Biol Blood Marrow Transplant xxx (2014) 1e2
1 2 3 American Society for Blood 4 and Marrow Transplantation 5 6 7 Q 7 Mitchell R. Smith* 8 Lymphoid Malignancies Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 9 10 11 overcome different biologic underpinnings of lymphoma; Article history: 12 Received 7 May 2014 that is, does alloHCT overcome “bad biology?” 13 Accepted 9 May 2014 Relative benefits of alloHCT are affected by advances in 14 nontransplantation therapies. Significant advances with B cell 15 signaling inhibitors, proapoptotic agents, and new antibody McClune et al. [1] utilize the Center for International Blood 16 therapeutics provide new non-HCT options. The BTK inhibitor and Marrow Transplant Research (CIBMTR) database to assess 17 ibrutinib is now FDA approved for previously treated chronic outcomes of 1248 patients 40 years of age or older who 18 lymphocytic leukemia [4] and mantle cell lymphoma [5], and Q 4 received reduced-intensity conditioning or nonmyeloablative 19 it is active in other indolent and some aggressive lymphomas. allogeneic hematopoietic transplantation (alloHCT) for non20 The PI3-kinase delta inhibitor idelalisib and the proapoptotic Hodgkin lymphoma between 2001 and 2007. Their analysis 21 BCL2 inhibitor ABT-199 are likely to be approved soon. Novel focuses on age and whether this treatment option is 22 antibodies and antibody-drug conjugates are active [6]. We underutilized in older patients. This large data set is impor23 also must be careful when comparing outcomes for the tant, as it contains much information on "real world" out24 selected patients who undergo alloHCT with the larger popcomes that will assist physicians and patients balance the 25 ulation of relapsed patients included in studies of these new risks and benefits as they confront the difficult decision about 26 agents. whether to proceed with alloHCT. 27 Pretransplantation evaluation is, in part, an attempt to Football coach Woody Hayes (or perhaps it was Darrell 28 identify pre-existing functional status to limit the percentage Royal, but that is another discussion) said years ago that 3 29 of patients for whom the procedure will be excessively toxic. things can happen when you pass a football, 2 of them bad. 30 Systematic assessment and quantification of comorbidities Nevertheless, the forward pass has still become an increas31 are useful, and we look forward to more extensive reporting of ingly important part of football, though we should not forget 32 the HCT-comorbidity index (HCT-CI) incorporated into the about the running game. Similarly, 3 things can also occur 33 CIBMTR database [7], as well as further refinements in the after alloHCT, 2 of them bad, ie, death (with or without 34 ability to predict nonrelapse mortality [8]. Comparison of relapse) or significant graft-versus-host disease. The “carrot” 35 populations undergoing HCT or not, adjusted by HCT-CI or balancing those risks is the possibility of prolonged unmain36 other comorbidity assessment, would be informative and tained remission. This report by McClune et al. [1] supplies 37 help address the recurring issue of selection bias inherent in data based on common clinical characteristics, including age, 38 the transplantation population. to help inform the discussion. The discussion is, of course, 39 Balancing potential benefit and risks, what can we now tell affected by the expected outcomes for non-HCT options, 40 the patient who is over age 55 with relapsed lymphoma when which vary significantly by lymphoma subtype and disease 41 we discuss these issues? Once we decide that the patient is a status, and are also rapidly changing with new targeted agents 42 suitable candidate for alloHCT, although we can quibble about available and in development; our “running game” is 43 the precise numbers, there are roughly equal chances for cure, improving as well. 44 disease relapse, or nonrelapse mortality (27% at 1 year for age As noted by McClune et al. [1], we need better measures of 45 55 to 64 and 34% age 65, more than one half of these by day who will benefit as well as who will be harmed with alloHCT. 