Abstract
Large studies comparing reduced-intensity/non-myeloablative conditioning (RIC/NMA) versus myeloablative conditioning (MAC) regimens in T-cell non-Hodgkin lymphoma (T-NHL) patients undergoing allogeneic transplant (alloHCT) have not been performed. 803 adults with peripheral T-cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma, aged 18-65yrs, undergoing alloHCT between 2008-2019 and reported to CIBMTR, with either MAC (n=258) or NMA/RIC regimens (n=545) were evaluated. There were no significant differences between the two cohorts in terms of patient sex, race, and performance scores. Significantly more patients in the RIC/NMA cohort had PB grafts, HCT-CI of ≥3 and chemosensitive disease compared to the MAC cohort. On multivariate analysis, overall survival (OS) was not significantly different in the RIC/NMA cohort relative to the MAC cohort (HR=1.01, 95%CI=0.79-1.29; P=0.95). Similarly, non-relapse mortality (NRM) (HR=0.85, 95%CI=0.61-1.19; P=0.34), risk of progression/relapse (HR=1.29; 95%CI=0.98-1.70; P=0.07) and therapy failure (HR=1.14; 95%CI=0.92-1.41, P=0.23) were not significantly different between the two cohorts. Relative to MAC, RIC/NMA was associated with significantly lower risk of grade 3-4 acute GVHD (HR=0.67; 95%CI=0.46-0.99, P=0.04). Among chemorefractory patients, there was no difference in OS, therapy failure, relapse, or NRM between RIC/NMA and MAC regimens. In conclusion, we found no association between conditioning intensity and outcomes after alloHCT for T-cell NHL.
Keywords: mature T-cell NHL, allogeneic transplant, myeloablative conditioning, reduced-intensity conditioning
Introduction
Mature T-cell lymphomas are a heterogeneous group of aggressive neoplasms that constitute approximately 15% of all non-Hodgkin lymphomas (NHL) in adults.(1) The most common subtypes within mature nodal T-cell lymphomas are peripheral T-cell lymphoma – not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALCL), and angioimmunoblastic T cell lymphomas (AITL). With the exception of ALCL (especially the anaplastic lymphoma kinase [ALK] positive subset), disease relapse following first line treatment in mature nodal T-cell lymphomas is expected in the majority of patients. In the relapsed/refractory setting available therapy options typically do not provide durable disease control,(2–4) and allogeneic hematopoietic cell transplant (alloHCT) remains the only potentially curative option.(5–9) In fact, with the rapidly declining utilization of alloHCT for aggressive B-cell lymphomas, T-cell NHL now constitutes the most common indication of alloHCT for lymphomas in the United States and Europe.(10)
The alloHCT conditioning regimens have a spectrum of dose-intensities, ranging from regimens at the lower end of the intensity spectrum (relying predominately on immunological effects to eradicate disease) to higher-intensity options (that depend on both cytoreductive and immunological mechanisms to control disease)(11). Reduced-intensity and non-myeloablative conditioning (RIC/NMA) regimens now account for the vast majority of alloHCT performed for lymphomas in the United States(7, 11–16). Although the RIC regimens are generally associated with a lower cumulative incidence of non-relapse mortality (NRM) relative to myeloablative conditioning (MAC) regimens, disease relapse remains the most common cause of treatment failure in patients with lymphoma undergoing alloHCT. Retrospective studies comparing conditioning regimen intensities, including predominantly patients with B-cell NHL or classical Hodgkin lymphoma, generally show higher NRM rates with high-intensity conditioning without a consistent survival benefit.(14, 17–22)
There are sparse data directly comparing clinical outcomes of patients who have undergone RIC/NMA versus MAC alloHCT for mature T-cell NHL(23). Using the observational database of the Center for International Blood and Marrow Transplant Research (CIBMTR), we report here the outcomes of PTCL-NOS, AITL and ALCL patients according to the intensity of alloHCT conditioning regimens.
Methods
Data source
The CIBMTR is a working group comprised of over 380 transplantation centers worldwide that provide data regarding HCT to a statistical center at the Medical College of Wisconsin (MCW). On-site audits ensure compliance of participating transplant centers in reporting all transplantations consecutively. Additionally, quality of data is further augmented through computerized affirmation of discrepancies, physicians’ review of submitted data, and on-site audits of participating centers. Observational studies are conducted by the CIBMTR in compliance with all pertinent federal regulations with regards to protection of human research participants. All patients included in this analysis have provided written consent for research. The International Review Board of MCW and the National Marrow Donor Program have approved this study.
