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The role of hematopoietic cell transplantation in adult ALL: Clinical equipoise persists
Leukemia Research 38 (2014) 176–179
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
The role of hematopoietic cell transplantation in adult ALL: Clinical equipoise persists K. Paulson a,b,∗ , D. Szwajcer a,b , C.B. Raymond c , M.D. Seftel d a
Section of Haematology/Oncology, Department of Internal Medicine, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada CancerCare Manitoba, Winnipeg, MB, Canada Manitoba Centre for Health Policy, University of Manitoba, Winnipeg, MB, Canada d Division of Medical Oncology&Hematology, Department of Medicine, University of Toronto, Toronto, ON, Canada b c
a r t i c l e
i n f o
Article history: Received 31 July 2013 Received in revised form 21 October 2013 Accepted 23 October 2013 Available online 1 November 2013 Keywords: Acute lymphoblastic leukemia Hematopoietic stem cell transplant Evidence based medicine
a b s t r a c t Adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) may be treated either with ongoing systemic chemotherapy or with allogeneic hematopoietic cell transplantation (alloHCT). Despite the presence of phase III trials to support clinical decision-making, we hypothesized that physicians who treat adult ALL would demonstrate wide practice variation. Canadian hematologists who treat ALL were surveyed electronically. Overall, 69 of 173 physicians responded (40%). There was high agreement with offering alloHCT for ALL with high-risk cytogenetics or induction failure after a single chemotherapy cycle. However, only a minority of respondents felt that age >35 years was an indication for alloHCT in CR1. Almost all respondents (96%) felt that a well-matched unrelated donor was an acceptable alternative to a sibling donor. There was uncertainty about the role of cord blood (53% agree) and the utility of reduced intensity conditioning HCT (41% agree). In contrast to the results of the MRC/ECOG study, respondents considered alloHCT to be particularly helpful in high-risk patients. Consensus was lacking on the use of cord blood, RIC alloHCT, and the application of MRD. Equipoise exists on the role of alloHCT in CR1 in ALL, suggesting that further trials in this area are required. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction The practice of evidence-based medicine faces many challenges in hematopoietic cell transplantation (HCT). Prospective randomized trials are rare, and lesser levels of evidence such as cohort studies and case series often guide clinical decision-making. In addition, HCT is a rapidly evolving field, and new techniques are often adopted into clinical practice before the availability of published clinical trials. The aim of this study was to understand how HCT clinicians integrate the available evidence to make practical decisions in the management of acute lymphoblastic leukemia (ALL). We chose ALL as a sentinel disease to study for several reasons. One large prospective trial was published in 2008, which produced results that challenged conventional clinical practice and prompted the publication of meta-analyses [1,2]. In addition, the use of new strategies such as reduced intensity conditioning (RIC) HCT, cord blood transplantation, and measurement of minimal residual disease (MRD) have been adopted without the availability
∗ Corresponding author at: ON2050, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, MB, Canada. Tel.: +1 204 771 7238; fax: +1 204 786 0196. E-mail addresses: [email protected], [email protected] (K. Paulson). 0145-2126/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2013.10.021
of high grade evidence to support their use. We sought to understand how clinicians practiced evidence-informed decision making in ALL, integrating the results of one large clinical trial into clinical practice. The optimal management of acute lymphoblastic leukemia (ALL) in adults requires initial remission induction chemotherapy accompanied by careful patient selection for allogeneic hematopoietic cell transplantation (AlloHCT). However, pediatriclike chemotherapy protocols are being adopted, with the hope that they might improve the complete response rate and overall survival and, for some patients, avoid the need for alloHCT in CR1 [3,4]. In addition, the field of HCT has been revolutionized over the last two decades, with widespread use of unrelated donors, the advent of RIC HCT, and dramatic reductions in treatment related mortality [5]. The pivotal MRC/ECOG study found a dramatically lower relapse rate among patients assigned to receive allogeneic HCT as compared to maintenance chemotherapy [1]. However, the lower relapse rate in allogeneic HCT was balanced by increased therapyrelated toxicity. In subgroup analysis, the benefit with HCT was isolated to standard risk patients, but not in high risk ones. This observation is contrary to clinical practice in most other hematologic malignancies, in which benefits with HCT are primarily seen in high-risk patients [6]. Survival after first relapse of ALL remains
K. Paulson et al. / Leukemia Research 38 (2014) 176–179
177
Table 1 Clinical characteristics identified by survey respondents for which alloHCT would be offered. The questions referred to a patient with Philadelphia chromosome negative ALL in CR1.