46 100 [1]). For the patient with relapsed aggressive lymphoma In considering benefit, it is somewhat surprising that histo47 after autologous stem cell transplantation (autoSCT), for logic subtype did not affect outcomes, somewhat at odds with 48 whom non-HCT options are limited and not curative, the another CIBMTR report [2]. One concern interpreting the data 49 potential for cure is indeed encouraging and should not be by subtype is the inclusion of mantle cell lymphoma with the 50 limited merely by age, at least up to age 75, based on these aggressive subtypes, in particular as mantle cell accounted for 51 data. Lack of effective nonestem cell transplantation options 42% of this group, as this type of lymphoma has different 52 likely explains why older patients in this cohort predomibiology and clinical behavior. As we further subdivide lym53 nantly had aggressive disease. Not having clear answers of phomas on the basis of mutational landscape and biologic 54 who will benefit, we generally adopt a shared decision55 Q 1 drivers [3], eg, diffuse large B cell lymphoma of germinal making process, involving physicians, patients, and patient center or nonegerminal center origin, or having MYC BCL2 56 families. An interesting attempt to gain expert physician translocations, it will be important to determine whether 57 guidance on the role of alloHCT in follicular lymphoma [9] graft-versus-leukemia effects and alloHCT outcomes 58 Q 3 identified some areas of consensus, others of disagreement. 59 Relatively unexplored is decision-making from the patient Financial disclosure: See Acknowledgments on page 2. 60 perspective, although there are some studies in the pediatric * Correspondence and reprint requests: Mitchell R. Smith, MD, PhD, Di61 rector of Lymphoid Malignancies Program, Taussig Cancer Institute, Clevepopulation [10]. My anecdotal observations are that oncolo62 land Clinic, 9500 Euclid Avenue, Cleveland, OH 44195. gists often focus on potential benefits, whereas patients often 63 E-mail address: [email protected].
Allogeneic Transplantation for Lymphoma: Risk-Benefit Balance Is in the Eye of the Beholder
1083-8791/$ e see front matter Ó 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2014.05.007
DIS 5.2.0 DTD YBBMT53461_proof 15 May 2014 3:49 am ce
ASBMT
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M.R. Smith / Biol Blood Marrow Transplant xxx (2014) 1e2
focus on risks of toxicity and especially mortality, particularly if they have had prior autoSCT. It would be worth learning more about decision-making from the patient standpoint to better assist in the process. This report by McClune et al. [1] continues the long history of CIBMTR contributions to the literature that help guide the wide range of the decisions involved in stem cell transplantation. Utility of these data in daily practice would be strengthened by streamlining the analytic process so that patients undergoing alloHCT more recently than 2007 are included, as well as comparing outcomes with those in the non-HCT populations adjusted for comorbidities, perhaps adapting the HCT-CI to the nonestem cell transplantation group or using comprehensive geriatric assessments. Meanwhile, recent advances in targeted therapies approved for indolent and mantle cell lymphoma are already altering the equation, and we anticipate similar advances for aggressive lymphomas. Although reasonable people may have different definitions of “encouraging,” these data do support the idea that age alone should not be a deciding factor in alloSCT. ACKNOWLEDGMENTS Conflict of interest statement: There are no conflicts of inQ 5 terest to report. Financial disclosure: ---. Q2
REFERENCES 1. McClune BL, Ahn KW, Wang HL, et al. Allotransplantation for those 40 years of age and greater with non-Hodgkin lymphoma. Biol Blood Marrow Transplant. 2014. Q6 2. Hale GA, Shresta S, Le-Rademacher J, et al. Alternate donor hematopoietic cell transplantation (HCT) in non-Hodgkin lymphoma using lower intensity conditioning: A report from the CIBMTR. Biol Blood Marrow Transplant. 2012;18:1036-1043. 3. Puvvada S, Kendrick S, Rimsza L. Molecular classification, pathway addiction, and therapeutic targeting in diffuse large B cell lymphoma. Cancer Genet. 2013;206:257-265. 4. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32-42. 5. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369: 507-516. 6. Fayad L, Offner F, Smith MR, et al. Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab. J Clin Oncol. 2013;31:573-583. 7. Sorror ML. How I assess comorbidities before hematopoietic cell transplantation. Blood. 2013;121:2854-2863. 8. Bolwell BJ. Are predictive factors clinically useful in bone marrow transplantation? Bone Marrow Transplant. 2003;32:853-861. 9. Montoto S, Corradini P, Dreyling M, et al. Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party. Haematologica. 2013;98:1014-1021. 10. Pentz RD, Pelletier W, Alderfer MA, et al. Shared decision-making in pediatric allogeneic blood and marrow transplantation: what if there is no decision to make? Oncologist. 2012;17:881-885.
