Leukemia (2021) 35:2076–2085 https://doi.org/10.1038/s41375-021-01213-5 ARTICLE Superior survival with pediatric-style chemotherapy compared to myeloablative allogeneic hematopoietic cell transplantation in older adolescents and young adults with Ph-negative acute lymphoblastic leukemia in first complete remission: analysis from CALGB 10403 and the CIBMTR Matthew J. Wieduwilt 1 Wendy Stock2 Anjali Advani 3 Selina Luger 4 Richard A. Larson 2 ● ● ● ● ● Martin Tallman5 Frederick Appelbaum6 Mei-Jie Zhang7,8 Khalid Bo-Subait7 Hai-Lin Wang7 ● ● ● ● ● Vijaya Raj Bhatt 9 Bhagirathbhai Dholaria 10 Mary Eapen7 Mehdi Hamadani 11 Omer Jamy12 ● ● ● ● ● Tim Prestidge 13 Michael Pulsipher 14 David Ritchie15 David Rizzieri16 Akshay Sharma 17 Pere Barba ● ● ● ● ● 18 ● Brenda M. Sandmaier 19,20 Marcos de Lima 21 Partow Kebriaei 22 Mark Litzow 23 Wael Saber7 ● ● ● ● ● Daniel Weisdorf 24 1234567890();,: Received: 17 September 2020 / Revised: 28 January 2021 / Accepted: 25 February 2021 / Published online: 30 March 2021 1234567890();,: © The Author(s) 2021. This article is published with open access Abstract Optimal post-remission therapy for adolescents and young adults (AYAs) with Ph-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is not established. We compared overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality (NRM) for patients receiving post-remission therapy on CALGB 10403 to a cohort undergoing myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT) in CR1. In univariate analysis, OS was superior with chemotherapy compared to MA allogeneic HCT (3-year OS 77% vs. 53%, P < 0.001). In multivariate analysis, allogeneic HCT showed inferior OS (HR 2.00, 95% CI 1.5–2.66, P < 0.001), inferior DFS (HR 1.62, 95% CI 1.25–2.12, P < 0.001), and increased NRM (HR 5.41, 95% CI 3.23–9.06, P < 0.001) compared to chemotherapy. A higher 5-year relapse incidence was seen with chemotherapy compared to allogeneic HCT (34% vs. 23%, P = 0.011). Obesity was independently associated with inferior OS (HR 2.17, 95% CI 1.63–2.89, P < 0.001), inferior DFS (HR 1.97, 95% CI 1.51–2.57, P < 0.001), increased relapse (1.84, 95% CI 1.31–2.59, P < 0.001), and increased NRM (HR 2.10, 95% CI 1.37–3.23, P < 0.001). For AYA ALL patients in CR1, post-remission therapy with pediatric-style chemotherapy is superior to MA allogeneic HCT for OS, DFS, and NRM. Introduction E2993 compared traditional adult chemotherapy or auto- logous HCT to MA allogeneic HCT in patients aged 15–59 The optimal post-remission therapy for AYAs with Ph- years with Ph-negative ALL. Overall survival (OS) was negative ALL in CR1 is not known in the era of pediatric- improved in standard-risk ALL patients with a donor, pri- inspired chemotherapy regimens with more intensive post- marily due to more relapse in the no donor group [1]. remission therapy than traditional adult regimens. Previous However, individual studies in adults comparing allogeneic studies suggested superiority of post-remission therapy with HCT to chemotherapy alone have not shown a clear benefit allogeneic HCT over chemotherapy. MRC UKALLXII/ of allogeneic HCT although meta-analyses support allo- geneic HCT in CR1 [2, 3]. A meta-analysis of 13 trials comparing allogeneic HCT to chemotherapy with or with- Supplementary information The online version contains out autologous HCT concluded that the benefit of allogeneic supplementary material available at https://doi.org/10.1038/s41375- HCT for patients with Ph-negative ALL in CR1 was limited 021-01213-5. to those under the age of 35 [2], the age group now com- * Matthew J. Wieduwilt monly treated with pediatric-style chemotherapy. In this matthew.wieduwilt@gmail.com metanalysis, which included the UKALLXII/E2993 study, Extended author information available on the last page of the article 5-year OS for patients <35 years of age was 53.7%, lower Superior survival with pediatric-style chemotherapy compared to myeloablative allogeneic hematopoietic. . . 2077 than the survival typically seen with pediatric-inspired 16–39 years with Philadelphia-chromosome/BCR-ABL1- chemotherapy in the AYA population [2, 4–8]. negative ALL in CR1 who started post-remission che- Pediatric-style chemotherapy may improve outcomes motherapy. The MA allogeneic HCT cohort consisted of for AYAs with Ph-negative ALL [4–8]. A meta-analysis patients aged 16–39 years with a diagnosis of Ph-negative of 11 trials showed superior OS, event-free survival ALL in CR1 undergoing post-remission therapy with a MA (EFS), and relapse rates in AYAs treated with pediatric- bone marrow or peripheral blood allogeneic HCT from a inspired chemotherapy relative to conventional adult matched sibling, matched related, or unrelated donor (URD) chemotherapy [9]. The DFCI Adult ALL Consortium in the U.S. from 11/1/2002 through 8/31/2012 reported to the reported on 74 patients aged 18–50 years with Ph- CIBMTR. Patients receiving syngeneic, haploidentical, or negative ALL treated with pediatric-style chemotherapy umbilical cord blood HCT were excluded. [10]. A 4-year EFS of 62% was observed. Seftel et al. compared the DFCI regimen to MA allogeneic HCT Objectives and endpoints outcomes using data from the Center for International Blood and Marrow Transplant Research (CIBMTR) [11]. The start time for outcomes was the date of CR1. The primary Relapse rates were similar between the two groups but objective was to compare OS between patients receiving post- pediatric-style chemotherapy was superior to allogeneic remission therapy with MA allogeneic HCT vs. chemother- HCT for 4-year OS and DFS, due primarily to lower rates apy. Secondary objectives included DFS, relapse rate, and of NRM with chemotherapy. In