MRD+ at day 28 >1 induction cycle to achieve CR1 Older age (>35) T-cell phenotype B-cell phenotype High WBC (>30 for B-cell, >100 for T-cell) CNS disease at diagnosis High risk cytogenetics
Agree
%
Neutral
%
Disagree
%
Responses
35 47 27 10 15 41 28 48
66.0 87.0 50.0 18.9 27.8 75.9 52.8 88.9
13 6 12 18 21 8 13 3
24.5 11.1 22.2 34.0 38.9 14.8 24.5 5.6
5 1 15 25 18 5 12 3
9.4 1.9 27.8 47.2 33.3 9.3 22.6 5.6
53 54 54 53 54 54 53 54
AlloHCT, allogeneic hematopoietic cell transplantation; MRD, minimal residual disease; CR1, first complete remission; WBC, white blood count; CNS, central nervous system.
Table 2 Donor options in patients who are candidates for AlloHCT, but lack an HLA matched sibling.
Well-matched unrelated donor (10/10 or 8/8) Partially matched unrelated donor (≤1 mismatched allele) Mismatched unrelated donor (≥2 mismatched alleles) Suitably matched cord blood Haploidentical donor
Agree
%
Neutral
%
Do not agree
%
Responses
49 34 2 27 6
96.1 66.7 4.0 52.9 12.2
0 8 8 16 14
0 15.7 16.0 31.4 28.6
2 9 40 8 29
3.9 17.6 80.0 15.7 59.2
51 51 50 51 49
AlloHCT, allogeneic hematopoietic cell transplantation.
dismal, with only 7% of patients in the MRC/ECOG trial surviving for 5 years after relapse. Thus, patient selection for allogeneic HCT remains one of the most important decisions facing clinicians who treat adults with ALL. Finally, recent studies have suggested that tyrosine kinase inhibitors (TKIs) may improve results in patients with Philadelphia positive (Ph+) ALL [7,8]. At least one pediatric study has suggested that AlloHCT may not be necessary in children and young adults with Ph+ ALL [9]. We sought to determine what the attitudes and practices of hematologists regarding patient selection for allogeneic HCT in ALL. Critical decisions include patient selection for allogeneic transplant, donor selection, the utility of RIC HCT, the value of MRD measurement, and the management of Ph+ ALL. The questions in the survey were designed to address these issues. The aim was to define which areas of practice had good agreement, and in which areas there was no consensus. Areas that lack consensus should be considered priorities for future research and clinical trials, and reflect uncertainty about the current evidence base. We hypothesized that physicians would be enthusiastic about the role of HCT in CR1, particularly in high risk ALL patients, in contradiction to the results of the MRC/ECOG study. In addition, we hypothesized that physicians would feel that well matched unrelated donors would be an acceptable alternative to sibling donors, resembling clinical practice in other areas of HCT. 2. Materials and methods The target population for our study consisted of Canadian hematologists who treated adults with ALL, as well as HCT physicians. Several methods were used to identify the target population. The membership list of the Canadian Blood and Marrow Transplant Group (CBMTG) was obtained. In addition, to capture non-transplant physicians who treat ALL, a list of hematologists at major academic tertiary care hospitals was obtained. These lists were reviewed, and duplicates were removed. Finally, major community hospitals across Canada with active oncology programs were identified, and hematologists at these centers were identified. An electronic survey was administered to our target population using the online tool SurveyMonkey. Questions were asked specifically about patient selection for allogeneic transplantation in adult ALL, the role of unrelated donor transplantation and cord blood transplantation, the role of RIC HCT, management of Ph+ ALL in CR1, and the role of MRD testing. In addition, there were short clinical vignettes asking respondents to choose between alloHCT and chemotherapy as the optimal post-remission therapy. The survey was pilot tested locally and was altered based on feedback. Physicians were excluded if they were not actively involved in the management of adults with ALL. An initial invitation email was distributed to all physicians in our target population. Several strategies were employed to encourage responses to the survey. Two
reminder emails were sent out to survey participants who had not yet responded. In addition, a draw for a small gift card was used. Both of these strategies have previously been shown to encourage response rates in surveys [10].