DIS 5.2.0 DTD YBBMT53461_proof 15 May 2014 3:49 am ce
159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190
1 2 3 American Society for Blood 4 and Marrow Transplantation 5 6 7 Q 7 Mitchell R. Smith* 8 Lymphoid Malignancies Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 9 10 11 overcome different biologic underpinnings of lymphoma; Article history: 12 Received 7 May 2014 that is, does alloHCT overcome “bad biology?” 13 Accepted 9 May 2014 Relative benefits of alloHCT are affected by advances in 14 nontransplantation therapies. Significant advances with B cell 15 signaling inhibitors, proapoptotic agents, and new antibody McClune et al. [1] utilize the Center for International Blood 16 therapeutics provide new non-HCT options. The BTK inhibitor and Marrow Transplant Research (CIBMTR) database to assess 17 ibrutinib is now FDA approved for previously treated chronic outcomes of 1248 patients 40 years of age or older who 18 lymphocytic leukemia [4] and mantle cell lymphoma [5], and Q 4 received reduced-intensity conditioning or nonmyeloablative 19 it is active in other indolent and some aggressive lymphomas. allogeneic hematopoietic transplantation (alloHCT) for non20 The PI3-kinase delta inhibitor idelalisib and the proapoptotic Hodgkin lymphoma between 2001 and 2007. Their analysis 21 BCL2 inhibitor ABT-199 are likely to be approved soon. Novel focuses on age and whether this treatment option is 22 antibodies and antibody-drug conjugates are active [6]. We underutilized in older patients. This large data set is impor23 also must be careful when comparing outcomes for the tant, as it contains much information on "real world" out24 selected patients who undergo alloHCT with the larger popcomes that will assist physicians and patients balance the 25 ulation of relapsed patients included in studies of these new risks and benefits as they confront the difficult decision about 26 agents. whether to proceed with alloHCT. 27 Pretransplantation evaluation is, in part, an attempt to Football coach Woody Hayes (or perhaps it was Darrell 28 identify pre-existing functional status to limit the percentage Royal, but that is another discussion) said years ago that 3 29 of patients for whom the procedure will be excessively toxic. things can happen when you pass a football, 2 of them bad. 30 Systematic assessment and quantification of comorbidities Nevertheless, the forward pass has still become an increas31 are useful, and we look forward to more extensive reporting of ingly important part of football, though we should not forget 32 the HCT-comorbidity index (HCT-CI) incorporated into the about the running game. Similarly, 3 things can also occur 33 CIBMTR database [7], as well as further refinements in the after alloHCT, 2 of them bad, ie, death (with or without 34 ability to predict nonrelapse mortality [8]. Comparison of relapse) or significant graft-versus-host disease. The “carrot” 35 populations undergoing HCT or not, adjusted by HCT-CI or balancing those risks is the possibility of prolonged unmain36 other comorbidity assessment, would be informative and tained remission. This report by McClune et al. [1] supplies 37 help address the recurring issue of selection bias inherent in data based on common clinical characteristics, including age, 38 the transplantation population. to help inform the discussion. The discussion is, of course, 39 Balancing potential benefit and risks, what can we now tell affected by the expected outcomes for non-HCT options, 40 the patient who is over age 55 with relapsed lymphoma when which vary significantly by lymphoma subtype and disease 41 we discuss these issues? Once we decide that the patient is a status, and are also rapidly changing with new targeted agents 42 suitable candidate for alloHCT, although we can quibble about available and in development; our “running game” is 43 the precise numbers, there are roughly equal chances for cure, improving as well. 44 disease relapse, or nonrelapse mortality (27% at 1 year for age As noted by McClune et al. [1], we need better measures of 45 55 to 64 and 34% age 65, more than one half of these by day who will benefit as well as who will be harmed with alloHCT. 