Patients
This analysis included adults between ages of 18-65 years diagnosed with PTCL-NOS, ALCL and AITL who underwent RIC/NMA or MAC alloHCT between 2008 and 2019. Patients 66 years and older were not included, as patients at advanced age are less likely to receive MAC regimens. Eligible donors included haploidentical donors, HLA-identical sibling donors and unrelated donors (MUD) matched at the allele-level at HLA-A, HLA-B, HLA-C and HLA-DRB1. Graft sources included bone marrow or peripheral blood. GVHD prophylaxis consisted of calcineurin inhibitor (CNI)-based approaches. Patients who received a haploidentical HCT and did not receive post-transplant cyclophosphamide-based GVHD prophylaxis were excluded. The patients were divided into two cohorts: MAC and NMA/RIC regimens. Patients with ex vivo T-cell depletion were excluded. Patient receiving in vivo T-cell depletion with anti-thymocyte globulin were included.
Definitions and endpoints
The intensity of alloHCT conditioning regimens was defined using consensus criteria(24). Disease response at the time of alloHCT was determined using the International Working Group criteria in use during the era of this analysis.(25–27). Patients not in a complete or partial remission at the time of alloHCT were considered chemorefractory. The primary endpoint was overall survival (OS). Death from any cause was considered an event. For progression-free survival (PFS), a patient was considered a treatment failure at the time of progression/relapse or death from any cause. Patients alive without evidence of disease relapse or progression were censored at last follow-up. Secondary outcomes included NRM and progression/relapse. NRM was defined as death without evidence of prior lymphoma progression/relapse; relapse was considered a competing risk. Progression/relapse was defined as progressive lymphoma after HCT or lymphoma recurrence after a CR; NRM was considered a competing risk. Acute GVHD and chronic GVHD were graded using established clinical criteria.(28, 29) Probabilities of PFS and OS were calculated using the Kaplan–Meier estimates. Neutrophil recovery was defined as the first of 3 successive days with ANC ≥500/μL after post-transplantation nadir. Platelet recovery was considered to have occurred on the first of three consecutive days with platelet count 20,000/μL or higher, in the absence of platelet transfusion for 7 consecutive days. For neutrophil and platelet recovery, death without the event was considered a competing risk.
Statistical analysis
The study compared conditioning intensities, MAC versus NMA/RIC, in patients who underwent allo-HCT for PTCL-NOS, ALCL and AITL. Chi-square test for categorical variables and Kruskal-Wallis test for continuous variables were used to compare baseline characteristics. The Cox model was used for OS and PFS. The proportional cause-specific hazards model was used for GVHD, relapse and NRM to account for competing risks(30). The proportional hazards assumption was tested by examining a time-varying effect for each risk factor and each outcome. A forward stepwise selection was used to identify significant variables while conditioning intensity was kept in all models. The interaction between conditioning intensity and significant variables were checked. Variables tested in the regression models included conditioning intensity, patient-related variables including patient’s age, sex, Karnofsky performance status, HCT comorbidity index, disease-related characteristics including time from diagnosis to HCT, lymphoma histology, history of autologous transplant and disease status at the time of alloHCT, as well as transplant-related factors including donor type, CMV serostatus, use of total body irradiation in conditioning and year of transplant.
To further confirm the regression analysis results, we conducted propensity score matching. To calculate propensity scores, we used multiple imputation using R package smcfcs and Rubin’s rule to handle missing covariates(31–33). Using calculated propensity scores, we matched MAC and RIC/NMA cohorts using R package MatchIt with 1:2 matching ratio for MAC and NMA/RIC(34). The marginal model was used to handle correlation within matched pairs(35). In addition, we also fitted regression models after restricting the patients to younger than or equal to 50 years old. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC) and R version 4.0.4 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Baseline characteristics
A total of 803 patients from 122 different CIBMTR reporting transplant centers, including 545 receiving RIC/NMA and 258 patients receiving MAC regimens met the eligibility criteria of this analysis (Table 1). Three NHL histologies were included in this analysis; 52% with PTCL-NOS, 31% with ALCL and 17% with AITL were in the MAC cohort. In patients that received RIC/NMA regimens, 45%, 27% and 28% had PTCL-NOS, ALCL and AITL, respectively. The median age of patients was significantly lower (46 years [range=18-66]) in the MAC cohort compared to (54 years [range=18-66]) patients who underwent RIC/NMA conditioning. There were no significant differences between the MAC and RIC/NMA cohorts in terms of patient gender, race, and Karnofsky performance scores. Significantly more patients in the RIC/NMA cohort had peripheral blood grafts (92% vs. 87%), history of prior autologous HCT (39% vs. 16%), HCT comorbidity index of 3 or higher (40% vs. 29%) and chemosensitive disease before alloHCT (87% vs. 79%; Table 1). Matched siblings as donors (54% vs. 44%), total body irradiation (TBI) containing conditioning (66% vs. 28%) and CNI plus methotrexate as GVHD prophylaxis (71% vs. 45%) were more frequent in MAC cohort. There was no significant difference in the baseline characteristics of the propensity score matched patient subset (N=360), except for higher median age in the RIC/MAC cohort (53 years vs. 49 years) (Supplemental Table 1S).