3. Results Overall, 69 of 173 physicians surveyed responded (40%). Of these, 40% had additional specialty training in the field of HCT. Most respondents (89%) saw less than 20 new cases annually, with 35% seeing less than 10 new patients per year. The initial question was regarding patient selection for alloHCT (Table 1). There was general agreement that patients with high-risk cytogenetics and a requirement for multiple cycles of induction chemotherapy would benefit from alloHCT. However, there was uncertainty about other clinical factors. Half of respondents recommended HCT for patients over age 35 (50%). In addition, the presence of CNS disease was felt to warrant proceeding to transplant by 53% of respondents. High white blood count (WBC) and the presence of MRD were, in general, thought to be indications for AlloHCT (66% and 75% favored transplant, respectively). T-cell phenotype was not felt to be a strong indication for transplant. Respondents were also asked which sources of stem cells they would consider in patients who lacked a matched sibling donor (Table 2). There was general consensus that a well-matched unrelated donor was an acceptable alternative to a matched sibling donor. 96% of physicians would proceed with an alloHCT in a patient who had a well-matched unrelated donor (fully matched at the allele level). In comparison, only 67% of physicians would proceed with alloHCT in a patient with a partially matched unrelated donor (one allele mismatch), and only 4% with a mismatched unrelated donor (two or more allele mismatches). Respondents were more enthusiastic about cord blood than haploidentical HCT, with 53% willing to offer a cord blood transplant, and only 12% wiling to offer a haploidentical HCT. Physicians were asked if they would proceed with a RIC alloHCT in patients who would ineligible for conventional myeloablative HCT due to advanced age or comorbidity (Table 3). Only 45% of respondents would offer a RIC alloHCT in this situation to all candidates for alloHCT. Next, we presented three clinical vignettes. We sought to understand how respondents would integrate the presence of MRD by presenting a patient with low risk disease (19-year-old female, low diagnostic white cell count, no CNS disease, and good response to
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K. Paulson et al. / Leukemia Research 38 (2014) 176–179
Table 3 Options in patients who are not candidates for myeloablative AlloHCT due to age/comorbidity. Agree RIC HCT, regardless of risk status RIC HCT only if very high risk for relapse Further chemotherapy without AlloHCT Autologous HCT
23 22 30 2
% 45.1 44.0 60.0 4.0
Neutral 7 11 14 2
%
Do not agree
%
Responses
13.7 22.0 28.0 4.0
21 17 6 46
41.2 34.0 12.0 92.0
51 50 50 50
AlloHCT, allogeneic hematopoietic cell transplantation; RIC HCT, reduced intensity conditioning hematopoietic cell transplantation.
remission induction chemotherapy), but with MRD positivity at the completion of induction chemotherapy. 67% of respondents chose AlloHCT as the preferred post-remission strategy. However, only 34% of respondents had access to MRD testing at their institution. Next, respondents were presented a case of a patient with Ph+ ALL without other high-risk features, and without detectable levels of the BCR-ABL fusion gene product at the completion of induction. 94% of respondents still recommended alloHCT, with only 4% suggesting ongoing chemotherapy combined with TKI therapy. Previously, respondents were asked if patients with highrisk clinical features (older age, elevated diagnostic WBC) should receive an alloHCT as the preferred post-remission treatment strategy. To ensure consistency in responses, the final clinical vignette presented a 45-year-old male with T-cell ALL, with a diagnostic WBC of 120, but with an excellent initial response to chemotherapy. Again, respondents preferred alloHCT to ongoing chemotherapy, with 79% of physicians suggesting alloHCT, 10% uncertain, and 10% preferring ongoing chemotherapy.
