Abstract
Purpose
To analyze the impact of graft versus host disease (GVHD) on the relapse rate of different lymphoma subtypes after allogeneic hematopoietic cell transplantation (allo-HCT).
Patients and Methods
Adult patients with a diagnosis of Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), peripheral T-cell lymphoma (PTCL), or mantle cell lymphoma (MCL) undergoing HLA-identical sibling or unrelated donor HCT between 1997 and 2009 were included.
Results
Two thousand six hundred and eleven cases were included. Reduced-intensity conditioning (RIC) regimen was used in 62.8% of the transplants. In a multivariate analysis of myeloablative cases (n=970), neither acute (aGVHD) nor chronic GVHD (cGVHD) were significantly associated with a lower incidence of relapse/progression in any lymphoma subtype. In contrast, the analysis of RIC cases (n=1641) showed that cGVHD was associated with a lower incidence of relapse/progression in FL (RR 0.51, p=0.049) and in MCL (RR 0.41, p=0.019). Patients with FL or MCL developing both aGVHD and cGVHD had the lowest risk of relapse (RR 0.14, p=0.007; and RR 0.15, p=0.0019, respectively). Of interest, the effect of GVHD on decreasing relapse was similar in patients with sensitive disease and chemoresistant disease. Unfortunately, both aGVHD and cGVHD had a deleterious effect on treatment related mortality (TRM) and overall survival (OS) in FL cases, and did not impact TRM, OS or PFS in MCL.
Conclusion
This study reinforces the use of RIC allo-HCT as a platform for immunotherapy in follicular and mantle cell lymphoma patients.
Introduction
A significant number of patients with lymphoma are not cured with conventional treatment or after high-dose therapy and autologous transplantation. Allo-HCT is a potential curative procedure for these patients due to the anti-lymphoma effect of both the cytotoxic drugs in the conditioning regimen and to the immune attack mediated by the donor's T-cells. Unfortunately, the conventional myeloablative conditioning regimen (MAB) of allo-HCT is associated with high non-relapse mortality (NRM) and, as a result, its role in the therapeutic algorithm for lymphoma remains controversial (1). Furthermore, the average age of patients with the most frequent subtypes of lymphoma is 60-65 years, an age when MAB transplants have prohibitive NRM. Allo-HCT with reduced intensity conditioning (RIC) regimens is associated with a lower rate of mortality, and now represents 80% of all allo-HCT in some types of lymphoma (2). RIC allo-HCT transplants would be an immunotherapy platform for different subtypes of lymphoma, if a potent graft versus lymphoma (GVLy) effect were demonstrated. The reported clinical evidence of a GVLy effect is less robust than that published for a graft versus leukemia effect. This may be due to the relatively limited number of allo-HCT lymphoma cases reported in most series, as well as the fact that different types of lymphoma are often analyzed together. The main objective of this study was to determine if GVHD was associated with a lower relapse rate in specific subtypes of lymphomas, and to analyze whether this effect differs in MAB and RIC transplants. We hypothesized that the different biological characteristics and growth kinetics between histological sub-types might determine a different impact of GVHD on relapse rate. We also wanted to identify whether a potential decreased relapse rate in patients developing GVHD would result in an overall improved clinical outcome.
Patients and Methods
Data source
The CIBMTR (formerly IBMTR) is a combined research program of the Medical College of Wisconsin and the National Marrow Donor Program. The CIBMTR comprises a voluntary network of more than 450 transplantation centers worldwide which contribute detailed data on consecutive allo-HCT and auto-HCT to a centralized statistical center. Observational studies conducted by the CIBMTR are performed in compliance with all applicable U.S. federal regulations pertaining to the protection of human research participants. Protected health information used in the performance of such research is collected and maintained in the CIBMTR capacity as a public health authority under the Health Insurance Portability and Accountability Act Privacy Rule. Additional details regarding the data source are described elsewhere (3).