Table 1.
Baseline patient characteristics
| Characteristic | MAC | RIC/NMA | P value1 |
|---|---|---|---|
| No. of patients | 258 | 545 | |
|
| |||
| Median Patient age – (range) | 46 (18-65) | 54 (18-65) | <.01a |
|
| |||
| Male sex - no. (%) | 169 (66) | 346 (63) | 0.58b |
|
| |||
| Karnofsky performance score - ≥90 no. (%) | 158 (61) | 310 (57) | 0.17b |
| Not reported | 3 (1) | 17 (3) | |
|
| |||
| Patient race - no. (%) | 0.09b | ||
| Caucasian | 190 (74) | 438 (80) | |
| African American | 30 (12) | 44 (8) | |
| Asian/Pacific islander | 12 (4) | 30 (5) | |
| Missing | 26 (10) | 33 (6) | |
|
| |||
| Peripheral Blood Graft - no. (%) | 224 (87) | 504 (92) | 0.01b |
|
| |||
| Donor type - no. (%) | <.01b | ||
| Matched sibling donors | 140 (54) | 238 (44) | |
| Haploidentical donors | 22 (9) | 69 (13) | |
| MUD with ATG | 25 (10) | 98 (18) | |
| MUD without ATG | 71 (28) | 140 (26) | |
|
| |||
| HCT-CI 3 or more - no. (%) | 75 (29) | 220 (40) | <.01b |
|
| |||
| Lines of prior therapy - median (min-max) | 2 (1-5) | 2 (1-5) | 0.28b |
|
| |||
| Remission status- no. (%) | <.01b | ||
| Complete remission2 | 110 (43) | 279 (51) | |
| Partial Remission | 93 (36) | 196 (36) | |
| Chemoresistant | 55 (21) | 70 (13) | |
|
| |||
| TBI in conditioning - no. (%) | <.01b | ||
| TBI-containing | 169 (66) | 155 (28) | |
| TBI-free | 89 (34) | 390 (72) | |
|
| |||
| Conditioning Regimens | |||
| CY/TBI | 122(47) | 1 (<1) | |
| Bu/CY | 35 (14) | - | |
| Flu/Bu | 46 (18) | 134 (25) | |
| Flu/TBI +/− others | 20 (7) | 59 (11) | |
| Flu/Mel +/− others | - | 187 (34) | |
| Flu/CY/TBI | 1 (<1) | 70 (13) | |
| Others | 34 (14) | 94 (17) | |
|
| |||
| GVHD prophylaxis - no. (%) | <.01b | ||
| Post-CY ± other(s) | 22 (9) | 69 (13) | |
| CNI + MMF ± other(s) (except post-CY) | 26 (10) | 153 (28) | |
| CNI + MTX ± other(s) (except MMF, post-CY) | 184 (71) | 246 (45) | |
| CNI + other(s) (except MMF, MTX, post-CY) | 18 (7) | 66 (12) | |
| CNI alone | 8 (3) | 11 (2) | |
|
| |||
| Lymphoma histology - no. (%) | <.01b | ||
| PTCL-NOS | 134 (52) | 243 (45) | |
| ALCL | 81 (31) | 147 (27) | |
| AITL | 43 (17) | 155 (28) | |
|
| |||
| History of autologous transplant - no. (%) | 40 (16) | 214 (39) | <.01b |
|
| |||
| Median Time from diagnosis to HCT - no. (%) | 12 (3-208) | 15 (2-247) | <.01a |
|
| |||
| Follow-up - median (min-max) | 62 (3-145) | 60 (3-145) | |
Abbreviations: ALCL, anaplastic large cell lymphoma; AITL, angioimmunoblastic T-cell lymphoma; Bu, busulfan; CNI, calcineurin inhibitor; CY, cyclophosphamide; Flu, fludarabine; GVHD, graft versus host disease; HCT, hematopoietic cell transplant; NMA, non-myeloablative; MAC, mel, melphalan; myeloablative conditioning; MMF, mycophenolate mofetil; MTX, methotrexate; PTCL-NOS, peripheral T cell lymphoma- not other specified; RIC, reduced intensity conditioning; TBI, total body irradiation.