multivariate analysis, NRM rate between the allogeneic HCT and chemotherapy allogeneic HCT was the only factor associated with cohorts. Additional secondary objectives included determi- inferior OS (HR 2.86, P < 0.0001). nation of patient and disease factors influencing outcomes of A single-arm, prospective, US Intergroup study led by post-remission therapy using either approach. The primary the Alliance for Clinical Trials in Oncology (CALGB endpoint of OS was defined as the time from CR1 to the last 10403) studied the feasibility of applying the pediatric COG contact date or death from any cause. Secondary endpoints AALL0232 standard-risk arm regimen to AYAs aged included NRM defined as time to death without evidence of 16–39 years with Ph-negative ALL [12]. The 3-year EFS leukemia recurrence with relapse as the competing risk, was 59% with a 3-year OS of 73%, an improvement com- relapse was defined as the cumulative incidence of leukemia pared to young adults treated with historical adult CALGB recurrence after CR1 with NRM as a competing risk, and regimens [13]. Given the large size of the study and its DFS was defined as the time from CR1 to leukemia relapse or enrollment of patients across the US, we used it as a model death. Surviving patients were censored at last time reported population to compare outcomes of pediatric-style post- alive and in continued remission. Allogeneic HCT cohort remission therapy to MA allogeneic HCT. endpoints included acute grade II–IV graft-versus-host dis- A major limitation of prior studies comparing allogeneic ease (GVHD) fulfilling the Consensus criteria and chronic HCT to chemotherapy is that the post-remission che- GVHD defined as the occurrence of symptoms in any organ motherapy was of lower intensity compared with current diagnostic of chronic GVHD. pediatric-style chemotherapy regimens. Pediatric-style post- remission therapy may improve relapse rates with low NRM Statistical analysis conceivably leading to superior survival relative to allo- geneic HCT. This study was designed to compare OS, DFS, Patient-, disease-, and transplant-related factors were com- relapse, and NRM in patients aged 16–39 years with Ph- pared between treatment groups using the Chi-square test negative ALL in CR1 undergoing post-remission therapy for categorical variables and the Wilcoxon two sample test with pediatric-inspired chemotherapy on CALGB 10403 vs. for continuous variables. Comparing outcomes in the MA allogeneic HCT. Results from this study directly transplant and chemotherapy groups required adjustment for inform the debate on the role of allogeneic HCT for AYA two sources of bias: differences in time to treatment/time to patients with Ph-negative ALL in CR1. transplant and differences in baseline characteristics of patients. Starting from CR1, left-truncated analysis methods were used to address the first potential bias, that patients Methods must survive in CR1 a sufficient length of time until transplant. At each time point (t) in this model, the risk set Study population in the chemotherapy cohort consists of all patients still under study, while the risk set in the transplant cohort The chemotherapy cohort consisted of patients receiving post- includes only those whose waiting time to transplant was remission chemotherapy on CALGB 10403 (NCT00558519). less than the current study time point (t). The probabilities Eligible patients from CALGB 10403 were patients aged of DFS and OS were calculated using the left-truncated 2078 M. J. Wieduwilt et al. Kaplan–Meier estimator. Probabilities of NRM and relapse allogeneic HCT cohorts included race (Caucasian, 75% vs. were generated using left-truncated cumulative incidence 89%), Karnofsky performance score (≥80, 91% vs. 88%), estimates to account for competing risks. The univariate white blood cell count at diagnosis, cytogenetics, extra- probabilities of relapse and NRM were compared using the medullary disease at diagnosis (present, 48% vs. 19%), and Gray’s test [14]. To adjust for the differences in baseline weeks from diagnosis to documentation of CR1 (median 4.4 characteristics, left-truncated Cox proportional hazards vs. 7.6 weeks). A large majority of patients in the allogeneic regression was used to compare the two treatment groups. HCT cohort patients received TBI-based conditioning Multivariate analysis factors included age, gender, race, (92%) from a well-matched related or URD (79%) within body mass index, Karnofsky performance status, ALL 6 months of documented CR1 (86%). Graft source was immunophenotype, white blood cell count at diagnosis, peripheral blood for 73% of transplants. GVHD prophylaxis cytogenetic risk group, extramedullary disease at diagnosis, was principally calcineurin inhibitor with methotrexate and time to documentation of CR1 (Table 1). The based (70%) with in vivo T-cell depletion used in 21% of assumption of proportional hazards for each factor in the transplants. Population characteristics are summarized in Cox model was tested using time-dependent covariates. Table 1. When the test indicated differential effects over time (nonproportional hazards), models were constructed break- Outcomes in univariate analysis ing the post-transplant time course into two periods, using the maximized partial likelihood method to find the most In univariate analysis, no differences in OS, relapse, or appropriate breakpoint. A backward stepwise model selec- NRM, were observed between allogeneic HCT and che- tion approach was used to identify all significant risk fac- motherapy at 100 days after the initiation of post-remission tors. Each step of model building contained the main effect therapy. At 3 and 5 years, OS was superior with che- for treatment groups. Factors, which were significant at a motherapy compared to allogeneic HCT (3-year OS 77% 5% level, were kept in the final model. The potential vs. 53%, P < 0.001, 5-year OS 66% vs. 47%, P < 0.001). interactions between main effect and all significant risk Also, 3- and 5-year DFS was superior with chemotherapy factors were tested. Adjusted probabilities of DFS and OS compared to allogeneic HCT (3-year DFS 68% vs. 50%, P were generated from the final Cox models stratified on < 0.001, 5-year DFS 58% vs. 44%, P = 0.004). Non-relapse treatment and weighted averages of covariate values using mortality was lower with chemotherapy compared to allo- the pooled sample proportion as the weight function. These geneic HCT (3-year NRM 6% vs. 24%, P = < 0.001. 