4. Discussion In this pan-Canadian survey of hematologists and transplantation physicians, we noted substantial uncertainty regarding the allocation of HCT for adults with ALL in CR1. A rapidly moving field and a paucity of prospective clinical trials make decision-making in adult ALL challenging. In some areas, there was homogeneity in clinical practice. For example, respondents felt strongly that alloHCT was the preferred post remission strategy for patients with Ph+ ALL. In addition, there was strong agreement that well-matched unrelated donors were an acceptable alternative should a matched sibling donor be unavailable. However, in other areas, there was significant disagreement. There was uncertainty about the role of cord blood HCT and RIC HCT. In addition, there was some disagreement about patient selection for alloHCT. In contrast to the MRC/ECOG study, the majority of respondents felt that alloHCT was the preferred treatment strategy for patients with high risk ALL in CR1. Finally, there appeared to be enthusiasm about the role of MRD measurement in patient selection for alloHCT, despite the lack of widespread availability of MRD testing. This uncertainty is also reflected in clinical practice guidelines. The National Comprehensive Cancer Network guidelines suggest continuing multiagent chemotherapy, but to consider allogeneic transplant in the setting of detectable minimal residual disease [11]. In contrast, the American Society for Blood and Marrow Transplantation suggest that, for patients in all risk groups, allogeneic stem cell transplant is “an appropriate treatment” [10]. The MRC/ECOG trial began recruiting patients in 1993, and was published in 2008 [1]. Both the practice of alloHCT and the chemotherapeutic management of ALL have undergone dramatic changes during and after this 15-year time interval. The efficient completion of clinical trials that incorporate these innovations should be a focus for the international leukemia and HCT community, to ensure that clinical trials keep pace with a rapidly moving field. As HCT is a relatively specialized field, and adult ALL a relatively rare disease, the practice of evidence-informed medicine is
challenging. Physicians must integrate information from disparate sources, and data available may not be from randomized control trials. In the absence of such trials, physicians may be relying on heuristic or intuitive decision making, drawing from other similar diseases [12]. Our study suggests that while clinicians seemed supportive of alloHCT in general, they were most eager to do so in patients with high-risk disease, in direct contrast with the results of the largest clinical trial in the area. AlloHCT provides better leukemia control as a result of both the chemo/radiotherapy-based conditioning regimen and a graft-versus-leukemia effect. This is balanced by higher toxicity. Thus, alloHCT would be expected to offer greater benefit in higher risk disease, where the risk of relapse is high enough to lead to a net survival benefit. This paradigm is confirmed by studies in most other hematologic malignancies [13–15]. The greater benefit seen in standard risk patients in the MRC/ECOG trial goes against conventional wisdom, as well as previous studies in ALL [16]. This discord suggests that new RCTs are required to determine the right patient selection criteria for transplant in ALL. Interestingly, respondents were enthusiastic about the role of MRD testing despite the fact that it was not available in most centers. This might stem from a desire in clinicians for new instruments to guide patient selection, given the concerns about current risk stratification tools. This study has several limitations. While we believe that Canadian hematologists have similar practice patterns to physicians in other regions, this might not be the case. In addition, this survey was conducted exclusively online, which might exclude some physicians who are less comfortable with internet-based technology. This might be a potential source of bias, and might have reduced the response rate. Finally, while we believe that a 40% response rate for a survey compared favorably to widely accepted standards, the respondents might not be representative of the hematology community in general. AlloHCT is likely to have a significant role in the future management of adult ALL. The clinical picture has been dramatically changed through both new strategies in chemotherapy (especially pediatric-like protocols) and through innovations in HCT (alternative donor sources, RIC HCT, and new strategies to guide patient selection). We found that physicians are uncertain about the optimal way to integrate this new information into practice. In particular, there was disagreement about patient selection for alloHCT, and in the role of RIC and cord blood HCT. These innovations have the potential to improve outcomes for patients. New RCTs should be encouraged to help clinicians understand how best to use these tools to improve outcomes for adults with ALL.
Conflict of interest statement None of the authors have any relevant conflicts of interest to disclose. There are no financial disclosures.
Role of the funding source No funding provided.
K. Paulson et al. / Leukemia Research 38 (2014) 176–179
Acknowledgements Contributors: KP provided the conception and design of the study, created survey questions, completed the survey, and wrote the manuscript. DS and CR, reviewed survey questions and provided input, and reviewed the final manuscript. MDS also provided the conception and design of the study, and reviewed and edited the final manuscript. References [1] Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the international ALL trial (MRC UKALL XII/ECOG E2993). Blood 2008;111(February (4)):1827–33. [2] Gupta V, Richards S, Rowe J, On behalf of the Acute Leukemia Stem Cell Transplantation Trialists’ Collaborative Group. Allogeneic, but not autologous, hematopoietic cell transplantation improves survival only among younger adults with acute lymphoblastic leukemia in first remission: an individual patient data meta-analysis. Blood 2013;121(January (2)):339–50. [3] Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, et al. Pediatric-inspired therapy in adults with Philadelphia chromosomenegative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol 2009;27(February (6)):911–8. [4] Stock W, Johnson JL, Stone RM, Kolitz JE, Powell BL, Wetzler M, et al. Dose intensification of daunorubicin and cytarabine during treatment of adult acute lymphoblastic leukemia: results of cancer and leukemia group B study 19802. Cancer 2012 June. [5] Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010;363(November (22)):2091–101. [6] Ljungman P, Bregni M, Brune M, Cornelissen J, de Witte T, Dini G, et al. Allogeneic and autologous transplantation for haematological diseases, solid tumours and