Hypothesis testing: a Kruskal-Wallis test b Pearson chi-square test
5 patients (2%) in MAC and 6 (1%) in RIC/NMA groups were in CR1 after 1 prior line of therapy at the time of alloHCT
Overall survival
On univariate analysis, the OS was 61% and 57% at 3- and 5-years in the MAC cohort, respectively. The respective figures for patient receiving RIC/NMA regimens were 64% and 59% (Figure 1A, Table 2). Among patients with chemoresistant disease before alloHCT, the 5-year OS was 55% and 49% in the MAC and RIC/NMA cohorts, respectively (p=0.55; Table 3). On multivariate analysis, after adjusting for all independently significant covariates (Karnofsky performance status, history of autologous transplant and year of transplant) the OS was not significantly different in RIC/NMA cohort relative to MAC (HR=1.01, 95%CI=0.79-1.29, p=0.95; Table 4).
Figure 1.
Overall survival (1A), non-relapse mortality (1B), relapse/progression (1C) and progression-free survival (1D) through 5-years of patients receiving myeloablative (MAC) and non-myeloablative (NMA)/reduced-intensity (RIC) conditioning regimen prior to an alloHCT for peripheral T-cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma.
Table 2.
Univariate outcomes of patients with peripheral T-cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma who received MAC versus RIC/NMA conditioning regimens prior to alloHCT.
| MAC (N = 258) | RIC/NMA (N = 545) | ||||
|---|---|---|---|---|---|
| Outcomes | N | Prob (95% CI) | N | Prob (95% CI) | P Value |
| Neutrophil recovery | 258 | 541 | |||
| 30-day | 95 (92-97)% | 97 (95-98)% | 0.34 | ||
| Platelet recovery | 250 | 535 | |||
| 100-day | 87 (83-91)% | 94 (91-96)% | 0.005 | ||
| Grade 2-4 acute GVHD | 245 | 510 | |||
| 180-day | 41 (35-48)% | 36 (32-40)% | 0.16 | ||
| Grade 3-4 acute GVHD | 245 | 510 | |||
| 180-day | 18 (14-23)% | 13 (10-16)% | 0.08 | ||
| Chronic GVHD | 244 | 520 | |||
| 1-year | 41 (35-47)% | 43.9 (40-48)% | 0.42 | ||
| 2-year | 50 (44-57)% | 51.9 (47-56)% | 0.70 | ||
| NRM | 256 | 540 | |||
| 100-day | 11 (8-16)% | 7 (5-9)% | 0.04 | ||
| 1-year | 17 (13-22)% | 12 (10-15)% | 0.09 | ||
| 3-year | 20 (16-26)% | 19 (16-23)% | 0.73 | ||
| 5-year | 24 (19-30)% | 23 (19-27)% | 0.76 | ||
| Progression/relapse | 256 | 540 | |||
| 1-year | 27 (22-33)% | 28 (24-31)% | 0.91 | ||
| 3-year | 30 (24-36)% | 31 (27-35)% | 0.69 | ||
| 5-year | 31 (25-37)% | 31 (28-36)% | 0.93 | ||
| PFS | 256 | 540 | |||
| 1-year | 56 (50-62)% | 60 (56-64)% | 0.26 | ||
| 3-year | 50 (44-56)% | 50 (45-54)% | 0.93 | ||
| 5-year | 45 (39-52)% | 46 (41-50)% | 0.86 | ||
| Overall survival | 258 | 545 | |||
| 1-year | 71 (65-76)% | 77 (73-80)% | 0.09 | ||
| 3-year | 61 (55-67)% | 64 (59-68)% | 0.52 | ||
| 5-year | 57 (51-63)% | 59 (54-63)% | 0.64 | ||
Abbreviations: GVHD, graft versus host disease; MAC, myeloablative conditioning; NMA, non-myeloablative; NRM, non-relapse mortality; PFS, progression-free survival; RIC, reduced intensity conditioning.
Table 3.