5-year adjusted probabilities estimate likelihood of outcomes in NRM 8% vs. 29%, P < 0.001). Cumulative relapse at 5 populations with similar prognostic factors. Chemotherapy years was significantly higher in the chemotherapy cohort patients who received a transplant during CR1 were cen- relative to the allogeneic HCT cohort (5-year relapse inci- sored for OS at time of transplant (N = 20). HCT-related dence 34% vs. 23%, P = 0.011). Univariate outcomes are variables were not analyzed in the multivariate since they summarized in Table 2 and Fig. 1. are not relevant in the chemotherapy cohort. The HCT cohort included a planned sub-analysis of donor effect Multivariate outcomes by treatment modality evaluating HLA-identical siblings vs. well-matched (8/8) URD or partially matched (7/8) URD and no differences For the entire study population (N = 480), OS was worse were seen in outcomes between the groups. Acute and with allogeneic HCT (HR 2.00, 95% CI 1.5–2.66, P < chronic GVHD was included following HCT as time- 0.001) and obesity (BMI ≥ 30 kg/m2, HR 2.17, 95% CI dependent covariates. 1.63–2.89, P < 0.001). Post-remission therapy with allo- geneic HCT led to inferior DFS (HR 1.62, 95% CI 1.25–2.12, P < 0.001) and higher risk of NRM (HR 5.41, Results 95% CI 3.23–9.06, P < 0.001). In the early post-remission period (≤15 months after CR1), relapse was more likely Patient populations with allogeneic HCT (HR 1.78, 95% CI 1.10–2.88, P = 0.02) while beyond 15 months after CR1 relapse was The chemotherapy cohort consisted of 263 patients treated more likely in the chemotherapy cohort (HR 0.34, 95% CI at 60 centers with a median age of 24 years (range 17–39) 0.19–0.62, P < 0.001). In addition to worse OS, obesity and median follow up of 65 months (range 1–109). The MA was associated with inferior DFS (HR 1.97, 95% CI allogeneic HCT cohort consisted of 217 patients treated at 1.51–2.57, P < 0.001), more relapse (HR 1.84, 95% 72 centers with a median age of 27 years (range 16–40) with CI 1.31–2.59, P < 0.001), and more NRM (HR 2.10, 95% a median follow up of 98 months (range 23–179). Sig- CI 1.37–3.23, P < 0.001). We included a planned nificant differences between the chemotherapy and multivariate sub-analysis comparing outcomes of Superior survival with pediatric-style chemotherapy compared to myeloablative allogeneic hematopoietic. . . 2079 Table 1 Population characteristics. Table 1 (continued) Characteristic CIBMTR HCT CALGB 10403 P value Characteristic CIBMTR HCT CALGB 10403 P value No. of patients 217 263 6–12 months 30 (14) No. of centers 72 60 >12 months 1 (0) Follow-up—median (min–max) 98 (24–173) 65 (1–109) TBI given for conditioning— 199 (92) Age at CR1, Years—no. (%) 0.08a no. (%) Median (min–max) 27 (16–40) 24 (17–39) Donor type—no. (%) 16–20 49 (23) 66 (25) HLA-identical sibling 75 (35) 21–29 94 (43) 132 (50) Other related 4 (2) 30–39 74 (34) 65 (25) Well-matched unrelated 93 (43) Gender—no. (%) 0.51a Partially matched unrelated 39 (18) Male 140 (65) 162 (62) Mis-matched unrelated 6 (3) Female 77 (35) 101 (38) Donor age, years—median 34 (19–59) Race—no. (%) <0.001b (min–max) Caucasian 193 (89) 197 (75) Donor/recipient gender—no. (%) Other 24 (11) 41 (16) F/M 49 (23) Unknown/missing 0 25 (10) Others 168 (77) BMI—no. (%) 0.55a Donor/recipient CMV match—no. (%) Not obese, BMI < 30 154 (71) 180 (68) +/− 71 (33) Obese, BMI ≥ 30 63 (29) 83 (32) −/+ 57 (26) Karnofsky performance score— <0.001b −/− 34 (16) no. (%) +/+ 52 (24) <80 12 (6) 23 (9) Missing 3 (1) ≥80 192 (88) 240 (91) Graft type—no. (%) Missing 13 (6) 0 Bone marrow 58 (27) Immunophenotype—no. (%) 0.09a Peripheral blood 159 (73) T-cell 43 (20) 65 (25) Year of transplant—no. (%) B-cell 169 (78) 197 (75) 2002–2005 93 (43) Unspecified 5 (2) 1 (0) 2006–2008 60 (28) White blood count at diagnosis 0.05a 2009–2012 64 (29) (×109)—no. (%) GVHD prophylaxis—no. (%) B-cell, <30 119 (55) 157 (60) Ex-vivo or CD34 selection 10 (5) B-cell, >30 50 (23) 40 (15) Tac + MTX ± others 109 (50) T-cell, <100 36 (17) 48 (18) CSA + MTX ± others 42 (19) T-cell, >100 7 (3) 17 (6) Others 52 (24) Unspecified, <30 1 (0) 0 Missing 4 (2) Unspecified, 30–100 3 (1) 0 T-cell depletion (ATG/ 45 (21) Unspecified, >100 1 (0) 0 Alemtuzumab)—no. (%) Missing 0 1 (0) Bold denotes variables included in regression models. Poor: complex Cytogenetics—no. (%) <0.001a (≥3 abnormalities), t(9;22), t(4;11), t(8;14), t(14;18), hypodiploid Normal 88 (41) 57 (22) (<46); normal: no abnormality; other: any abnormality not in poor. Poor 35 (16) 63 (24) Others:_ATG + CsA + MTX + MMF + ursodiol (n = 1), ATG + Other 68 (31) 39 (15) tacrolimus ± others (n = 7), corticosteroid + CsA ± others (n = 3), Missing 26 (12) 104 (40) cortisosteroid + tacroimus ± others (n = 5), CsA + tacrolimus (n = 1), Extramedullary disease at <0.001a CsA + MMF (n = 3), CsA + MTX + MMF (n = 1), tacrolimus (n = diagnosis—no. (%) 3), tacrolimus + sirolimus ± others (n = 15), tacrolimus + MMF ± No 176 (81) 137 (52) others (n = 10), MMF + sirolimus (n = 1), MTX (n = 2). Yes 41 (19) 126 (48) a Hypothesis testing: Pearson chi-square test. CNS envolvement 11 (5) 27 (10) b Hypothesis testing: Fisher exact test. Time to achieve CR1, weeks— <0.001a no. (%) Median (min–max) 7.6 (1.3–56) 4.4 (2.3–14.4) ≤4 weeks 35 (16) 25 (10) HLA-identical siblings and well-matched (8/8) URDs to 4–8 weeks 82 (38) 234 (89) the chemotherapy cohort but findings were similar to the >8 weeks 100 (46) 4 (2) complete transplant cohort. Multivariate outcomes are Transplant characteristics summarized in Table 3. In addition, multivariate analysis Time from CR1 to HCT, months—no. (%) evaluating outcomes by cytogenetic risk (standard vs. Median (min–max) 3.3 (0.2–18.8) poor) and HCT time period (2002–2006 vs. 2007–2012) <6 months 186 (86) showed similar results to the full study population (Sup- plementary Tables 1 and 2). 2080 M. J. Wieduwilt et al. Table 2 Univariate estimates for allogeneic HCT vs. chemotherapy. [15]. The finding suggested that allogeneic HCT is a safe Outcome Myeloablative Pediatric chemotherapy and effective option for all high-risk ALL patients regard- allogeneic HCT (CALGB 10403) less of MRD status. (CIBMTR) To help clarify the role of allogeneic HCT in AYAs with N Probability, % N Probability, % P Ph-negative ALL in CR1 treated with pediatric-style che- (95% CI) (95% CI) motherapy, Seftel et al. compared 108 adults 18–50 years of Overall 217 263 <0.001 age treated with the Dana-Farber Consortium pediatric-style survival regimen at 13 centers in the northeastern US and eastern 100-day 95 (88–99)% 99 (98–100)% 0.090 Canada to a CIBMTR allogeneic HCT cohort [11]. No 1-year 72 (65–79)% 91 (87–94)% <0.001 difference in relapse was observed but higher NRM, lower 3-year 53 (46–60)% 77 (71–82)% <0.001 DFS, and lower OS was seen with allogeneic HCT. Nota- 5-year 47 (40–54)% 66 (60–72)% <0.001 bly, allogeneic HCT was the only multivariate factor pre- Relapse 215 256 0.016 dictive of shorter OS (HR 3.12 (1.99–4.90), P < 0.0001). Limitations of the study included a chemotherapy cohort 100-day 0 (0–2)% 0 (0–2)% 0.909 with small numbers of patients from a select and geo- 1-year 11 (7–16)% 10 (7–15)% 0.803 graphically limited group of centers compared to the 3-year 21 (16–27)% 26 (21–32)% 0.216 CIBMTR cohort. As such, the generalizability of the find- 5-year 23 (17–29)% 34 (28–40)% 0.011 ings is unclear but support deferring allogeneic HCT for Non-relapse 215 256 <0.001 mortality relapse in AYAs receiving pediatric-style post-remission therapy. 100-day 1 (0–3)% 1 (0–2)% 0.536 CALGB 10403 was a national, single-arm, Phase II 1-year 17 (12–22)% 4 (2–7)% <0.001 study of the feasibility of treating patients aged 16–39 years 3-year 24 (19–30)% 6 (3–9)% <0.001 with Ph-negative ALL with the standard-risk arm of the 5-year 29 (23–35)% 8 (5–12)% <0.001 COG AALL0232 regimen [12, 13]. The study analyzed 295 Disease-free 215 256 <0.001 survival patients at 60 centers across the United States, among which 263 achieved complete remission after initial treatment. 100-day 95 (88–99)% 99 (97–100)% 0.133 Comparing this patient cohort to a contemporary CIBMTR 1-year 66 (59–73)% 85 (80–89)% <0.001 allogeneic HCT cohort, we found improved OS with 3-year 50 (43–57)% 68 (62–73)% <0.001 pediatric-style post-remission chemotherapy relative to MA 5-year 44 (38–51)% 58 (52–65)% 0.004 allogeneic HCT with an absolute 5-year survival improve- ment of 19%. Although overall relapse was higher with pediatric-style chemotherapy, the high NRM with allo- Discussion geneic HCT had a large negative impact on OS. In multi- variate analysis, allogeneic HCT was significantly Allogeneic HCT is indicated for Ph-negative ALL in CR1 associated with reduced OS, reduced DFS, and increased based on trials using donor vs. no donor comparisons. NRM. Differences in relapse between the cohorts seen in UKALLXII/ECOG2993 showed improved survival with our study versus the Seftel et al. study [11] may be related allogeneic HCT for adults aged 15–54 years with Ph- to differences in chemotherapy regimens, patient com- negative ALL when compared to chemotherapy or auto- pliance, patient eligibility, and/or statistical power. In con- logous HCT (5-year OS 54% vs. 44%, P = 0.007) [1]. trast to the high-risk Ph-negative ALL patients treated on Gupta et al. found in a meta-analysis of 13 studies that the GRAALL2003/2005, patients treated with CALGB allogeneic HCT for Ph-negative ALL benefited patients 10403 consolidation had significantly improved survival under age 35 years relative to traditional adult chemother- relative to allogeneic HCT patients. The different patient apy (Odd ratio of death = 0.79; 95% CI, 0.70–0.90, P = populations or possibly the different post-remission regi- 0.0003) [2]. However, pediatric-style regimens with more mens may explain the superiority of chemotherapy over intensive post-remission therapy appear to have improved allogeneic HCT seen in our study. outcomes for AYA patients with Ph-negative ALL in ret- In pediatric patients with ALL receiving chemotherapy, rospective comparisons [4–9]. A retrospective analysis of obesity is associated with increased NRM, increased GRAALL2003/2005 studies showed that, for adults aged relapse, and decreased OS [16–22], but a negative effect of 15–55 years with high-risk Ph-negative ALL, allogeneic obesity has not been routinely seen in adults [23]. CALGB HCT demonstrated equivalent survival to pediatric-style 10403 found that obese AYA patients with ALL had sig- chemotherapy in patients MRD-negative after induction and nificantly reduced DFS compared with nonobese patients a survival benefit for patients MRD-positive after induction [13]. We found that obesity was associated with decreased Superior survival with pediatric-style chemotherapy compared to myeloablative allogeneic hematopoietic. . . 