Patients
We analyzed two thousand six hundred and eleven cases of patients older than 18 years old who were undergoing HLA-identical sibling or unrelated-donor HCT for lymphoma reported to the CIBMTR between 1997 and 2009. Lymphoma types were categorized as Hodgkin lymphoma (HL) (n=466), diffuse large B-cell lymphoma (DLBCL) (n=579), follicular lymphoma (FL) (n=871), peripheral T-cell lymphoma (PTCL) (n=195), and mantle cell lymphoma (MCL) (n=500). Cord blood and ex-vivo T-cell depleted grafts were excluded.
Study endpoints
The main goal of this study was to compare the association of GVHD on the relapse rates in patients with different lymphoma subtypes and to analyze whether this association differs in MAB and RIC/non-myeloablative (NMA) (4). We also analyzed the impact of GVHD on NRM, overall survival (OS), and progression-free survival (PFS). Acute and chronic GVHD (aGVHD and cGVHD, respectively) were defined as the occurrence of grade II, III, or IV skin, gastrointestinal, or liver abnormalities which fulfill the consensus criteria of aGVHD (5), and limited and extensive cGVHD (6). NRM was defined as death after the transplant without relapse or progression, where relapse and progression were competing risks. Those patients who survived without recurrence or progression were censored at the time of last contact. OS was defined as time from transplant to death. Death from any cause was considered an event. PFS was defined as survival after the transplant without recurrence or lymphoma progression. Recurrence or progression of the disease and death were counted as events. Those patients receiving donor lymphocyte infusions were censored when receiving the first dose. Those patients who survived without recurrence or progression were censored at the time of last contact.
Statistical analysis
Multivariate analyses were performed using Cox proportional hazards models. A stepwise model building approach was used to identify the significant risk factors associated with the outcomes of relapse/progression, NRM, PFS, and OS. The assumption of proportional hazards for each factor in the Cox model was tested using time-dependent covariates. When the test indicated differential effects over time (non-proportional hazards), models were constructed breaking the post-transplant time course into two periods, using the maximized partial likelihood method to find the most appropriate breakpoint. The proportionality assumptions were further tested. A backward stepwise model selection approach was used to identify all significant risk factors. The main-effect variable was defined as the time-dependent occurrence of aGVHD only versus aGVHD + cGVHD versus cGVHD only versus neither. Each step of model-building included the main “treatment” effect. Factors which were significant at a level of 5% were kept in the final model. The potential interactions between the main effect and all significant risk factors were tested. The effect of GVHD on the relapse rate with 95% confidence intervals (CI) was reported for each lymphoma subtype and compared between lymphoma subtypes. The variables considered in the multivariate models were as follows. Patient-related: age at transplant, sex, Karnofsky performance status at transplant. Disease-related: lymphoma histology, disease stage at diagnosis, B symptoms at diagnosis, number of lines of chemotherapy prior to transplant, disease status at transplant, rituximab prior to transplant. Transplant-related: interval from diagnosis to transplant, prior autologous transplant, interval from auto to allo, donor-recipient CMV status, donor-recipient sex match, conditioning regimen, donor type, graft type, year of transplant, ATG/Alemtuzumab, GVHD prophylaxis. To clarify whether the effect of GVHD on decreasing relapse if present was in both sensitive and chemoresistant cases, we performed a multivariate analysis in which the main variable of interest was GVHD and the main outcome was relapse/progression. If in the multivariate analysis, disease status independently influenced relapse/progression, we then performed an interaction analysis, to see precisely whether GVHD had a different effect in the group of patients with sensitive disease vs those patients with chemoresistant disease. A day-180 post-HCT landmark analysis method was also used to compute the cumulative incidence of relapse/progression in patients who had aGVHD and/or cGVHD versus without aGVHD or cGVHD.
Results
Patient characteristics (Table 1)
Table 1.
