HC, Hoster E, Hermine O, et al: Treatment of older patients with mantle-cell lymphoma. N Engl J Med 367:520-531, 2012 13. Hermine O, Hoster E, Walewski J, et al: Alternating courses of 3⫻ CHOP and 3⫻ DHAP plus rituximab followed by a high dose ARA-C containing myeloablative regimen and autologous stem cell transplantation (ASCT) increases overall survival when compared to 6 courses of CHOP plus rituximab followed by myeloablative radiochemotherapy and ASCT in mantle cell lymphoma: Final analysis of the MCL Younger trial of the European Mantle Cell Lymphoma Network. 54th American Society of Hematology Annual Meeting and Exposition, Atlanta, GA, December 8-11, 2012 (abstr 151)
14. Tam CS, Bassett R, Ledesma C, et al: Mature results of the M. D. Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. Blood 113:4144-4152, 2009 15. Dietrich S, Tielesch B, Rieger M, et al: Patterns and outcome of relapse after autologous stem cell transplantation for mantle cell lymphoma. Cancer 117:1901-1910, 2011 16. Liu H, Johnson JL, Koval G, et al: Detection of minimal residual disease following induction immunochemotherapy predicts progression free survival in mantle cell lymphoma: Final results of CALGB 59909. Haematologica 97:579585, 2012 17. Norton L, Simon R: The Norton-Simon hypothesis revisited. Cancer Treat Rep 70:163-169, 1986 18. Ansell SM, Tang H, Kurtin PJ, et al: Temsirolimus and rituximab in patients with relapsed or refractory mantle cell lymphoma: A phase 2 study. Lancet Oncol 12:361-368, 2011 19. Wang M, Fayad L, Wagner-Bartak N, et al: Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: A phase 1/2 clinical trial. Lancet Oncol 13:716-723, 2012 20. Wang ML, Rule S, Martin P, et al: Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 369:507-516, 2013 21. Rinaldi A, Kwee I, Taborelli M, et al: Genomic and expression profiling identifies the B-cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma. Br J Haematol 132:303-316, 2006 22. Leonard JP, LaCasce AS, Smith MR, et al: Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 119:4597-4607, 2012
DOI: 10.1200/JCO.2013.53.2762; published online ahead of print at www.jco.org on December 16, 2013
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www.jco.org
© 2013 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
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Is Early Hematopoietic Stem-Cell Transplantation Necessary in Mantle-Cell Lymphoma? Mitchell R. Smith, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH See accompanying article on page 273
The unifying concept defining mantle-cell lymphoma (MCL) as a t(11;14)-containing lymphoma driven by cyclin D1 dates to the early 1990s.1 With median survival of 3 to 5 years, MCL was then considered aggressive. Now, however, with overall survival (OS) in the range of 7 years, even without novel agents, and the lack of a plateau in survival, it is reasonable to consider MCL as a low-grade lymphoma. Accepting this concept removes the sense of urgency to begin aggressive therapy that often accompanies this diagnosis. It also affects interpretation of appropriate clinical trial end points. Although curative therapy is our ultimate goal, at present the goal of therapy, including high-dose chemotherapy with autologous hematopoietic stem-cell transplantation (HDC/aHCT), is prolongation of OS. In the absence of data indicating that this is achievable, studies often use progressionfree survival (PFS) as a surrogate end point that is not yet validated as a predictor of long-term outcome. Selecting optimal treatment approaches for MCL is often as much art as science, and there is no single correct approach. An evolving general approach is to offer intensive regimens, now usually including HDC/aHCT, to young, fit patients, whereas older, less fit patients receive less intensive therapy, such as bendamustine-rituximab. However, an OS benefit for HDC/aHCT has not been convincingly demonstrated, and novel agents such as the BTK inhibitor ibrutinib are changing the field. The large Center for International Blood and Marrow Transplant Research (CIBMTR) database of treatment outcomes for HCT in MCL, reported in the article by Fenske et al2 that accompanies this editorial, provides important historical data that support the use of HDC/aHCT and reduced-intensity conditioning allogeneic stem-cell transplantation (RIC-alloHCT) in the subset of patients with chemotherapy-sensitive MCL, and provides lessons regarding the role and timing of autologous and RIC-alloHCT. Analysis of this large cohort with mature follow-up confirms good outcomes for chemotherapysensitive patients undergoing HCT early in their course and the expected balance of