2081 Fig. 1 Overall survival, disease-free survival, relapse, and non-relapse mortality from first complete remission (CR1) of chemotherapy (chemo) and allogeneic HCT (HCT) cohorts. Upper left, adjusted overall survival; upper right, adjusted disease- free survival; lower left, cumulative incidence of relapse; lower right, cumulative incidence of non-relapse mortality. OS and DFS in this study and the effect was seen in both the One limitation of this study is that minimal information chemotherapy and allogeneic HCT cohorts. The difference on MRD in both cohorts prevented meaningful comparisons was due to both increased relapse and increased NRM in between MRD-positive and MRD-negative patients in both obese patients. The curative potential of both chemotherapy cohorts. As such, the role of allogeneic HCT vs. che- and allogeneic HCT appears to be reduced in obese AYAs motherapy in MRD-positive patients could not be explored. with ALL. Adipocytes appear to protect ALL cells from the In addition, it is possible that the allogenic HCT cohort had toxic effects of chemotherapy including daunorubicin, by higher risk features not identified here, including higher sequestration and metabolism, and asparaginase, through rates of MRD positivity, although if true this did not the release of glutamine [24–29]. NRM was also higher in translate into high relapse rates in the allogeneic HCT obese patients perhaps owing to lower tolerability of treat- cohort and would not be expected to affect NRM, the pri- ment due to comorbidities, high doses of therapy dosed on mary reason for the reduced survival seen with allogeneic body-surface area, or alternative pharmacokinetics or HCT relative to pediatric-style chemotherapy. The che- pharmacodynamics of drugs in the obese population. motherapy regimens received prior to allogeneic HCT in the Prior large studies focusing of obesity in adults undergoing transplant cohort were also not available and this may affect allogeneic HCT for hematologic malignancies have relapse rates and possibly NRM. Again, however, relapse not found a deleterious effect of obesity on OS or relapse rates were low with allogeneic HCT and superior to che- with some studies showing increased NRM [30–34]. It is motherapy whereas NRM was substantially higher with possible that the negative effect of obesity on OS and allogeneic HCT, an outcome less likely to be impacted by relapse seen here may be unique to ALL and the prior treatment with ALL-directed chemotherapies relative AYA population. to the chemotherapy cohort. Another limitation is the lack 2082 M. J. Wieduwilt et al. Table 3 Multivariate analysis. MRD-positive patients in CR1, although more study is Outcomes N HR (95% CI) P value needed. Obesity in AYAs with ALL warrants further Overall survival investigation as a potentially modifiable factor that nega- Main effect tively impacted survival. Chemotherapy 261 Reference Allogeneic HCT 217 2.00 <0.001 Acknowledgements CIBMTR Support List: The CIBMTR is sup- (1.50–2.66) ported primarily by Public Health Service U24CA076518 from the Body mass index (kg/m2) National Cancer Institute (NCI), the National Heart, Lung and Blood <30 332 Reference Institute (NHLBI) and the National Institute of Allergy and Infectious ≥30 146 2.17 <0.001 Diseases (NIAID); U24HL138660 from NHLBI and NCI; (1.63–2.89) U01HL128568 from the NHLBI; HHSH250201700006C, and Disease-free survival HHSH250201700007C from the Health Resources and Services Main effect Administration (HRSA); and N00014-18-1-2850, N00014-18-1-2888, Chemotherapy 261 Reference and N00014-20-1-2705 from the Office of Naval Research. Additional Allogeneic HCT 215 1.62 <0.001 (1.25–2.12) federal support is provided by P01CA111412, R01CA152108, Body mass index (kg/m2) R01CA215134, R01CA218285, R01CA231141, R01AI128775, <30 331 Reference R01HL126589, R01HL129472, R01HL130388, R01HL131731, ≥30 145 1.97 <0.001 U01AI069197, U01AI126612, and BARDA. Support is also provided (1.51–2.57) by Be the Match Foundation, Boston Children’s Hospital, Dana-Far- Relapse ber, St. Baldrick’s Foundation, Stanford University, the Medical Allogeneic HCT vs. chemotherapy ≤ 15 months after CR1 1.78 0.02 College of Wisconsin the National Marrow Donor Program, and from (1.10–2.88) the following commercial entities: AbbVie; Actinium Pharmaceuticals, Allogeneic HCT vs. chemotherapy > 15 months after CR1 0.34 <0.001 (0.19–0.62) Inc.; Adaptive Biotechnologies; Adienne SA; Allovir, Inc.; Amgen Body mass index (kg/m2) Inc.; Angiocrine Bioscience; Astellas Pharma US; AstraZeneca; Atara <30 331 Reference Biotherapeutics, Inc.; bluebird bio, Inc.; Bristol-Myers Squibb Co.; ≥30 145 1.84 <0.001 Celgene Corp.; CSL Behring; CytoSen Therapeutics, Inc.; Daiichi- (1.31–2.59) Sankyo Co., Ltd.; Gamida-Cell, Ltd.; Genentech Inc; HistoGenetics, Non-relapse mortality Inc.; Incyte Corporation; Janssen Biotech, Inc.; Jazz Pharmaceuticals, Main effect Inc.; Johnson & Johnson; Kiadis Pharma; Kite, a Gilead Company; Chemotherapy 261 Reference Kyowa Kirin; Legend Biotech; Magenta Therapeutics; Mallinckrodt Allogeneic HCT 215 5.41 <0.001 LLC; Merck & Company, Inc.; Merck Sharp & Dohme Corp.; Mil- (3.23–9.06) lennium, the Takeda Oncology Co.; Miltenyi Biotec, Inc.; Novartis Body mass index (kg/m2) Pharmaceuticals Corporation; Omeros Corporation; Oncoimmune, <30 331 Reference Inc.; Orca Biosystems, Inc.; Pfizer, Inc.; Pharmacyclics, LLC; Sanofi ≥30 145 2.10 <0.001 (1.37–3.23) Genzyme; Shire; Sobi, Inc.; Stemcyte; Takeda Pharma; Terumo BCT; Viracor Eurofins; Vor Bio Pharma; Xenikos BV. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the of testing for the Ph-like phenotype and IKAROS mutation/ Department of Defense, Health Resources and Services Administration loss in the allogeneic HCT cohort. Although traditional (HRSA), or any other agency of the U.S. Government. This research was supported by a training grant from the National Institutes of high-risk cytogenetic features had no impact on outcomes, Health, Clinical Pharmacoepidemiology training grant (Grant No. we were unable to assess if patients with Ph-like ALL may T32-GM075766 to CWE) and the Alex’s Lemonade Stand Foundation benefit from allogeneic HCT in CR1. Notable difference in (CWE). CIBMTR supports accessibility of research in accord with the the cohorts included extramedullary disease at diagnosis National Institutes of Health (NIH) Data Sharing Policy and the National Cancer Institute (NCI) Cancer Moonshot Public Access and and longer time to documentation of CR1 in the allogeneic Data Sharing Policy. The CIBMTR only releases de-identified datasets HCT cohort. Outside a formal clinical trial, documentation that comply with all relevant global regulations regarding privacy and of extramedullary disease may be incomplete and the timing confidentiality. of remission assessments may vary based on treatment regimen used and post-induction marrow assessments, Additional contributing co-authors from the writing committee Abhinav Deol, Ajoy Dias, Alexandra Gomez-Arteaga, Alison Loren, which in the transplant cohort were not determined by trial Amer Beitinjaneh, Antonio Jimenez, Arnon Nagler, Ayman Saad, B. timepoints. Last, changes in treatment modalities, addition Mona Wirk, Betty Hamilton, Biju George, Bipin Savani, Brenda of new therapeutic agents, and improvements in supportive Cooper, Brian Friend, Bruce Camitta, Celalettin Ustun, Cesar Freytes, care may have changed relapse rates and NRM in both Christen Ebens, Christopher Kanakry, David Valcarcel, Dipenkumar Modi, Dorothy Pan, Edmund Waller, Edwin Horwitz, Eric Huselton, populations since 2012. Gary Schiller, Geoffrey Uy, George Yaghmour, Giancarlo Fatobene, For AYAs with Ph-negative ALL in CR1, we conclude Gregory Hale, Guillermo J. Ruiz Arguelles, Haydar Frangoul, Hemant that AYAs receiving post-remission therapy with pediatric- Murthy, Hillard Lazarus, Hisham Abdel-Azim, Hongtao Liu, Ian style chemotherapy for Ph-negative ALL in CR1 should not Nivison-Smith, Ibrahim Ahmed, Ibrahim Aldoss, James Gajewski, Jan Cerny, Jeannine McCune, Jean-Yves Cahn, Jignesh Dalal, Joerg routinely undergo allogeneic HCT. Allogeneic HCT is Halter, John Raegan, John Wagner, Jong Wook Lee, Joseph Maa- warranted for patients refractory to or relapsing after karon, Kalyan Nadiminti, Kirk Schultz, Lazaros Lekakis, Lena pediatric-style regimens and may be warranted for high-risk Winestone, Leo F. Verdonck, Lori Muffly, Lynn Savoie, Madiha Superior survival with pediatric-style chemotherapy compared to myeloablative allogeneic hematopoietic. . . 2083 Iqbal, Mahmoud ALjurf, Manish Gandhi, Marc Bierings, Marjolein Celgene, personal fees from Kadmon, personal fees from Pfizer, per- van der Poel, Matthew Seftel, Maxim Norkin, Maxwell Krem, Mel- sonal fees from Incyte, personal fees from BMS, outside the submitted hem Solh, Michael Boyiadzis, Michael Byrne, Michael Grunwald, work. RAL reports personal fees from Amgen, personal fees from Michael Verneris, Miguel Angel Diaz, Minoo Battiwalla, Mitchell AstraZeneca, personal fees from Agios, personal fees from CVS/ Cairo, Mitchell Sabloff, Mohamed A. Kharfan-Dabaja, Monzr M. Al Caremark, personal fees and clinical trials from Celgene, personal fees Malki, Nasheed M. Hossain, Natasha Kekre, Nathan Sunita, Neel from Delta Fly, personal fees from Epizyme, personal fees and clinical Bhatt, Neil Palmisiano, Nelli Bejanyan, Nelson Chao, Olakekan trials from Novartis, personal fees from Takeda, clinical trials from Oluwole, Olle Ringden, Pashna Munshi, Passweg Jakob, Paul Castillo Astellas, clinical trials from Cellectis, clinical trials from Daiichi-San- Caro, Peter Wiernik, Rammurti Kamble, Ran Reshef, Reinhold kyo, clinical trials from Rafael Pharmaceuticals, clinical trials from Munker, Reshma Ramlal, Richard Larson, Richard Lin, Richard Forty Seven, outside the submitted work. DW reports grants from Maziarz, Richard Olsson, Robert Peter Gale, Robert Soiffer, Roni Incyte, personal fees from FATE Therapeutics, outside the submitted Shouval, Rory Shallis, Ryan Cassaday, Ryotaro Nakamura, Saar Gill, work. 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AS reports salary support from Vertex Pharmaceuticals/CRISPR Therapeutics paid to the Conflict of interest PBP reports Advisory from CELGENE-BMS, institution, non-financial support from Novartis, non-financial support Advisory from NOVARTIS, Advisory from KITE-GILEAD, Advisory from Magenta Therapeutics, outside the submitted work. He is the from AMGEN, outside the submitted work. MT reports personal fees principal investigator of a clinical trial for gene therapy of sickle cell from Miami Cancer Symposium, personal fees from NCCN, personal disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics. fees from UC Davis, personal fees from Mayo Clinic, personal fees The sponsor provides funding for the clinical trial, which includes from American Society of Hematology, personal fees from New salary support paid to his institution. This is not related in any way to Orleans, personal fees from ASCO, personal fees from Vanderbilt this work product. He also has research collaboration with Novartis, University, personal fees from Targeted Oncology, personal fees from Magenta Therapeutics, and Bluebird Bio for which he is not financially Indy, personal fees from Emirates Hematology Society, personal fees compensated in any way. 