Patient Demographics and Clinical Characteristics
| Variable | HL | DLBCL | FL | PTCL | MCL |
|---|---|---|---|---|---|
| Number of patients | 466 | 579 | 871 | 195 | 500 |
| Age at transplant, years | |||||
| Median (range) | 32 (18-69) | 49 (18-70) | 49 (21-70) | 45 (18-69) | 56 (23-75) |
| Sex | |||||
| Male | 278 (60) | 338 (58) | 506 (58) | 139 (71) | 411 (82) |
| Female | 188 (40) | 241 (42) | 365 (42) | 56 (29) | 89 (18) |
| Karnofsky score | |||||
| <90% | 138 (30) | 221 (38) | 245 (28) | 76 (39) | 145 (29) |
| ≥90% | 288 (62) | 325 (56) | 592 (68) | 111 (57) | 322 (64) |
| Missing | 40 ( 9) | 33 ( 6) | 34 ( 4) | 8 ( 4) | 33 ( 7) |
| Median number of prior chemotherapy lines | 4 | 4 | 3 | 3 | 3 |
| Rituximab prior to transplant | |||||
| Yes | 25 (5) | 302 (52) | 486 (56) | 6 (3) | 279 (56) |
| No | 441 (95) | 277 (48) | 385 (44) | 189 (97) | 221 (44) |
| Disease status prior to transplant | |||||
| Chemosensitive | 287 (62) | 339 (59) | 589 (68) | 126 (65) | 359 (72) |
| Chemoresistant | 166 (36) | 202 (35) | 243 (28) | 61 (31) | 108 (22) |
| Missing | 13 (3) | 38 (7) | 39 (4) | 8 (4) | 33 (7) |
| Interval from diagnosis to transplant, months | 36 (5-413) | 20 (2-309) | 38 (1-352) | 13 (2-159) | 26 (3-175) |
| Prior autologous transplant | |||||
| No | 155 (33) | 431 (74) | 775 (89) | 170 (87) | 405 (81) |
| Yes | 311 (67) | 148 (26) | 96 (11) | 25 (13) | 95 (19) |
| Interval from auto to allo, months | 36 (5-413) | 20 (2-309) | 38 (1-352) | 13 (2-159) | 26 (3-175) |
| Type of donor | |||||
| HLA-identical sibling | 100 (21) | 231 (40) | 461 (53) | 89 (46) | 213 (43) |
| URD well-matched | 219 (47) | 218 (38) | 254 (29) | 69 (35) | 202 (40) |
| URD partially matched | 117 (25) | 94 (16) | 100 (11) | 24 (12) | 63 (13) |
| URD mismatched | 24 ( 5) | 22 ( 4) | 19 ( 2) | 5 ( 3) | 8 ( 2) |
| UNR unknown | 6 (1) | 14 (2) | 37 (4) | 8 (5) | 14 (3) |
| Conditioning intensity | |||||
| MAB | 123 (26) | 268 (46) | 331 (38) | 99 (51) | 149 (30) |
| RIC | 261 (56) | 224 (39) | 307 (35) | 64 (33) | 177 (35) |
| NMA | 82 (18) | 87 (15) | 233 (27) | 32 (16) | 174 (35) |
| Graft type | |||||
| Bone marrow | 115 (25) | 153 (26) | 216 (25) | 33 (17) | 92 (18) |
| Peripheral blood | 351 (75) | 426 (74) | 655 (75) | 162 (83) | 408 (82) |
| Year of transplant | |||||
| 1997-2000 | 56 (12) | 120 (21) | 202 (23) | 11 (6) | 84 (17) |
| 2001-2004 | 180 (39) | 188 (32) | 320 (37) | 61 (31) | 171 (34) |
| 2005-2009 | 230 (49) | 271 (47) | 349 (40) | 123 (63) | 245 (49) |
| ATG/Alemtuzumab | |||||
| ATG + Alemtuzumab | 1 (<1) | 0 | 0 | 0 | 1 (<1) |
| ATG alone | 119 (26) | 126 (22) | 144 (17) | 35 (18) | 103 (21) |
| Alemtuzumab alone | 40 (9) | 48 (8) | 67 (8) | 18 (9) | 58 (12) |
| No ATG or Alemtuzumab | 304 (65) | 389 (67) | 649 (75) | 139 (71) | 324 (65) |
| Missing | 2 (<1) | 16 (3) | 11 (1) | 3 (2) | 14 (3) |
| GVHD prophylaxis | |||||
| Tacrolimus +/− others | 273 (59) | 312 (54) | 444 (51) | 107 (55) | 259 (52) |
| Cyclosporine +/− others | 182 (39) | 246 (42) | 390 (45) | 79 (41) | 229 (46) |
| Other GVHD prophylaxis | 11 (3) | 21 (4) | 37 (5) | 9 (6) | 12 (2) |
| Median follow up of survivors, median (range) | 61 (3-170) | 57 (3-170) | 63 (3-175) | 48 (3-161) | 60 (3-168) |
Abbreviations: HL, Hodgkin lymphoma, DLBCL, diffuse large B cell lymphoma; FL, follicular lymphoma, PTCL, peripheral T cell lymphoma; MCL, mantle cell lymphoma; URD= unrelated donor; MAB, myeloablative; RIC, reduced intensity conditioning; NMA, non-myeloablative; GVHD, graft versus host disease
The patient median age was younger in HL, with a male predominance in MCL and PTCL. There were no differences with respect to the proportion of patients with chemosensitive versus chemoresistant disease. A higher proportion of patients with HL had undergone a prior autologous transplant. More patients in the HL group had undergone an unrelated donor transplant as compared to the rest of the patients. There were no differences in the use of ATG/Alemtuzumab or in postransplant GVHD prophylaxis between lymphoma subgroups.