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immune disorders: current practice in Europe 2009. Bone Marrow Transplant 2010;45(February (2)):219–34. Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, Larson RA, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood 2007;110(October (7)):2309–15. Ribera JM, Oriol A, González M, Vidriales B, Brunet S, Esteve J, et al. Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: final results of the CSTIBES02 trial. Haematologica 2010;95(January (1)):87–95. Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, et al. Improved early event-free survival with imatinib in Philadelphia chromosomepositive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol 2009;27(November (31)):5175–81. Oliansky DM, Larson RA, Weisdorf D, Dillon H, Ratko TA, Wall D, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of adult acute lymphoblastic leukemia: update of the 2006 evidence-based review. Biol Blood Marrow Transplant 2012;18(January (1)), 18.e6–36.e6. National Comprehensive Cancer Network. Acute Lymphoblastic Leukemia (Version 1.2013) [Available from: http://www.nccn.org/professionals/ physician gls/pdf/all.pdf, Retrieved 22.09.13]. Bravata DM. Making medical decisions under uncertainty. Semin Med Pract 2000;3(2):6–13. Khouri IF. Allogeneic stem cell transplantation in follicular lymphoma. Best Pract Res Clin Haematol 2011;24(June (2)):271–7. Hallam S, Gribben JG. Stem cell transplantation in chronic lymphocytic leukaemia – steering a safe course over shifting sands. Best Pract Res Clin Haematol 2010;23(March (1)):109–19. Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. J Am Med Assoc 2009;301(June (22)):2349–61. Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, et al. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol 2004;22(October (20)):4075–86.
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
The role of hematopoietic cell transplantation in adult ALL: Clinical equipoise persists K. Paulson a,b,∗ , D. Szwajcer a,b , C.B. Raymond c , M.D. Seftel d a
Section of Haematology/Oncology, Department of Internal Medicine, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada CancerCare Manitoba, Winnipeg, MB, Canada Manitoba Centre for Health Policy, University of Manitoba, Winnipeg, MB, Canada d Division of Medical Oncology&Hematology, Department of Medicine, University of Toronto, Toronto, ON, Canada b c
a r t i c l e
i n f o
Article history: Received 31 July 2013 Received in revised form 21 October 2013 Accepted 23 October 2013 Available online 1 November 2013 Keywords: Acute lymphoblastic leukemia Hematopoietic stem cell transplant Evidence based medicine
a b s t r a c t Adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) may be treated either with ongoing systemic chemotherapy or with allogeneic hematopoietic cell transplantation (alloHCT). Despite the presence of phase III trials to support clinical decision-making, we hypothesized that physicians who treat adult ALL would demonstrate wide practice variation. Canadian hematologists who treat ALL were surveyed electronically. Overall, 69 of 173 physicians responded (40%). There was high agreement with offering alloHCT for ALL with high-risk cytogenetics or induction failure after a single chemotherapy cycle. However, only a minority of respondents felt that age >35 years was an indication for alloHCT in CR1. Almost all respondents (96%) felt that a well-matched unrelated donor was an acceptable alternative to a sibling donor. There was uncertainty about the role of cord blood (53% agree) and the utility of reduced intensity conditioning HCT (41% agree). In contrast to the results of the MRC/ECOG study, respondents considered alloHCT to be particularly helpful in high-risk patients. Consensus was lacking on the use of cord blood, RIC alloHCT, and the application of MRD. Equipoise exists on the role of alloHCT in CR1 in ALL, suggesting that further trials in this area are required. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction The practice of evidence-based medicine faces many challenges in hematopoietic cell transplantation (HCT). Prospective randomized trials are rare, and lesser levels of evidence such as cohort studies and case series often guide clinical decision-making. In addition, HCT is a rapidly evolving field, and new techniques are often adopted into clinical practice before the availability of published clinical trials. The aim of this study was to understand how HCT clinicians integrate the available evidence to make practical decisions in the management of acute lymphoblastic leukemia (ALL). We chose ALL as a sentinel disease to study for several reasons. One large prospective trial was published in 2008, which produced results that challenged conventional clinical practice and prompted the publication of meta-analyses [1,2]. In addition, the use of new strategies such as reduced intensity conditioning (RIC) HCT, cord blood transplantation, and measurement of minimal residual disease (MRD) have been adopted without the availability
∗ Corresponding author at: ON2050, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, MB, Canada. Tel.: +1 204 771 7238; fax: +1 204 786 0196. E-mail addresses: [email protected], [email protected] (K. Paulson). 0145-2126/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2013.10.021