Subgroup univariate outcomes: chemoresistant patients
| MAC (N = 55) | NMA/RIC (N = 70) | ||||
|---|---|---|---|---|---|
| Outcomes | N | Prob (95% CI) | N | Prob (95% CI) | P Value |
| NRM | 55 | 70 | 0.47 | ||
| 100-day | 11 (4-21)% | 14 (7-24)% | 0.57 | ||
| 1-year | 14 (7-25)% | 17 (9-27)% | 0.69 | ||
| 3-year | 16 (8-28)% | 19 (11-29)% | 0.72 | ||
| 5-year | 19 (9-31)% | 25 (15-37)% | 0.42 | ||
| Progression/Relapse | 55 | 70 | 0.56 | ||
| 1-year | 42 (29-55)% | 40 (29-52)% | 0.88 | ||
| 3-year | 44 (31-57)% | 40 (29-52)% | 0.72 | ||
| 5-year | 49 (35-63)% | 40 (29-52)% | 0.36 | ||
| PFS | 55 | 70 | 0.98 | ||
| 1-year | 44 (31-57)% | 43 (31-54)% | 0.89 | ||
| 3-year | 40 (27-53)% | 41 (29-52)% | 0.94 | ||
| 5-year | 32 (20-46)% | 35 (23-46)% | 0.81 | ||
| Overall survival | 55 | 70 | 0.74 | ||
| 1-year | 66 (53-77)% | 65 (54-76)% | 1.00 | ||
| 3-year | 62 (48-74)% | 55 (43-67)% | 0.48 | ||
| 5-year | 55 (41-68)% | 49 (37-62)% | 0.55 | ||
Abbreviations: MAC, myeloablative conditioning; NMA, non-myeloablative; NRM, non-relapse mortality; PFS, progression-free survival; RIC, reduced intensity conditioning.
Table 4.
Multivariate analysis of patients with PTCL, ALCL and AITL patients receiving alloHCT during 2008-2019.
| Grade 2-4 acute GVHD | N | HR (95% CI) | p-value | Overall p-value |
|---|---|---|---|---|
| MAC | 245 | 1 | 0.09 | |
| NMA/RIC | 510 | 0.81 (0.64-1.03) | 0.09 | |
| Grade 3-4 acute GVHD | N | HR (95% CI) | p-value | Overall p-value |
| MAC | 245 | 1 | 0.04 | |
| NMA/RIC | 510 | 0.67 (0.46-0.99) | 0.04 | |
| Grade 3-4 acute GHVD adjusted for significant covariate: Donor type. | ||||
| Chronic GVHD | N | HR (95% CI) | p-value | Overall p-value |
| MAC | 244 | 1 | 0.83 | |
| NMA/RIC | 520 | 0.98 (0.79-1.21) | 0.83 | |
| Chronic GVHD adjusted for significant covariates: Donor type, Time from diagnosis to transplant. | ||||
| Non-relapse mortality | N | HR (95% CI) | p-value | Overall p-value |
| MAC | 256 | 1 | 0.34 | |
| NMA/RIC | 540 | 0.85 (0.61-1.19) | 0.34 | |
| NRM adjusted for significant covariates: Age, KPS, and Year of transplant. | ||||
| Progression/relapse | N | HR (95% CI) | p-value | Overall p-value |
| MAC | 256 | 1 | 0.07 | |
| NMA/RIC | 540 | 1.29 (0.98-1.70) | 0.07 | |
| Progression/relapse adjusted for significant covariates: Disease status, NHL histology, History of autologous transplant. | ||||
| Progression free survival | N | HR (95% CI) | p-value | Overall p-value |
| MAC | 256 | 1 | 0.23 | |
| NMA/RIC | 540 | 1.14 (0.92-1.41) | 0.23 | |
| Progression free survival adjusted for significant covariates: NHL histology Disease status, History of autologous transplant, Year of transplant. | ||||
| Overall Survival | N | HR (95% CI) | p-value | Overall p-value |
| MAC | 258 | 1 | 0.95 | |
| NMA/RIC | 545 | 1.01 (0.79-1.29) | 0.95 | |
| Overall survival adjusted for significant covariates: KPS, History of autologous transplant, Year of transplant. | ||||
Abbreviations: ALCL, anaplastic large cell lymphoma; AITL, angioimmunoblastic T-cell lymphoma; GVHD, graft versus host disease; HR, hazard ratio; MAC, myeloablative conditioning; NMA, non-myeloablative; NRM, non-relapse mortality; PTCL-NOS, peripheral T cell lymphoma- not other specified; RIC, reduced intensity conditioning.
There were 322 reported deaths. The most common cause of death was primary disease in 41% and 33% of patients in MAC and RIC/NMA, respectively. GVHD accounted 18% and 20% of deaths in MAC and RIC/NMA cohorts, respectively, while infections accounted for 15% and 18% of deaths in similar order (details in Supplemental Table 2S)
Non-relapse mortality
On univariate analysis (Table 2), the NRM at 100-days was significantly higher in the MAC cohort (11%) compared to NMA/RIC cohort (7%; P=0.04; Figure 1B). The 5-year NRM in similar order was 24% and 23%, respectively. In the chemoresistant subset (Table 3) the 5-year NRM in the MAC and RIC/MAC cohorts was 19% and 25% (p=0.42), respectively. After adjusting for all independently significant covariates (age, Karnofsky performance status, and year of transplant) on multivariate analysis the NRM risk was not significantly lower after RIC/NMA relative to MAC (HR=0.85, 95%CI=0.61-1.19; P=0.34; Table 4).
Relapse and progression-free survival
The cumulative incidence of progression/relapse at 5-years, was similar in both cohorts at 31% (P=0.93; Figure 1C; Table 2). Among the chemoresistant cohort, the 5-year cumulative incidence of progression/relapse was 49% following MAC compared to 40% following NMA/RIC (P=0.81; Table 3). On multivariate analysis (Table 4), the risk of progression/relapse was not significantly higher with NMA/RIC relative to MAC (HR=1.29; 95%CI=0.98-1.70; P=0.07) cohorts.
The 5-year PFS of patients receiving MAC and RIC/NMA was 45% and 46%, respectively (P=0.86; Table 2). The respective figures for the chemoresistant subgroup were 32% and 35% (Table 3). On multivariate analysis, the risk of therapy failure (inverse of PFS) was not significantly different following RIC/NMA relative to MAC (HR=1.14; 95%CI=0.92-1.41, P=0.23; Table 4).
RIC vs. NMA regimens
There was no difference in the survival outcomes of patients receiving RIC vs. NMA conditioning regimens. The 5-year NRM, relapse, PFS and OS of patient receiving RIC vs. NMA conditioning regimens was 23% vs. 22%; 31% vs. 34%; 46% vs. 44% and 59% vs. 58% respectively (all p-values non-significant).
Hematopoietic recovery
The cumulative incidence of neutrophil recovery at day 30 was not significantly different between the RIC/NMA cohort (97%) and the MAC cohort (95%; P=0.34; Table 2). The cumulative incidence of platelet recovery at day 100 was significantly higher in the RIC/NMA cohort at 94% compared to 87% in the MAC cohort (P=0.005).
Acute and chronic GVHD
On univariate analysis, the day 180 cumulative incidence of grade 3-4 acute GVHD following MAC and RIC was 18% and 13%, respectively (P=0.08, Table 2; Figure 2). On multivariate analysis, relative to MAC, RIC/NMA was associated with significantly lower risk of grade 3-4 acute GVHD (HR=0.67; 95%CI=0.46-0.99, P=0.04; Table 4). The 2-year cumulative incidence of chronic GVHD following MAC and RIC was 50% and 51.9%, respectively (P=0.70, Table 2). On multivariate analysis, the risk of chronic GVHD was not significantly different following RIC/NMA relative to MAC (HR=0.98; 95%CI=0.79-1.21, P=0.83; Table 4).
Figure 2.
Cumulative incidence of grade 3-4 acute GvHD in patients receiving myeloablative (MAC) and non-myeloablative (NMA)/reduced-intensity (RIC) conditioning regimens
Propensity score matched subset
Multivariate analysis on a propensity score matched subset (Table 1S) showed results concordant with multivariate analysis in the overall study population with no statistically significant differences between the MAC and RIC/NMA cohorts in terms of chronic GVHD, NRM, relapse risk and survival outcomes, and lower grade 3-4 acute GVHD risk among the RIC/NMA recipients (Table 5).
Table 5.
Multivariate analysis of outcomes: propensity score matched data
| Grade 2-4 acute GVHD | N | HR (95% CI) | Overall p-value |
|---|---|---|---|
| MAC | 182 | 1 | 0.37 |
| RIC/NMA | 156 | 0.86 (0.62-1.20) | |
| Grade 3-4 acute GVHD | N | HR (95% CI) | Overall p-value |
| MAC | 182 | 1 | 0.02 |
| RIC/NMA | 156 | 0.49 (0.26-0.91) | |
| Chronic GVHD | N | HR (95% CI) | Overall p-value |
| MAC | 190 | 1 | 0.45 |
| RIC/NMA | 166 | 1.12 (0.83-1.51) | |
| Non-relapse mortality | N | HR (95% CI) | Overall p-value |
| MAC | 190 | 1 | 0.79 |
| RIC/NMA | 166 | 0.94 (0.58-1.50) | |
| Progression/relapse | N | HR (95% CI) | Overall p-value |
| MAC | 190 | 1 | 0.48 |
| RIC/NMA | 166 | 1.14 (0.80-1.62) | |
| Progression free survival | N | HR (95% CI) | Overall p-value |
| MAC | 190 | 1 | 0.87 |
| RIC/NMA | 166 | 1.02 (0.77-1.35) | |
| Overall Survival | N | HR (95% CI) | Overall p-value |
| MAC | 192 | 1 | 0.96 |
| RIC/NMA | 168 | 0.99 (0.72-1.36) |
Abbreviations: GVHD, graft versus host disease; HR, hazard ratio; MAC, myeloablative conditioning; NMA, non-myeloablative; NRM, non-relapse mortality; RIC, reduced intensity conditioning.
Outcomes of patients in complete or partial remission at the time of alloHCT are shown in Supplemental Table 3S. Multivariate analysis restricted to patients ≤ 50 years of age (Supplemental Table 4S) showed results in line with overall study population.
Discussion
In this large registry analysis, we evaluated the impact of conditioning regimen intensity on the outcomes of 803 patients with mature nodal T-cell lymphomas undergoing an alloHCT in 122 CIBMTR reporting transplant centers. We found no significant difference with regards to OS, PFS, and cumulative incidences of NRM and relapse among patients receiving MAC or RIC/NMA regimens. There was, however, a significant reduction in the risk of grade 3-4 acute GVHD in patients that received NMA/RIC compared to MAC regimens.
There is a paucity of data comparing MAC versus RIC/NMA in patients with T-cell NHL. In a prior smaller CIBMTR study (era: 1996-2006; alloHCT N=126)(6), where 59 patients received MAC and 36 RIC/NMA regimens, disease relapse was more frequent with RIC (3-year relapse MAC vs. RIC = 32% vs. 40%), while NRM was higher with MAC (3-year NRM MAC vs. RIC = 32% vs. 27%), with OS favoring lower-intensity approaches (3-year OS MAC vs. RIC = 39% vs. 52%). A recent retrospective study from Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) included 285 patients with T-cell NHL transplanted during 2006-2014.(23) Sixty-two percent of patients in the study received RIC regimen while 38% received MAC. The 2-year relapse rate was 22% in the MAC group and 17% in the RIC group. The 2-year NRM in similar order 21% and 24% respectively. In addition, no significant difference between MAC and RIC for OS (p = 0.5) or event-free survival (p = 0.55) was seen. Of note in addition to common nodal variants of T-cell NHL (i.e. PTCL-NOS, AITL, ALCL), the French analysis also included a sizeable subset of rare T-cell and NK-cell subtypes. In a more homogenous cohort, our analysis reports concordant finding, but in addition shows a higher risk of severe acute GVHD following MAC regimens.
Higher intensity conditioning regimens can, in theory, provide post-transplant disease control among refractory patients, to allow time for graft-versus lymphoma effects to develop. An important observation from our current analysis is that, even among the subset of patients with refractory disease at alloHCT (N=125; Table 3), MAC regimens provided no significant benefit in terms of reducing the risk of disease relapse, PFS or OS. These observations are in line with prior data for refractory aggressive B-cell NHL, where MAC have not been conclusively shown to provide better disease control.(19, 36–38) In addition, a prior registry study limited to AITL patients undergoing alloHCT also did not suggest a benefit of MAC over RIC/NMA approaches.(39) The current analysis (era: 2008-2019; N=803; upper age limit 65 years; limited to PTCL-NOS; AITL, ALCL), allows us to also interpret modern alloHCT outcomes in T-cell NHL, relative to historical data reported by prior CIBMTR study(6) (1996-2006; N=126; upper age limit 60 years; limited to PTCL-NOS; AITL, ALCL). These two analyses suggest that among patients receiving MAC regimens the 3-year NRM rates have improved from 32% to 20% and 3-year OS from 39% to 61%. Among patients receiving RIC/NMA regimens the 3-year NRM has improved from 27% to 19%, and 3-year OS from 52% to 64%.
A recent registry analysis from the Spanish GETH/GELTAMO Centers(40) evaluated 201 patients with mature T and natural killer (NK) T cell neoplasia who received allo-HCT in Spanish centers over the course of 25 years (1995-2018). Out of 201 patients in their study, 28 were diagnosed with PTCL-NOS, 43 with AITL and 23 with ALCL. Majority of the patients in their study, like our analysis, had undergone peripheral blood alloHCT. Approximately 74% received RIC and 26% had received MAC regimens. Post-transplant cyclophosphamide was used as GVHD prophylaxis in 22.4% of cases. The 2-year OS and PFS were 65.5% and 58.2%, respectively, largely similar to findings in our study. They found a significant difference in HR for type of conditioning regimen employed (RIC vs MAC; HR 1.8; 95% CI, 1.2 to 2.8; P = 0.008) on univariate Cox analysis for PFS, which was not noted in our cohort.
Our analysis has several important limitations. We excluded patients older than 65 years of age, to focus on an age range where both low and high intensity conditioning approaches could be considered by transplant physicians. The cohort comparisons based on registry data is one of the major limitations of the study. These data cannot account for reasons a particular conditioning approach was selected for a given patient. We used propensity score matching to balance the distributions of important covariates between the cohorts and reduce effects of confounding variables. Differences in practice across various centers can impact survival outcomes. Hence, we examined center effect and found none in this particular analysis. Our study is underpowered to detect small effect sizes. Histological diagnosis was not centrally reviewed for this study. Patients included in this study had the 3 most common mature T-cell NHL histologies. There was a lack of interaction between main effect and the three subtypes arguing against differential effect of various conditioning regimens relative to NHL histologies.
In this large registry analysis of PTCL-NOS, ALCL and AITL subtypes of NHL comparing various conditioning regimen intensity, we found no significant difference in survival outcomes of patients that received RIC/NMA or MAC regimens, although the latter was associated with a higher risk of grade 3-4 acute GVHD. No advantage of MAC platforms was seen, even in the subset of patients with refractory disease at the time of alloHCT.
Supplementary Material
ACKNOWLEDGEMENTS:
The CIBMTR is supported primarily by Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); HHSH250201700006C from the Health Resources and Services Administration (HRSA); and N00014-20-1-2705 and N00014-20-1-2832 from the Office of Naval Research; Support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and from the following commercial entities: Actinium Pharmaceuticals, Inc.; Adienne SA; Allovir, Inc.; Amgen, Inc.; Angiocrine Bioscience; Astellas Pharma US; bluebird bio, Inc.; Bristol Myers Squibb Co.; Celgene Corp.; CSL Behring; CytoSen Therapeutics, Inc.; Daiichi Sankyo Co., Ltd.; ExcellThera; Fate Therapeutics; Gamida-Cell, Ltd.; Genentech Inc; Incyte Corporation; Janssen/Johnson & Johnson; Jazz Pharmaceuticals, Inc.; Kiadis Pharma; Kite, a Gilead Company; Kyowa Kirin; Legend Biotech; Magenta Therapeutics; Merck Sharp & Dohme Corp.; Millennium, the Takeda Oncology Co.; Miltenyi Biotec, Inc.; Novartis Pharmaceuticals Corporation; Omeros Corporation; Oncoimmune, Inc.; Orca Biosystems, Inc.; Pfizer, Inc.; Pharmacyclics, LLC; Sanofi Genzyme; Stemcyte; Takeda Pharma; Vor Biopharma; Xenikos BV.
Disclosure of conflict of interest:
S. Ahmed reports: research funding from SeaGen, Tessa Therapeutics, Merck. Consulting or Advisory role: SeaGen, Tessa Therapeutics
M. Shadman Consulting, Advisory Boards, steering committees or data safety monitoring committees: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio, Regeneron and Atara Biotherapeutics. Research Funding: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab.
D. Modi: advisory board member in SeaGen, MorphoSys. Research funding from Genentech.
J. Brammer reports Research Support/Funding: Celgene Corporation, Incyte Corporation, consulting/advisory boards for Seattle Genetics, Kymera Therapeutics, Secura Bio, Diiichi Sankyo, Dren Bio.
A. Rezvani reports Scientific Advisory boards for Nohla and Kaleido. Medical expert witness for the US Department of Justice. Research support from Pharmacyclics. Author’s brother is an employee of Johnson & Johnson.
C. Sauter reports: Consultancy/Advisory boards: Juno Therapeutics, Sanofi-Genzyme, Spectrum Pharmaceuticals, Novartis, Genmab, Precision Biosciences, Kite/a Gilead Company, Celgene/BMS, Gamida Cell, Karyopharm Therapeutics, GSK; Research Funding: Juno Therapeutics, Celgene/BMS, Bristol-Myers Squibb, Precision Biosciences and Sanofi-Genzyme.
A. Herrera reports: Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Seattle Genetics, Karyopharm, Genentech/Roche, ADC Therapeutics, Tubulis, Takeda, AstraZeneca; Research Funding: Bristol-Myers Squibb (Inst), Genentech/Roche (Inst), Merck (Inst), Seattle Genetics (Inst), ADC Therapeutics (Inst), Gilead/Kite Pharma (Inst).
M. Hamadani reports: Consultancy: Incyte Corporation; ADC Therapeutics; Pharmacyclics, Omeros, Verastem, Genmab, Morphosys. Speaker’s Bureau: Sanofi Genzyme, AstraZeneca, BeiGene.
Following authors have no conflicts of interest to disclose = M. Savani, F. Khimani, A. Cashen, J. Zain, T.S. Fenske, M.A. Kharfan-Dabaja.
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