Transplantation outcomes (Table 2)
Table 2.
Univariate analysesa
| Outcomes | HL | DLBCL | FL | PTCL | MCL | P-values* |
|---|---|---|---|---|---|---|
| aGVHD | 40 (36-44) | 35 (31-39) | 34 (31-37) | 39 (32-46) | 36 (32-40) | 0.208 |
| cGVHD | 47 (43-52) | 33 (29-37) | 45 (42-49) | 49 (41-56) | 43 (38-47) | <0.001 |
| NRM | 41 (36-46) | 47 (43-51) | 36 (33-39) | 38 (31-46) | 43 (39-48) | 0.001 |
| Relapse/Progression | 38 (34-43) | 31 (27-34) | 14 (12-17) | 32 (25-39) | 25 (21-29) | <0.001 |
| PFS | 21 (17-25) | 22 (19-26) | 50 (47-54) | 30 (23-37) | 32 (27-36) | <0.001** |
| OS | 29 (25-33) | 24 (21-28) | 56 (53-59) | 37 (29-45) | 41 (36-45) | <0.001** |
Abbreviations: HL, Hodgkin lymphoma, DLBCL, diffuse large B cell lymphoma; FL, follicular lymphoma, PTCL, peripheral T cell lymphoma; MCL, mantle cell lymphoma; aGVHD, acute graft versus host disease II-IV; cGVHD, chronic graft versus host disease limited and extensive; NRM, non-relapse mortality; PFS, progression-free survival; OS, overall survival.
Probabilities of aGVHD (at 100 days), cGVHD (at 1 year), NRM and relapse/progression (both at 5 years) were calculated using the cumulative incidence estimate. PFS and OS (both at 5 years) were calculated using the Kaplan-Meier product limit estimate.
Pointwise test
Log-rank test
OS at 5 years was better for FL and MCL than for HL and DLBCL. Similarly, 5-year PFS was better for FL compared to the rest of the patients (Figures 1 and 2) . The five-year cumulative incidence of relapse was also different between lymphoma subgroups (Figure 3). There was no significant difference between the lymphoma subgroups in the 100-day cumulative incidence of aGVHD grades II–IV. The rate of 1-year cGVHD was not significantly different for HL, FL, PTCL, and MCL, but was lower for DLBCL.
Figure 1.
Overall Survival of the different lymphoma subtypes, in the overall group.
Figure 2.
Progression free survival of the different lymphoma subtypes, in the overall group.
Figure 3.
Cumulative incidence of relapse per lymphoma subtype in the overall group (Figure 1a), in Myeloablative conditioning (Figure 1b) and Reduced intensity conditioning (Figure 1c).
Association of acute and chronic GVHD on the incidence of relapse/progression
We first examined the effects of GVHD in the entire cohort, including MAB and RIC/NMA conditioning (n=2611). In a multivariate analysis, cGVHD was associated with a lower risk of relapse/progression in MCL (RR 0.41; 95% CI 0.21-0.80; p=0.009), but not in the other lymphoma subtypes (Supplementary Table 1).