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Pfizer, personal fees from Novartis, personal fees from Sanofi-Aventis, org/licenses/by/4.0/. personal fees from Incyte, personal fees from Gilead, personal fees from Jazz, consulting and presentation to FDA for biosimilar review from Celltron/Teva, consulting and Advisory Board from Mustang, References consulting from Bayer, research support, consultant, Speakers Bureau, Advisory Board from Stemline, personal fees from Celegene, outside 1. Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, the submitted work. MdL reports grants from Pfizer, grants from Fielding AK, et al. In adults with standard-risk acute 2084 M. J. Wieduwilt et al. lymphoblastic leukemia, the greatest benefit is achieved from a 16. Butturini AM, Dorey FJ, Lange BJ, Henry DW, Gaynon PS, Fu C, matched sibling allogeneic transplantation in first complete et al. Obesity and outcome in pediatric acute lymphoblastic leu- remission, and an autologous transplantation is less effective than kemia. J Clin Oncol. 2007;25:2063–9. conventional consolidation/maintenance chemotherapy in all 17. Gelelete CB, Pereira SH, Azevedo AMB, Thiago SL, Mundim M, patients: final results of the International ALL Trial (MRC Land MGP, et al. Overweight as a prognostic factor in children with UKALL XII/ECOG E2993). Blood. 2008;111:1827–33. acute lymphoblastic leukemia. Obesity. 2011;19:1908–11. 2. Gupta V, Richards S, Rowe J. Allogeneic, but not autologous, 18. Ethier MC, Alexander S, Abla O, Green G, Lam R, Sung L. hematopoietic cell transplantation improves survival only among Association between obesity at diagnosis and weight change younger adults with acute lymphoblastic leukemia in first remis- during induction and survival in pediatric acute lymphoblastic sion: an individual patient data meta-analysis. Blood. leukemia. Leuk Lymphoma. 2012;53:1677–81. 2013;121:339–50. 19. Orgel E, Sposto R, Malvar J, Seibel NL, Ladas E, Gaynon PS, 3. Pidala, J, Diulbegovic, B, Anasetti, C, Kharfab-Dabajam M, et al. Impact on survival and toxicity by duration of weight Kumar A. Allogeneic hematopoietic cell transplantation for adult extremes during treatment for pediatric acute lymphoblastic leu- acute lymphoblastic leukemia (ALL) in first complete remission. kemia: a report from the Children’s Oncology Group. J Clin Cochrane Database Syst Rev. 2011;2011:CD008818. Oncol. 2014;32:1331–7. 4. Boissel N, Auclerc MF, Lheritier V, Perel Y, Thomas X, Leblanc 20. Denton, CC, Rawlins, YA, Oberley, MJ, Bhojwani, D, and Orgel, T, et al. Should adolescents with acute lymphoblastic leukemia be E. Predictors of hepatotoxicity and pancreatitis in children and treated as old children or young adults? Comparison of the French adolescents with acute lymphoblastic leukemia treated according FRALLE-93 and LALA-94 trials. J Clin Oncol. 2003;21:774–80. to contemporary regimens. Pediatr Blood Cancer. 2018;65. https:// 5. de Bont JM, Holt B, Dekker AW, van der Does-van den Berg A, doi.org/10.1002/pbc.26891. Sonneveld P, Pieters R.Significant difference in outcome for 21. Meenan CK, Kelly JA, Wang L, Ritchey AK, Maurer SH. Obesity adolescents with acute lymphoblastic leukemia treated on pedia- in pediatric patients with acute lymphoblastic leukemia increases tric vs adult protocols in the Netherlands. Leukemia. the risk of adverse events during pre-maintenance chemotherapy. 2004;18:2032–5. Pediatr Blood Cancer. 2019;66:e27515. 6. Ramanujachar R, Richards S, Hann I, Goldstone A, Mitchell C, 22. Núñez-Enríquez JC, Gil-Hernández AE, Jiménez-Hernández E, Vora A, et al. Adolescents with acute lymphoblastic leukaemia: Fajardo-Gutierrez A, Medina-Sanson A, Flores-Lujano J, et al. outcome on UK national paediatric (ALL97) and adult (UKALL- Overweight and obesity as predictors of early mortality in Mex- XII/E2993) trials. Pediatr Blood Cancer. 2007;48:254–61. ican children with acute lymphoblastic leukemia: a multicenter 7. Stock W, La M, Sanford B, Bloomfield C, Vardiman JW, Gaynon cohort study. BMC Cancer. 2019;19:708. P, et al.What determines the outcomes for adolescents and young 23. Heiblig M, Elhamri M, Nicolini FE, Wattel E, Michallet M, Salles adults with acute lymphoblastic leukemia treated on cooperative G, et al. Effect of initial body mass index on survival outcome of group protocols? A comparison of Children’s Cancer Group and patients with acute leukemia: a single-center retrospective study. Cancer and Leukemia Group B studies. Blood. 2008;112:1646–54. Clin Lymphoma Myeloma Leuk. 2015;15:S7–13. 8. Toft N, Birgens H, Abrahamsson J, Griskevicius L, Hallbook H, 24. Behan JW, Yun JP, Proektor MP, Ehsanipour EA, Arutyunyan A, Heyman M, et al. Results of NOPHO ALL2008 treatment for Moses AS, et al. Adipocytes impair leukemia treatment in mice. patients aged 1-45 years with acute lymphoblastic leukemia. Cancer Res. 2009;69:7867–74. Leukemia. 2018;32:606–15. 25. Yun JP, Behan JW, Heisterkamp N, Butturini A, Klemm L, Ji L, 9. Ram R, Wolach O, Vidal L, Gafter-Gvili A, Shpilberg O, Raa- et al. Diet-induced obesity accelerates acute lymphoblastic leu- nani. Adolescents and young adults with acute lymphoblastic kemia progression in two murine models. Cancer Prev Res. leukemia have a better outcome when treated with pediatric- 2010;3:1259–64. inspired regimens: systematic review and meta-analysis. Am J 26. Pramanik R, Sheng X, Ichihara B, Heisterkamp N, Mittelman SD. Hematol. 