of high grade evidence to support their use. We sought to understand how clinicians practiced evidence-informed decision making in ALL, integrating the results of one large clinical trial into clinical practice. The optimal management of acute lymphoblastic leukemia (ALL) in adults requires initial remission induction chemotherapy accompanied by careful patient selection for allogeneic hematopoietic cell transplantation (AlloHCT). However, pediatriclike chemotherapy protocols are being adopted, with the hope that they might improve the complete response rate and overall survival and, for some patients, avoid the need for alloHCT in CR1 [3,4]. In addition, the field of HCT has been revolutionized over the last two decades, with widespread use of unrelated donors, the advent of RIC HCT, and dramatic reductions in treatment related mortality [5]. The pivotal MRC/ECOG study found a dramatically lower relapse rate among patients assigned to receive allogeneic HCT as compared to maintenance chemotherapy [1]. However, the lower relapse rate in allogeneic HCT was balanced by increased therapyrelated toxicity. In subgroup analysis, the benefit with HCT was isolated to standard risk patients, but not in high risk ones. This observation is contrary to clinical practice in most other hematologic malignancies, in which benefits with HCT are primarily seen in high-risk patients [6]. Survival after first relapse of ALL remains
K. Paulson et al. / Leukemia Research 38 (2014) 176–179
177
Table 1 Clinical characteristics identified by survey respondents for which alloHCT would be offered. The questions referred to a patient with Philadelphia chromosome negative ALL in CR1.
MRD+ at day 28 >1 induction cycle to achieve CR1 Older age (>35) T-cell phenotype B-cell phenotype High WBC (>30 for B-cell, >100 for T-cell) CNS disease at diagnosis High risk cytogenetics
Agree
%
Neutral
%
Disagree
%
Responses
35 47 27 10 15 41 28 48
66.0 87.0 50.0 18.9 27.8 75.9 52.8 88.9
13 6 12 18 21 8 13 3
24.5 11.1 22.2 34.0 38.9 14.8 24.5 5.6
5 1 15 25 18 5 12 3
9.4 1.9 27.8 47.2 33.3 9.3 22.6 5.6
53 54 54 53 54 54 53 54
AlloHCT, allogeneic hematopoietic cell transplantation; MRD, minimal residual disease; CR1, first complete remission; WBC, white blood count; CNS, central nervous system.
Table 2 Donor options in patients who are candidates for AlloHCT, but lack an HLA matched sibling.
Well-matched unrelated donor (10/10 or 8/8) Partially matched unrelated donor (≤1 mismatched allele) Mismatched unrelated donor (≥2 mismatched alleles) Suitably matched cord blood Haploidentical donor
Agree
%
Neutral
%
Do not agree
%
Responses
49 34 2 27 6
96.1 66.7 4.0 52.9 12.2
0 8 8 16 14
0 15.7 16.0 31.4 28.6
2 9 40 8 29
3.9 17.6 80.0 15.7 59.2
51 51 50 51 49
AlloHCT, allogeneic hematopoietic cell transplantation.
dismal, with only 7% of patients in the MRC/ECOG trial surviving for 5 years after relapse. Thus, patient selection for allogeneic HCT remains one of the most important decisions facing clinicians who treat adults with ALL. Finally, recent studies have suggested that tyrosine kinase inhibitors (TKIs) may improve results in patients with Philadelphia positive (Ph+) ALL [7,8]. At least one pediatric study has suggested that AlloHCT may not be necessary in children and young adults with Ph+ ALL [9]. We sought to determine what the attitudes and practices of hematologists regarding patient selection for allogeneic HCT in ALL. Critical decisions include patient selection for allogeneic transplant, donor selection, the utility of RIC HCT, the value of MRD measurement, and the management of Ph+ ALL. The questions in the survey were designed to address these issues. The aim was to define which areas of practice had good agreement, and in which areas there was no consensus. Areas that lack consensus should be considered priorities for future research and clinical trials, and reflect uncertainty about the current evidence base. We hypothesized that physicians would be enthusiastic about the role of HCT in CR1, particularly in high risk ALL patients, in contradiction to the results of the MRC/ECOG study. In addition, we hypothesized that physicians would feel that well matched unrelated donors would be an acceptable alternative to sibling donors, resembling clinical practice in other areas of HCT. 2. Materials and methods The target population for our study consisted of Canadian hematologists who treated adults with ALL, as well as HCT physicians. Several methods were used to identify the target population. The membership list of the Canadian Blood and Marrow Transplant Group (CBMTG) was obtained. In addition, to capture non-transplant physicians who treat ALL, a list of hematologists at major academic tertiary care hospitals was obtained. These lists were reviewed, and duplicates were removed. Finally, major community hospitals across Canada with active oncology programs were identified, and hematologists at these centers were identified. An electronic survey was administered to our target population using the online tool SurveyMonkey. Questions were asked specifically about patient selection for allogeneic transplantation in adult ALL, the role of unrelated donor transplantation and cord blood transplantation, the role of RIC HCT, management of Ph+ ALL in CR1, and the role of MRD testing. In addition, there were short clinical vignettes asking respondents to choose between alloHCT and chemotherapy as the optimal post-remission therapy. The survey was pilot tested locally and was altered based on feedback. Physicians were excluded if they were not actively involved in the management of adults with ALL. An initial invitation email was distributed to all physicians in our target population. Several strategies were employed to encourage responses to the survey. Two
reminder emails were sent out to survey participants who had not yet responded. In addition, a draw for a small gift card was used. Both of these strategies have previously been shown to encourage response rates in surveys [10].