46 100 [1]). For the patient with relapsed aggressive lymphoma In considering benefit, it is somewhat surprising that histo47 after autologous stem cell transplantation (autoSCT), for logic subtype did not affect outcomes, somewhat at odds with 48 whom non-HCT options are limited and not curative, the another CIBMTR report [2]. One concern interpreting the data 49 potential for cure is indeed encouraging and should not be by subtype is the inclusion of mantle cell lymphoma with the 50 limited merely by age, at least up to age 75, based on these aggressive subtypes, in particular as mantle cell accounted for 51 data. Lack of effective nonestem cell transplantation options 42% of this group, as this type of lymphoma has different 52 likely explains why older patients in this cohort predomibiology and clinical behavior. As we further subdivide lym53 nantly had aggressive disease. Not having clear answers of phomas on the basis of mutational landscape and biologic 54 who will benefit, we generally adopt a shared decision55 Q 1 drivers [3], eg, diffuse large B cell lymphoma of germinal making process, involving physicians, patients, and patient center or nonegerminal center origin, or having MYC BCL2 56 families. An interesting attempt to gain expert physician translocations, it will be important to determine whether 57 guidance on the role of alloHCT in follicular lymphoma [9] graft-versus-leukemia effects and alloHCT outcomes 58 Q 3 identified some areas of consensus, others of disagreement. 59 Relatively unexplored is decision-making from the patient Financial disclosure: See Acknowledgments on page 2. 60 perspective, although there are some studies in the pediatric * Correspondence and reprint requests: Mitchell R. Smith, MD, PhD, Di61 rector of Lymphoid Malignancies Program, Taussig Cancer Institute, Clevepopulation [10]. My anecdotal observations are that oncolo62 land Clinic, 9500 Euclid Avenue, Cleveland, OH 44195. gists often focus on potential benefits, whereas patients often 63 E-mail address: [email protected].
Allogeneic Transplantation for Lymphoma: Risk-Benefit Balance Is in the Eye of the Beholder
1083-8791/$ e see front matter Ó 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2014.05.007
DIS 5.2.0 DTD YBBMT53461_proof 15 May 2014 3:49 am ce
ASBMT
64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126
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M.R. Smith / Biol Blood Marrow Transplant xxx (2014) 1e2
focus on risks of toxicity and especially mortality, particularly if they have had prior autoSCT. It would be worth learning more about decision-making from the patient standpoint to better assist in the process. This report by McClune et al. [1] continues the long history of CIBMTR contributions to the literature that help guide the wide range of the decisions involved in stem cell transplantation. Utility of these data in daily practice would be strengthened by streamlining the analytic process so that patients undergoing alloHCT more recently than 2007 are included, as well as comparing outcomes with those in the non-HCT populations adjusted for comorbidities, perhaps adapting the HCT-CI to the nonestem cell transplantation group or using comprehensive geriatric assessments. Meanwhile, recent advances in targeted therapies approved for indolent and mantle cell lymphoma are already altering the equation, and we anticipate similar advances for aggressive lymphomas. Although reasonable people may have different definitions of “encouraging,” these data do support the idea that age alone should not be a deciding factor in alloSCT. ACKNOWLEDGMENTS Conflict of interest statement: There are no conflicts of inQ 5 terest to report. Financial disclosure: ---. Q2
REFERENCES 1. McClune BL, Ahn KW, Wang HL, et al. Allotransplantation for those 40 years of age and greater with non-Hodgkin lymphoma. Biol Blood Marrow Transplant. 2014. Q6 2. Hale GA, Shresta S, Le-Rademacher J, et al. Alternate donor hematopoietic cell transplantation (HCT) in non-Hodgkin lymphoma using lower intensity conditioning: A report from the CIBMTR. Biol Blood Marrow Transplant. 2012;18:1036-1043. 3. Puvvada S, Kendrick S, Rimsza L. Molecular classification, pathway addiction, and therapeutic targeting in diffuse large B cell lymphoma. Cancer Genet. 2013;206:257-265. 4. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32-42. 5. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369: 507-516. 6. Fayad L, Offner F, Smith MR, et al. Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab. J Clin Oncol. 2013;31:573-583. 7. Sorror ML. How I assess comorbidities before hematopoietic cell transplantation. Blood. 2013;121:2854-2863. 8. Bolwell BJ. Are predictive factors clinically useful in bone marrow transplantation? Bone Marrow Transplant. 2003;32:853-861. 9. Montoto S, Corradini P, Dreyling M, et al. Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party. Haematologica. 2013;98:1014-1021. 10. Pentz RD, Pelletier W, Alderfer MA, et al. Shared decision-making in pediatric allogeneic blood and marrow transplantation: what if there is no decision to make? Oncologist. 2012;17:881-885.
DIS 5.2.0 DTD YBBMT53461_proof 15 May 2014 3:49 am ce
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