better disease control, possibly curative, but with higher toxicity, for RIC-alloSCT. Patients in this database were selected as having chemotherapy-sensitive disease and proceeding to HCT. Because the data cutoff was 2007, definition of complete remission (CR) likely varied with time and may not have been uniform, and most patients were treated before newer effective agents were available. Few patients received rituximab after HCT. Use of multivariable analysis from time of diagnosis as a better outcome indicator than the commonly reported time from HCT is helpful and should be adopted in other settings. Although it is common, as in the study by Fenske at Journal of Clinical Oncology, Vol 32, No 4 (February 1), 2014: pp 265-267
al,2 to analyze autologous and allogeneic HCT outcomes together, it is important to bear in mind the quite different theoretical mechanisms of benefit for these two procedures which, although obvious, are often obscured by our semantics of referring to both as transplantation. HDC/aHCT supports higher doses of myelosuppressive chemotherapy, and has not been curative in MCL or other indolent lymphomas; RIC-alloHCT is an immunologic attack that may be curative, but at a cost of significant short- and long-term toxicities. Lack of demonstrable benefit in OS for RIC-alloHCT is an important finding. I agree with the placement of RIC-alloHCT in the authors’ algorithm and will not discuss RIC-alloHCT further. Once we accept that HDC/aHCT is not curative in MCL and that OS is improving with other therapies, it is worth stepping back to consider the goals of therapy in MCL. Fenske et al2 conclude that so-called early HCT provides excellent outcomes and improves OS compared with so-called late HCT; however, the latter finding may reflect a biologic selection, and the outcomes may in fact be similar to non-HCT approaches. In prognostically favorable groups, such as MCL with a low MCL International Prognostic Index (MIPI) score3 or low proliferative rates by gene expression4 or Ki67,5 OS is already quite long. Patient selection of a younger population with low MIPI scores for HDC/aHCT may make results seem favorable. The important question of whether intensive therapies overcome poor prognostic features, which would support the authors’ algorithm recommending that all patients in first or second complete remission (CR1 or CR2) undergo HCT, remains unknown. In fact, analysis of patients with high MIPI scores in two studies showed poor outcomes despite HDC/aHCT.6,7 The National Comprehensive Cancer Network data showed similar outcomes with intensive therapy with or without HCT.8 The Nordic Lymphoma Group demonstrated marked improvement with inclusion of rituximab and high-dose cytarabine; HCT was already included in their historical control data.7 The only randomized comparison of HDC/aHCT and non-HCT consolidation with interferon failed to show a survival benefit, and antedated use of rituximab and high-dose cytarabine.9 In the CIBMTR data, OS is not much longer than PFS, raising concern about efficacy of subsequent therapy after HDC/aHCT. Treatment strategies using non-HDC/ aHCT consolidation or maintenance can provide comparable OS; for example, in unselected patients, the estimated 5-year OS rate is 73% with radioimmunotherapy,10 the 3-year OS rate is 91% with rituximab,11 and in patients older than age 60 years who respond to rituximab plus cyclophosphamide, doxorubicin, vincristine, and © 2013 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
265
Editorial
prednisone, the median OS is 67 months.12 In other indolent B-cell lymphomas for which HDC/aHCT is not curative, it is not generally used in CR1 but is reserved for those patients with more aggressive clinical behavior documented by early relapse. The CIBMTR data suggest benefit of HDC/aHCT later in the disease course if patients remain chemotherapy sensitive. Although this differs from current practice in many centers, it provides support for a potential study testing HDC/aHCT consolidation in CR1 versus CR2. Thus, although having all responding patients undergo early HDC/aHCT has become generally accepted, whether this strategy is optimal remains uncertain, especially as new active agents become available. Too often we assess HDC/aHCT results as an isolated procedure, and this is a necessary limitation of registry studies. We know that dose-intense and dose-dense approaches can affect overall treatment efficacy, but we do not always incorporate that into treatment strategies. The importance of considering HDC/aHCT as part of a comprehensive strategy is illustrated by observations that outcomes are influenced by inclusion of high-dose cytarabine induction