3. Results Overall, 69 of 173 physicians surveyed responded (40%). Of these, 40% had additional specialty training in the field of HCT. Most respondents (89%) saw less than 20 new cases annually, with 35% seeing less than 10 new patients per year. The initial question was regarding patient selection for alloHCT (Table 1). There was general agreement that patients with high-risk cytogenetics and a requirement for multiple cycles of induction chemotherapy would benefit from alloHCT. However, there was uncertainty about other clinical factors. Half of respondents recommended HCT for patients over age 35 (50%). In addition, the presence of CNS disease was felt to warrant proceeding to transplant by 53% of respondents. High white blood count (WBC) and the presence of MRD were, in general, thought to be indications for AlloHCT (66% and 75% favored transplant, respectively). T-cell phenotype was not felt to be a strong indication for transplant. Respondents were also asked which sources of stem cells they would consider in patients who lacked a matched sibling donor (Table 2). There was general consensus that a well-matched unrelated donor was an acceptable alternative to a matched sibling donor. 96% of physicians would proceed with an alloHCT in a patient who had a well-matched unrelated donor (fully matched at the allele level). In comparison, only 67% of physicians would proceed with alloHCT in a patient with a partially matched unrelated donor (one allele mismatch), and only 4% with a mismatched unrelated donor (two or more allele mismatches). Respondents were more enthusiastic about cord blood than haploidentical HCT, with 53% willing to offer a cord blood transplant, and only 12% wiling to offer a haploidentical HCT. Physicians were asked if they would proceed with a RIC alloHCT in patients who would ineligible for conventional myeloablative HCT due to advanced age or comorbidity (Table 3). Only 45% of respondents would offer a RIC alloHCT in this situation to all candidates for alloHCT. Next, we presented three clinical vignettes. We sought to understand how respondents would integrate the presence of MRD by presenting a patient with low risk disease (19-year-old female, low diagnostic white cell count, no CNS disease, and good response to
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K. Paulson et al. / Leukemia Research 38 (2014) 176–179
Table 3 Options in patients who are not candidates for myeloablative AlloHCT due to age/comorbidity. Agree RIC HCT, regardless of risk status RIC HCT only if very high risk for relapse Further chemotherapy without AlloHCT Autologous HCT
23 22 30 2
% 45.1 44.0 60.0 4.0
Neutral 7 11 14 2
%
Do not agree
%
Responses
13.7 22.0 28.0 4.0
21 17 6 46
41.2 34.0 12.0 92.0
51 50 50 50
AlloHCT, allogeneic hematopoietic cell transplantation; RIC HCT, reduced intensity conditioning hematopoietic cell transplantation.
remission induction chemotherapy), but with MRD positivity at the completion of induction chemotherapy. 67% of respondents chose AlloHCT as the preferred post-remission strategy. However, only 34% of respondents had access to MRD testing at their institution. Next, respondents were presented a case of a patient with Ph+ ALL without other high-risk features, and without detectable levels of the BCR-ABL fusion gene product at the completion of induction. 94% of respondents still recommended alloHCT, with only 4% suggesting ongoing chemotherapy combined with TKI therapy. Previously, respondents were asked if patients with highrisk clinical features (older age, elevated diagnostic WBC) should receive an alloHCT as the preferred post-remission treatment strategy. To ensure consistency in responses, the final clinical vignette presented a 45-year-old male with T-cell ALL, with a diagnostic WBC of 120, but with an excellent initial response to chemotherapy. Again, respondents preferred alloHCT to ongoing chemotherapy, with 79% of physicians suggesting alloHCT, 10% uncertain, and 10% preferring ongoing chemotherapy.