We next looked at the association of GVHD with relapse/progression in two different groups according to the intensity of the conditioning regimen: MAB and RIC/NMA. In patients transplanted with MAB, neither aGVHD nor cGVHD were significantly associated with a lower risk of relapse/progression in any type of lymphoma. In contrast, in patients transplanted with RIC/NMA regimen (n=1641), cGVHD was associated with a lower incidence of relapse/progression in FL (RR 0.51, p=0.049) and in MCL (RR 0.41, p=0.019). Patients with FL and with MCL developing both aGVHD and cGVHD had the lowest risk of relapse (RR 0.12; 95% CI 0.03-0.49; p=0.003, and RR 0.14; 95% CI 0.04-0.49; p=0.0019, respectively) (Table 3 and Table 3a). We also analyzed the impact of GVHD on relapse rate depending on whether the group was either chemosensitive or chemoresistant, which was performed for the overall group, for myeloablative, and for RIC transplants. Of interest, the effect of GVHD on decreasing relapse was similar in patients with sensitive disease and chemoresistant disease (see interaction analysis results at the bottom of Table 3 and Table 3a).
Table 3.
Multivariate analysis of the Influence of GVHD on Relapse/Progression in Mantle Cell and Follicular Lymphoma (Acute GVHD II-IV)
| RR (95% CI) | P | |
|---|---|---|
| MAB allo-HCT | ||
| MCL (N=149)* | ||
| aGVHD II-IV | 1.51 (0.37-6.12) | 0.56 |
| cGVHD | 0.42 (0.08-2.19) | 0.30 |
| aGVHD II-IV + cGVHD vs. no-GVHD | 1.32 (0.23-7.49) | 0.75 |
| Disease status | ||
| Sensitive | 1.00 | |
| Resistant | 2.51 (1.02-6.18) | 0.05 |
| Missing | 3.12 (1.17-8.34) | 0.024 |
| FL (N=331)** | ||
| aGVHD II-IV | 0.87 (0.17-4.56) | 0.87 |
| cGVHD | 1.22 (0.34-4.40) | 0.76 |
| aGVHD II-IV + cGVHD vs. no-GVHD | 1.34 (0.35-5.10) | 0.67 |
| Disease status | ||
| Sensitive | 1.00 | |
| Resistant | 3.20 (1.54-6.66) | 0.002 |
| Missing | 1.29 (0.17-10.04) | 0.81 |
| RIC/NMA allo-HCT*** | ||
| MCL (N=351) | ||
| aGVHD II-IV | 1.04 (0.49-2.19) | 0.92 |
| cGVHD | 0.41 (0.20-0.86) | 0.019 |
| aGVHD II-IV + cGVHD vs. no-GVHD | 0.15 (0.04-0.50) | 0.002 |
| Disease status | ||
| Sensitive | 1.00 | |
| Resistant | 1.96 (1.22-3.15) | 0.006 |
| Missing | 0.15 (0.02-1.06) | 0.057 |
| FL (N=540)**** | ||
| aGVHD II-IV | 0.46 (0.16-1.28) | 0.14 |
| cGVHD | 0.51 (0.26-0.99) | 0.049 |
| aGVHD II-IV + cGVHD vs. no-GVHD | 0.14 (0.03-0.58) | 0.007 |
Abbreviations: allo-HCT= allogeneic hematopoietic cell transplantation; MCL, mantle cell lymphoma; FL, follicular lymphoma; MAB, myeloablative; RIC= reduced intensity conditioning; NMA= non-myeloablative stem cell transplantation; aGVHD, acute graft versus host disease II-IV; cGVHD, chronic graft versus host disease limited and extensive
Interaction test between GVHD disease status (p=0.79). Three degree freedom test.
Interaction test between GVHD disease status (p=0.45). Three degree freedom test.
Interaction test between GVHD disease status (p=0.36). Three degree freedom test.
Disease status was not significant
Table 3a.