regimens7,13 and use of rituximab pre- or peri-HCT,9,14,15 and that patients in molecular remission at the time of HDC/aHCT have better outcomes.7,13,16 Mathematical models of cell killing (eg, NortonSimon hypothesis17) predict that applying HDC/aHCT at a time of minimal residual disease is important, so timing of HDC/aHCT relative to the last treatment, rituximab purging, and whether induction and pre-HCT conditioning regimens are non– cross resistant may all factor into efficacy outcomes for HDC/aHCT. These provide the potential to improve outcomes of regimens that include HDC/aHCT without altering the basic procedure. Other ways to improve HDC/ aHCT outcomes may include better definition of patients who will benefit, perhaps on the basis of pretreatment risk stratification, but also response-adapted approaches that might include achieving CR before HDC/aHCT. CR was a marker of improved outcome in the CIBMTR data,2 even with the caveat that CR was not uniformly defined. Strict definition of CR, such as by positron emission tomography scanning or molecular monitoring of minimal residual disease, needs further exploration, but molecular monitoring to define CR before HDC/aHCT and to allow early intervention after HDC/aHCT does seem useful.7 I foresee use of HDC/aHCT in MCL more closely following its use in myeloma, where, with only modestly active chemotherapy and a median survival of 3 to 5 years, prolongation of PFS by HDC/aHCT was deemed to be a favorable outcome and HDC/aHCT became standard consolidation treatment in first remission. Over the last decade, the advent of effective, well-tolerated, biologically targeted novel agents in myeloma in induction and maintenance treatment has markedly improved outcomes and brought the benefit of HDC/aHCT into question, with appropriate clinical trials underway. We can see novel agents in MCL changing treatment paradigms in a similar fashion. Rituximab maintenance markedly prolonged PFS in patients with MCL responding to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.12 Novel classes of agents with activity in heavily pretreated patients with relapsed MCL include the proteasome inhibitor bortezomib, the immune modulator lenalidomide, and the mammalian target of rapamycin inhibitor temsirolimus, each having modest single-agent activity but with higher response rates when combined with rituximab.18,19 More exciting are agents that target B-cell receptor signal pathways, in particular B-cell receptor signaling through BTK. The BTK inhibitor ibrutinib yields response rates of 266
© 2013 by American Society of Clinical Oncology
approximately 70%,20 which appear durable in some patients, although more data and longer follow-up, in particular to determine what happens when MCL becomes resistant to BTK inhibition, are needed. Improved efficacy and/or decreased toxicity may come from later generations of agents in these classes, alternative targets in these pathways such as SYK inhibition,21 or targeting related pathways such as phosphatidylinositol 3-kinase. Additional pathways also hold promise. CDK inhibition as a means to attack the pathognomonic cyclin D1 abnormality in MCL has been demonstrated in a proof-ofconcept study with biologic end points.22 Normal as well as malignant mantle cells express BCL2, and BH3 mimetics that overcome this block to apoptosis are active in MCL. Our goal in the next decade will be to optimize the integration of ibrutinib, and soon other agents, into our treatment protocols. Given the number of potential pathways, exponential possible combinations, and potential applications in induction, consolidation, or maintenance therapy, along with the barriers to clinical trial accrual, achieving this goal will be a challenge. We need to accept that we want answers to broad questions, such as whether each class of active drugs is most useful in induction or consolidation/maintenance therapy, rather than which drug in that class might provide a small advantage, and which combinations of pathway inhibition are synergistic. This will require cooperation and careful planning to best use our resources. US Intergroup development of national trials suggests that we can succeed in this endeavor. Meanwhile, given gaps in our knowledge, recommending HDC/aHCT for patients whose MCL is responding to treatment is neither right nor wrong, but if done should be part of an overall strategy, preferably within a clinical trial. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Mitchell R. Smith, Cephalon (Teva) (C), Celgene (C) Stock Ownership: None Honoraria: Mitchell R. Smith, Spectrum, Roche/Genentech Research Funding: None Expert Testimony: None Patents: None Other Remuneration: None REFERENCES 1. Raffeld M, Jaffe ES: Bcl-1, t(11;14), and mantle cell-derived lymphomas. Blood 78:259-263, 1991 2. Fenske TS, Zhang M-J, Carreras J, et al: Autologous or reduced-intensity conditioning for allogeneic hematopoietic cell transplantation for chemotherapysensitive mantle-cell lymphoma: Analysis of transplantation timing and modality. J Clin Oncol 32:273-281, 2014 3. Hoster E, Dreyling M, Klapper W, et al: A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood 111:558-565, 2008 4. Rosenwald A, Wright G, Wiestner A, et al: The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell 3:185-197, 2003 5. Determann O, Hoster E, Ott G, et al: Ki-67 predicts outcome in advancedstage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: Results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group. Blood 111:2385-2387, 2008 6. Budde LE, Guthrie KA, Till BG, et al: Mantle cell lymphoma international prognostic index but not pretransplantation induction regimen predicts survival for patients with mantle-cell lymphoma receiving high-dose therapy and autologous stem-cell transplantation. J Clin Oncol 29:3023-3029, 2011 JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Editorial
7. Geisler CH, Kolstad A, Laurell A, et al: Nordic MCL2 trial update: Six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC ⫹ autologous stem-cell support: Still very long survival but late relapses do occur. Br J Haematol 158:355-362, 2012 8. LaCasce AS, Vandergrift JL, Rodriguez MA, et al: Comparative outcome of initial therapy for younger patients with mantle cell lymphoma: An analysis from the NCCN NHL Database. Blood 119:2093-2099, 2012 9. Dreyling M, Lenz G, Hoster E, et al: Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: Results of a prospective randomized trial of the European MCL Network. Blood 105:2677-2684, 2005 10. Smith MR, Li H, Gordon L, et al: Phase II study of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy followed by yttrium-90-ibritumomab tiuxetan in untreated mantle-cell lymphoma: Eastern Cooperative Oncology Group Study E1499. J Clin Oncol 30:3119-3126, 2012 11. Kahl BS, Li H, Smith MR, et al: Mature results from ECOG study E1405: A phase II study of VcR-CVAD with maintenance rituximab for previously untreated mantle cell lymphoma. 54th American Society of Hematology Annual Meeting and Exposition, Atlanta, GA, December 8-11, 2012 (abstr 153) 12. Kluin-Nelemans HC, Hoster E, Hermine O, et al: Treatment of older patients with mantle-cell lymphoma. N Engl J Med 367:520-531, 2012 13. Hermine O, Hoster E, Walewski J, et al: Alternating courses of 3⫻ CHOP and 3⫻ DHAP plus rituximab followed by a high dose ARA-C containing myeloablative regimen and autologous stem cell transplantation (ASCT) increases overall survival when compared to 6 courses of CHOP plus rituximab followed by myeloablative radiochemotherapy and ASCT in mantle cell lymphoma: Final analysis of the MCL Younger trial of the European Mantle Cell Lymphoma Network. 54th American Society of Hematology Annual Meeting and Exposition, Atlanta, GA, December 8-11, 2012 (abstr 151)
14. Tam CS, Bassett R, Ledesma C, et al: Mature results of the M. D. Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. Blood 113:4144-4152, 2009 15. Dietrich S, Tielesch B, Rieger M, et al: Patterns and outcome of relapse after autologous stem cell transplantation for mantle cell lymphoma. Cancer 117:1901-1910, 2011 16. Liu H, Johnson JL, Koval G, et al: Detection of minimal residual disease following induction immunochemotherapy predicts progression free survival in mantle cell lymphoma: Final results of CALGB 59909. Haematologica 97:579585, 2012 17. Norton L, Simon R: The Norton-Simon hypothesis revisited. Cancer Treat Rep 70:163-169, 1986 18. Ansell SM, Tang H, Kurtin PJ, et al: Temsirolimus and rituximab in patients with relapsed or refractory mantle cell lymphoma: A phase 2 study. Lancet Oncol 12:361-368, 2011 19. Wang M, Fayad L, Wagner-Bartak N, et al: Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: A phase 1/2 clinical trial. Lancet Oncol 13:716-723, 2012 20. Wang ML, Rule S, Martin P, et al: Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 369:507-516, 2013 21. Rinaldi A, Kwee I, Taborelli M, et al: Genomic and expression profiling identifies the B-cell associated tyrosine kinase Syk as a possible therapeutic target in mantle cell lymphoma. Br J Haematol 132:303-316, 2006 22. Leonard JP, LaCasce AS, Smith MR, et al: Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 119:4597-4607, 2012
DOI: 10.1200/JCO.2013.53.2762; published online ahead of print at www.jco.org on December 16, 2013
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