4. Discussion In this pan-Canadian survey of hematologists and transplantation physicians, we noted substantial uncertainty regarding the allocation of HCT for adults with ALL in CR1. A rapidly moving field and a paucity of prospective clinical trials make decision-making in adult ALL challenging. In some areas, there was homogeneity in clinical practice. For example, respondents felt strongly that alloHCT was the preferred post remission strategy for patients with Ph+ ALL. In addition, there was strong agreement that well-matched unrelated donors were an acceptable alternative should a matched sibling donor be unavailable. However, in other areas, there was significant disagreement. There was uncertainty about the role of cord blood HCT and RIC HCT. In addition, there was some disagreement about patient selection for alloHCT. In contrast to the MRC/ECOG study, the majority of respondents felt that alloHCT was the preferred treatment strategy for patients with high risk ALL in CR1. Finally, there appeared to be enthusiasm about the role of MRD measurement in patient selection for alloHCT, despite the lack of widespread availability of MRD testing. This uncertainty is also reflected in clinical practice guidelines. The National Comprehensive Cancer Network guidelines suggest continuing multiagent chemotherapy, but to consider allogeneic transplant in the setting of detectable minimal residual disease [11]. In contrast, the American Society for Blood and Marrow Transplantation suggest that, for patients in all risk groups, allogeneic stem cell transplant is “an appropriate treatment” [10]. The MRC/ECOG trial began recruiting patients in 1993, and was published in 2008 [1]. Both the practice of alloHCT and the chemotherapeutic management of ALL have undergone dramatic changes during and after this 15-year time interval. The efficient completion of clinical trials that incorporate these innovations should be a focus for the international leukemia and HCT community, to ensure that clinical trials keep pace with a rapidly moving field. As HCT is a relatively specialized field, and adult ALL a relatively rare disease, the practice of evidence-informed medicine is
challenging. Physicians must integrate information from disparate sources, and data available may not be from randomized control trials. In the absence of such trials, physicians may be relying on heuristic or intuitive decision making, drawing from other similar diseases [12]. Our study suggests that while clinicians seemed supportive of alloHCT in general, they were most eager to do so in patients with high-risk disease, in direct contrast with the results of the largest clinical trial in the area. AlloHCT provides better leukemia control as a result of both the chemo/radiotherapy-based conditioning regimen and a graft-versus-leukemia effect. This is balanced by higher toxicity. Thus, alloHCT would be expected to offer greater benefit in higher risk disease, where the risk of relapse is high enough to lead to a net survival benefit. This paradigm is confirmed by studies in most other hematologic malignancies [13–15]. The greater benefit seen in standard risk patients in the MRC/ECOG trial goes against conventional wisdom, as well as previous studies in ALL [16]. This discord suggests that new RCTs are required to determine the right patient selection criteria for transplant in ALL. Interestingly, respondents were enthusiastic about the role of MRD testing despite the fact that it was not available in most centers. This might stem from a desire in clinicians for new instruments to guide patient selection, given the concerns about current risk stratification tools. This study has several limitations. While we believe that Canadian hematologists have similar practice patterns to physicians in other regions, this might not be the case. In addition, this survey was conducted exclusively online, which might exclude some physicians who are less comfortable with internet-based technology. This might be a potential source of bias, and might have reduced the response rate. Finally, while we believe that a 40% response rate for a survey compared favorably to widely accepted standards, the respondents might not be representative of the hematology community in general. AlloHCT is likely to have a significant role in the future management of adult ALL. The clinical picture has been dramatically changed through both new strategies in chemotherapy (especially pediatric-like protocols) and through innovations in HCT (alternative donor sources, RIC HCT, and new strategies to guide patient selection). We found that physicians are uncertain about the optimal way to integrate this new information into practice. In particular, there was disagreement about patient selection for alloHCT, and in the role of RIC and cord blood HCT. These innovations have the potential to improve outcomes for patients. New RCTs should be encouraged to help clinicians understand how best to use these tools to improve outcomes for adults with ALL.
Conflict of interest statement None of the authors have any relevant conflicts of interest to disclose. There are no financial disclosures.
Role of the funding source No funding provided.
K. Paulson et al. / Leukemia Research 38 (2014) 176–179
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