Multivariate analysis of the Influence of GVHD on Relapse/Progression in Mantle Cell and Follicular Lymphoma (Acute GVHD III-IV)
| RR (95% CI) | P | |
|---|---|---|
| MAB allo-HCT* | ||
| MCL (N=149) | ||
| aGVHD III-IV | 1.66 (0.33-8.41) | 0.54 |
| cGVHD | 0.66 (0.14-3.22) | 0.61 |
| aGVHD III-IV + extensive cGVHD vs. no-GVHD | 1.37 (0.16-12.13) | 0.78 |
| Disease status | ||
| Sensitive | 1.00 | |
| Resistant | 2.52 (1.03-6.17) | 0.044 |
| Missing | 3.17 (1.18-8.50) | 0.022 |
| FL (N=331)** | ||
| aGVHD III-IV | 1.47 (0.40-5.44) | 0.56 |
| cGVHD | 0.65 (0.22-1.93) | 0.44 |
| Disease status | ||
| Sensitive | 1.00 | |
| Resistant | 3.30 (1.58-6.90) | 0.002 |
| Missing | 1.21 (0.16-9.35) | 0.86 |
| RIC/NMA allo-HCT*** | ||
| MCL (N=351) | ||
| aGVHD III-IV | 0.98 (0.44-2.15) | 0.94 |
| cGVHD | 0.27 (0.11-0.66) | 0.004 |
| aGVHD III-IV + extensive cGVHD vs. no-GVHD | 0.20 (0.05-0.85) | 0.029 |
| Disease status | ||
| Sensitive | 1.00 | |
| Resistant | 1.88 (1.16-3.04) | 0.010 |
| Missing | 0.15 (0.02-1.08) | 0.060 |
| FL (N=540)**** | ||
| aGVHD III-IV | 0.24 (0.06-0.99) | 0.049 |
| cGVHD | 0.43 (0.21-0.87) | 0.018 |
Abbreviations: allo-HCT= allogeneic hematopoietic cell transplantation; MCL, mantle cell lymphoma; FL, follicular lymphoma; MAB, myeloablative; RIC= reduced intensity conditioning; NMA= non-myeloablative stem cell transplantation; aGVHD, acute graft versus host disease II-IV; cGVHD, chronic graft versus host disease limited and extensive
Interaction test between GVHD disease status (p=0.79). Three degree freedom test.
Interaction test between GVHD disease status (p=0.45). Three degree freedom test.
Interaction test between GVHD disease status (p=0.36). Three degree freedom test.
Disease status was not significant
To obtain a graphical illustration of the association of GVHD on relapse rate in RIC allo-HCT in FL and MCL, we performed a day-180 landmark study. Three hundred and sixty-seven out of 540 FL cases, and 208 out of 351 MCL cases fulfilled the condition of being alive and in remission at 180 days post-transplant. Results from the landmark analysis were very similar to those observed in the multivariate analysis, and, thus, those patients with FL and MCL developing both aGVHD and cGVHD had the lowest risk of relapse, those developing either aGVHD or cGVHD had an intermediate risk of relapse, and those patients developing neither aGVHD nor cGVHD had the highest risk of relapse (Figure 4).
Figure 4.
Landmark analysis at 180 days after RIC allo-HCT showing the cumulative incidence of relapse in patients who had: a) no acute GVHD, no chronic GVHD (AG-N/CG-N); b) acute GVHD, no chronic GVHD (AG-Y/CG-N); c) no acute GVHD, chronic GVHD (AG-N/CG-Y); and d) both acute GVHD and chronic GVHD (AG-Y/CG-Y) in Mantle Cell Lymphoma and in Follicular Lymphoma
Impact of acute and chronic GVHD on overall survival, non-relapse mortality, and progression-free survival
GVHD was reported as the primary cause of death in 13% of the cases in HL, 10% in DLBCL, 17% in FL, 13% in PTCL, and 15% in MCL (Table 4). In a time-dependent multivariate analysis, aGVHD was associated with an inferior OS and NRM in all lymphoma subtypes. When analyzed in the two specific lymphoma groups in which GVHD was associated with lower relapse, i.e. patients with FL and MCL who underwent RIC/NMA transplants, both aGVHD and cGVHD had a deleterious effect on NRM and OS in FL cases, and did not impact NRM, OS or PFS in MCL. (Supplementary Table 2).
Table 4.
Causes of death
| Variable | HL | DLBCL | FL | PTCL | MCL |
|---|---|---|---|---|---|
| Number of deaths | 331 | 433 | 403 | 112 | 293 |
| Graft rejection | 1 (<1) | 1 (<1) | 1 (<1) | 0 | 1 (<1) |
| Infection | 46 (14) | 70 (16) | 80 (20) | 22 (20) | 49 (17) |
| IpN | 9 (3) | 22 (5) | 24 (6) | 3 (3) | 9 (3) |
| ARDS | 7 (2) | 12 (3) | 10 (2) | 1 (1) | 12 (4) |
| GVHD | 44 (13) | 43 (10) | 69 (17) | 15 (13) | 43 (15) |
| Primary disease | 147 (44) | 187 (43) | 79 (20) | 41 (37) | 90 (31) |
| Organ failure | 33 (10) | 58 (13) | 67 (17) | 20 (18) | 43 (15) |
| Second malignancy | 2 (1) | 1 (<1) | 12 (3) | 0 | 6 (2) |
| Hemorrhage | 8 (2) | 11 (3) | 10 (2) | 4 (4) | 11 (4) |
| Accidental death | 1 (<1) | 0 | 2 (<1) | 0 | 2 (1) |
| Vascular | 6 (2) | 2 (<1) | 6 (1) | 2 (2) | 5 (2) |
| Toxicity | 10 (3) | 9 (2) | 18 (4) | 1 (1) | 10 (3) |
| Other-not specified/unknown | 17 (5) | 17 (4) | 25 (6) | 3 (3) | 12 (4) |
Abbreviations: HL, Hodgkin lymphoma, DLBCL, diffuse large B cell lymphoma; FL, follicular lymphoma, PTCL, peripheral T cell lymphoma; MCL, mantle cell lymphoma; IpN, interstitial pneumonia; ARDS, acute respiratory distress syndrome; GVHD, graft versus host disease
Discussion
A potential clinical impact of GVLy in FL and MCL has been discussed in two recent reviews (1, 8). Two international-registry series reported a lower relapse rate in patients with FL who underwent allo-HCT compared to those receiving an auto-HCT (9, 10), but they did not find any association between aGVHD or cGVHD and recurrence after allo-HCT. Here we show, for the first time in a very large series of FL patients who underwent allo-HCT, an association between GVHD and a lower relapse rate. As far as MCL is concerned, one study (11) has suggested a lower relapse rate after allo-HCT than after auto-HCT. In the univariate analysis, patients with cGVHD had a lower actuarial probability of relapse than those patients without this complication. However, a multivariate analysis was not performed, and competing risks were not taken into consideration. Here we demonstrate a strong association of cGVHD with decreased relapse after allo-HCT for MCL analyzed in a multivariate study, considering cGVHD as a time-dependent variable. This is in line with studies showing a high relapse rate of MCL after allo-HCT when donor T-cells are eliminated from the graft (12, 13). Thus, we suggest an important role of GVLy in reducing relapse rates in FL and MCL. A landmark analysis confirmed the effect of GVHD on relapse rate in FL and MCL. Thus, as also was observed in the multivariate analysis, patients with FL and MCL developing both aGVHD and cGVHD had the lowest risk of relapse (Figure 4). Of interest, the effect of GVHD on decreasing relapse was similar in patients with sensitive disease and chemoresistant disease (Table 3 and Table 3a, interaction analysis).
An intriguing result from this study is that the association of GVHD and decreased relapse in FL and MCL lymphoma was observed only in allo-HCT performed with RIC/NMA regimens, and not after MAB transplants. One may speculate that the more intense MAB regimen already provides a significantly more cytotoxic, anti-lymphoma effect, than the RIC/NMA regimen, making the addition of an allogeneic effect less obvious. From a clinical point of view, this disparity may have little relevance, since the vast majority of lymphoma patients now receive RIC/NMA regimen as part of their allo-HCT. From a biological point of view, this peculiarity is difficult to explain since the effect of alloreactive T-cells developing both GVHD and GVLy should be similar, regardless of the intensity of the conditioning regimen. This difference might also be statistically justified. Thus, the initial smaller sample size for MAB transplants than for RIC/NMA transplants, and the fact that more patients died in the MAB group early after allo-HCT, may have led to a poorer detection of associations of GVHD and lower relapse. Similar observations of an association of GVHD on a decreasing relapse rate in RIC/NMA, but not in MAB allo-HCT, have also been described in acute myeloblastic leukemia and in myelodysplastic syndromes (14, 15).
In this study we did not observe an association between GVHD and a lower rate of relapse in DLBCL. This is in line with previous studies showing that relapse after auto-HCT for DLBCL patients is quite similar to that after allo-SCT (7, 16). However, allo-HCT may be a salvage therapy for patients with DLBCL relapsing after an auto-HCT (17, 18). For HL, in 1996 the EBMT published a lower relapse rate after MAB allo-HCT than after auto-HCT, but this was offset by a very high NRM associated with MAB (19). More recently, in a multivariate analysis the EBMT has not found an association of GVHD with relapse rate in HL who underwent RIC (20), although in a landmark analysis patients with cGVHD had a lower incidence of relapse. In the present study, which included a much larger number of patients, we did not observe an association of GVHD with a lower relapse rate in HL using a Cox model, in line with the EBMT results. If these results are confirmed in other studies, allo-HCT for DLBCL and HL should be only offered within the context of a clinical trial designed to improve GVLy effect. As far as PTCL is concerned, we were not able to demonstrate a relationship between GVHD and a lower rate of relapse. The low number of patients with this disease included in the study precludes us from drawing firm conclusions.
The association of GVHD with lower relapse rate herein observed in FL and MCL, but not in DLBCL, HL, and PTCL are in line with results observed in short series of lymphoma patients treated with donor lymphocytes infusion (DLI). There are at least three studies showing a potent effect of DLI to treat FL and MCL relapses after allo-HCT (13, 21, 22). In contrast, DLI seem to have very limited activity as a salvage treatment for patients with DLBCL relapsing after allo-HCT (23). Results of DLI in HL and PTCL (16, 24, 25) are more encouraging, without achieving the excellent results obtained in FL and MCL lymphoma. Thus, DLI is very effective in FL and MCL, of moderate effect in HL and PTCL, and very limited in DLBCL. These, together with our own results, support the presence of a strong GVLy effect after allo-HCT in FL and MCL. The low proliferation rate of indolent lymphomas might be one reason that explains an effective role of the donor's immune system to control tumor growth in these lymphoma subtypes.
The beneficial effect of GVHD on a lower relapse rate in FL and MCL did not translate into an overall clinical outcome advantage. This negative impact of GVHD, despite decreasing the relapse rate, as has been reported in other diseases (26, 27). Strategies combining attenuation of GVHD with post-HCT treatment maintenance, and potentiating GVLy effect, with late DLI or chimeric antigen receptor-modified T-cells (CARs) (28), could improve the clinical outcome of FL and MCL patients undergoing RIC allo-HCT.
Supplementary Material
Acknowledgements
We would like to acknowledge the following authors for their contributions to the manuscript: Phillippe Aramand, Jean-Yves Cahn, Jennifer Ann Domm, Gregory Hale, Peiman Hematti, Nandita Khera, Thomas R. Klumpp, John Koreth, Aleksandr Lazaryan, Michael Lill, Maria Teresa Lupo-Stanghellini, Carolyn Mulroney, Eduardo Olavarria, and Helene Schoemans.
The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two grants from the Office of Naval Research (N00014-12-1-0142 and N00014-13-1-0039); and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen, Inc.; an anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.;*Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc.; Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *TerumoBCT; *Teva Neuroscience, Inc.; *THERAKOS, Inc.; University of Minnesota; University of Utah; and *Wellpoint, Inc.
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 Department of Defense, Health Resources and Services Administration (HRSA), or any other agency of the U.S. Government.
Footnotes
Corporate Members
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