2012;87:472–8. Adipose tissue attracts and protects acute lymphoblastic leukemia 10. DeAngelo DJ, Stevenson KE, Dahlberg SE, Silverman LB, cells from chemotherapy. Leuk Res. 2013;37:503–9. Couban S, Supko JG, et al. Long-term outcome of a pediatric- 27. Ehsanipour EA, Sheng X, Behan JW, Wang X, Butturini A, Avramis inspired regimen used for adults aged 18-50 years with newly VI, et al. Adipocytes cause leukemia cell resistance to L-asparaginase diagnosed acute lymphoblastic leukemia. Leukemia. via release of glutamine. Cancer Res. 2013;73:2998–3006. 2015;29:526–34. 28. Sheng X, Tucci J, Parmentier JH, Ji L, Behan JW, Heisterkamp N, 11. Seftel MD, Neuberg D, Zhang MJ, Wang H-L, Ballen KK, Ber- et al. Adipocytes cause leukemia cell resistance to geron J, et al. Pediatric-inspired therapy compared to allografting daunorubicin via oxidative stress response. Oncotarget. for Philadelphia chromosome-negative adult ALL in first complete 2016;7:73147–59. remission. Am J Hematol. 2016;91:322–9. 29. Sheng X, Parmentier JH, Tucci J, Pei H, Cortez-Toledo O, Dieli- 12. Larsen EC, Devidas M, Chen S, Salzar WL, Raetz EA, Loh ML, Conwright CM, et al. Adipocytes sequester and metabolize the et al. Dexamethasone and high-dose methotrexate improve out- chemotherapeutic daunorubicin. Mol Cancer Res. come for children and young adults with high-risk b-acute lym- 2017;15:1704–13. phoblastic leukemia: a report from Children’s Oncology Group 30. Le Blanc K, Ringdén O, Remberger M. A low body mass index is Study AALL0232. J Clin Oncol. 2016;34:2380–8. correlated with poor survival after allogeneic stem cell trans- 13. Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan plantation. Haematologica. 2003;88:1044–52. CG, et al. A pediatric regimen for older adolescents and young 31. Nikolousis E, Nagra S, Paneesha S, Delgado J, Holder K, Bratby adults with acute lymphoblastic leukemia: results of CALGB L, et al. Allogeneic transplant outcomes are not affected by body 10403. Blood. 2019;133:1548–59. mass index (BMI) in patients with haematological malignancies. 14. Gray, RJ. A class of K-sample tests for comparing the cumulative Ann Hematol. 2010;89:1141–5. incidence of a competing risk. Ann Stat. 1988;16:1141–54. 32. Navarro WH, Agovi MA, Logan BR, Ballen K, Bolwell BJ, 15. Dhedin N, Huynh A, Maury S, Tabrizi R, Beldjord K, Asnafi V, Frangoul H, et al. Obesity does not preclude safe and effective et al. Role of allogeneic stem cell transplantation in adult patients myeloablative hematopoietic cell transplantation (HCT) for acute with Ph-negative acute lymphoblastic leukemia. Blood. myelogenous leukemia (AML) in adults. Biol Blood Marrow 2015;125:2486–96. Transplant. 2010;16:1442–50. Superior survival with pediatric-style chemotherapy compared to myeloablative allogeneic hematopoietic. . . 2085 33. Aplenc R, Zhang MJ, Sung L, Zhu X, Ho VT, Cooke K, et al. 34. Fuji S, Takano K, Mori T, Eto T, Taniguchi S, Ohashi K, et al. Effect of body mass in children with hematologic malignancies Impact of pretransplant body mass index on the clinical outcome undergoing allogeneic bone marrow transplantation. Blood. after allogeneic hematopoietic SCT. Bone Marrow Transplant. 2014;123:3504–11. 2014;49:1505–12. Affiliations Matthew J. Wieduwilt 1 Wendy Stock2 Anjali Advani 3 Selina Luger 4 Richard A. Larson 2 ● ● ● ● ● Martin Tallman5 Frederick Appelbaum6 Mei-Jie Zhang7,8 Khalid Bo-Subait7 Hai-Lin Wang7 ● ● ● ● ● Vijaya Raj Bhatt 9 Bhagirathbhai Dholaria 10 Mary Eapen7 Mehdi Hamadani 11 Omer Jamy12 ● ● ● ● ● Tim Prestidge 13 Michael Pulsipher 14 David Ritchie15 David Rizzieri16 Akshay Sharma 17 Pere Barba ● ● ● ● ● 18 ● Brenda M. Sandmaier 19,20 Marcos de Lima 21 Partow Kebriaei 22 Mark Litzow 23 Wael Saber7 ● ● ● ● ● Daniel Weisdorf 24 1 14 University of California, San Diego Medical Center, La Jolla, CA, Section of Transplantation and Cellular Therapy, Children’s USA Hospital Los Angeles Cancer and Blood Disease Institute, USC 2 Keck School of Medicine, Los Angeles, CA, USA University of Chicago Medicine, Chicago, IL, USA 15 3 Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA Melbourne, Vic, Australia 4 Abramson Cancer Center, University of Pennsylvania Medical 16 Division of Hematologic Malignancies and Cellular Therapy, Center, Philadelphia, PA, USA Duke University, Durham, NC, USA 5 Leukemia Service, Department of Medicine, Memorial Sloan 17 Department of Bone Marrow Transplantation and Cellular Kettering Cancer Center, New York, NY, USA Therapy, St. Jude Children’s Research Hospital, Memphis, TN, 6 USA Fred Hutchinson Cancer Research Center, Seattle, WA, USA 18 7 Vall Hebron University Hospital—Universitat Autonoma de Center for International Blood and Marrow Transplant Research, Barcelona, Barcelona, Spain Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA 19 Division of Medical Oncology, University of Washington, 8 Seattle, WA, USA Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, WI, USA 20 Clinical Research Division, Fred Hutchinson Cancer Research 9 Center, Seattle, WA, USA The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA 21 Seidman Cancer Center, University Hospitals Case Medical 10 Center, Cleveland, OH, USA Vanderbilt University Medical Center, Nashville, TN, USA 22 11 Department of Stem Cell Transplantation, Division of Cancer BMT and Cellular Therapy Program, Department of Medicine, Medicine, The University of Texas MD Anderson Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA Houston, TX, USA 12 University of Alabama at Birmingham, Birmingham, AL, USA 23 Division of Hematology and Transplant Center, Mayo Clinic, 13 Blood and Cancer Centre, Starship Children’s Hospital, Rochester, MN, USA Auckland, New Zealand 24 Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA