The best conditioning regimen before allogeneic transplantation for high-risk diffuse large B-cell lymphoma (DLBCL) remains to be clarified. We analyzed data from 396 recipients of allotransplants for DLBCL receiving myeloablative (MAC; n = 165), reduced intensity (RIC; n = 143), or nonmyeloablative conditioning (NMAC; n = 88) regimens. Acute and chronic GVHD rates were similar across the groups. Five-year nonrelapse mortality (NRM) was higher in MAC than RIC and NMAC (56% vs 47% vs 36%; P = .007). Five-year relapse/progression was lower in MAC than in RIC/NMAC (26% vs 38% vs 40%; P = .031). Five-year progression-free survival (15%-25%) and overall survival (18%-26%) did not differ significantly between the cohorts. In multivariate analysis, NMAC and more recent transplant year were associated with lower NRM, whereas a lower Karnofsky performance score (< 90), prior relapse resistant to therapy, and use of unrelated donors were associated with higher NRM. NMAC transplants, no prior use of rituximab, and prior relapse resistant to therapy were associated with a greater risk of relapse/progression. In conclusion, allotransplantation with RIC or NMAC induces long-term progression-free survival in selected DLBCL patients with a lower risk of NRM but with higher risk of lymphoma progression or relapse.

Approximately 80% of patients with diffuse large B-cell lymphoma (DLBCL) and other aggressive lymphomas may be cured by modern therapy.1-3  Some of those who do not achieve remission or who relapse can be rescued by high-dose chemotherapy and an autologous hematopoietic cell transplant (AHCT).4  Others, including those relapsing after an AHCT, are sometimes treated with an allogeneic transplant (alloHCT).5,6  However, because of the relatively low numbers of DLBCL patients included in published reports of alloHCT, the heterogeneity of histologic subtypes, differing conditioning protocols, and the short follow-up, the role of alloHCT for DLBCL patients still remains unclear. The use of myeloablative conditioning (MAC) was shown to achieve long-term survival of 40%-50%, but high transplant-related mortality up to 30%-40% seemed to limit this option to selected patients.7-9  It remains to be seen whether reduced-intensity conditioning (RIC) and nonmyeloablative conditioning (NMAC) may result in improved outcomes of lymphoma patients, as higher relapse rates between 30% and 80% were reported.10-15 

We analyzed outcomes of 396 recipients of alloHCT for DLBCL reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) to compare these conditioning approaches.

Subject selection

We reviewed all subjects with DLBCL reported to the CIBMTR 2000-2009 and included adult recipients of a first allogeneic HLA-matched related or unrelated T cell replete grafts for primary induction failure or relapse of DLBCL. All subjects whose data were included in this study provided institutional review board-approved consent to participate in the CIBMTR Research Database and have their data included in observational research studies. Each individual study does not receive institutional review board approval as these studies are not human subject research studies according to the OHRP Guidance on Research Involving Coded Private Information or Biologic Specimens (October 16, 2008). Individual studies, including this one, undergo administrative review by the institutional review board chair to ensure that the study, which was conducted in accordance with the Declaration of Helsinki, meets the criteria in the CIBMTR Research Database protocol. Subjects < 18 or ≥ 70 years of age (n = 19), twin transplants (n = 4), recipients with in vitro T cell–depleted transplants (n = 25), related mismatched donor (n = 13), complete response 1 status before transplantation (n = 15), recipients with < 6 months from autologous to allogeneic transplant (n = 12), recipients of cord blood cell grafts (n = 17), and recipients of second allogeneic transplants were excluded (n = 3). A total of 396 patients with DLBCL met the inclusion criteria; 228 were male. Median age was 54 years (range, 18-69 years). A total of 125 (32%) patients received a prior AHCT. A total of 129 patients received a related HLA-matched transplant, 267 received an unrelated donor alloHCT (HLA-matched: n = 168; partially HLA-matched: n = 68; HLA-mismatched: n = 31) after MAC (n = 165, 42%), RIC (n = 143, 36%), or NMAC (n = 88, 22%) regimens (see “Study endpoints and definitions”). Antithymocyte globulin was given to 88 subjects (Tables 1 and 2).

Table 1

Characteristics of patients in the different conditioning groups

ParameterMAC (n = 165)RIC (n = 143)NMAC (n = 88)P
Median age, y (range) 48 (18-66) 54 (20-69) 54 (19-69) < .001 
Age group at alloHCT, y     
    18-29 22 (13%) 14 (10%) 7 (8%) .001 
    30-39 27 (16%) 20 (14%) 13 (15%)  
    40-49 49 (30%) 25 (17%) 11 (13%)  
    50-59 58 (35%) 55 (38%) 35 (40%)  
    60-64 7 (4%) 23 (16%) 16 (18%)  
Male sex 97 (59%) 87 (61%) 44 (50%) .248 
Karnofsky score at alloHCT < 90 63 (38%) 56 (39%) 36 (41%) .977 
Lymphoma stage at diagnosis     
    I-II 42 (25%) 44 (31%) 34 (39%) .007 
    III-IV 118 (72%) 85 (59%) 45 (51%)  
    Missing 5 (3%) 14 (10%) 9 (10%)  
BM involvement at diagnosis 43 (26%) 35 (24%) 14 (16%) .039 
B symptoms at diagnosis 75 (45%) 38 (27%) 22 (25%)  
No. of chemotherapy lines before alloHCT     
    1 4 (2%) 4 (3%) 2 (2%) .002 
    2 41 (25%) 24 (17%) 6 (7%)  
    3 38 (23%) 25 (17%) 18 (20%)  
    4 33 (20%) 45 (31%) 32 (36%)  
    5 40 (24%) 34 (24%) 30 (34%)  
    Missing 9 (6%) 11 (8%)  
Radiation before alloHCT 53 (32%) 68 (48%) 44 (50%) .005 
Rituximab before alloHCT 106 (64%) 96 (67%) 64 (73%) .392 
Prior autologous HCT 29 (18%) 51 (36%) 45 (51%) < .001 
Disease status before transplantation     
    PIF-sensitive 35 (21%) 14 (10%) 7 (8%) < .001 
    PIF-resistant 41 (25%) 21 (15%) 6 (7%)  
    Relapse-sensitive 32 (19%) 36 (25%) 24 (27%)  
    Relapse-resistant 28 (17%) 22 (15%) 17 (19%)  
    CR2+ 19 (12%) 34 (24%) 30 (34%)  
    Relapse untreated/unknown 2 (1%) 3 (2%) 1 (1%)  
    Missing 8 (5%) 13 (9%) 3 (3%)  
Median interval from diagnosis to alloHCT, mo (range) 17 (4-238) 27 (5-309) 36 (8-198) < .001 
Interval between diagnosis and alloHCT, mo     
    < 12 49 (30%) 18 (13%) 8 (9%) < .001 
    12-24 58 (35%) 44 (31%) 21 (24%)  
    24-36 16 (10%) 24 (17%) 15 (17%)  
    36-60 15 (9%) 25 (17%) 20 (23%)  
    > 60 25 (15%) 29 (20%) 24 (27%)  
Interval from autologous to allogeneic HCT, mo     
    6-12 12 (41%) 15 (29%) 10 (22%) .263 
    12-24 12 (41%) 17 (33%) 17 (38%)  
    24-36 1 (3%) 10 (20%) 4 (9%)  
    36-48 1 (3%) 4 (8%) 4 (9%)  
    48-60 2 (4%) 4 (9%)  
    > 60 3 (10%) 3 (6%) 6 (13%)  
    No prior autologous HCT 136 (82%) 92 (64%) 43 (49%)  
ParameterMAC (n = 165)RIC (n = 143)NMAC (n = 88)P
Median age, y (range) 48 (18-66) 54 (20-69) 54 (19-69) < .001 
Age group at alloHCT, y     
    18-29 22 (13%) 14 (10%) 7 (8%) .001 
    30-39 27 (16%) 20 (14%) 13 (15%)  
    40-49 49 (30%) 25 (17%) 11 (13%)  
    50-59 58 (35%) 55 (38%) 35 (40%)  
    60-64 7 (4%) 23 (16%) 16 (18%)  
Male sex 97 (59%) 87 (61%) 44 (50%) .248 
Karnofsky score at alloHCT < 90 63 (38%) 56 (39%) 36 (41%) .977 
Lymphoma stage at diagnosis     
    I-II 42 (25%) 44 (31%) 34 (39%) .007 
    III-IV 118 (72%) 85 (59%) 45 (51%)  
    Missing 5 (3%) 14 (10%) 9 (10%)  
BM involvement at diagnosis 43 (26%) 35 (24%) 14 (16%) .039 
B symptoms at diagnosis 75 (45%) 38 (27%) 22 (25%)  
No. of chemotherapy lines before alloHCT     
    1 4 (2%) 4 (3%) 2 (2%) .002 
    2 41 (25%) 24 (17%) 6 (7%)  
    3 38 (23%) 25 (17%) 18 (20%)  
    4 33 (20%) 45 (31%) 32 (36%)  
    5 40 (24%) 34 (24%) 30 (34%)  
    Missing 9 (6%) 11 (8%)  
Radiation before alloHCT 53 (32%) 68 (48%) 44 (50%) .005 
Rituximab before alloHCT 106 (64%) 96 (67%) 64 (73%) .392 
Prior autologous HCT 29 (18%) 51 (36%) 45 (51%) < .001 
Disease status before transplantation     
    PIF-sensitive 35 (21%) 14 (10%) 7 (8%) < .001 
    PIF-resistant 41 (25%) 21 (15%) 6 (7%)  
    Relapse-sensitive 32 (19%) 36 (25%) 24 (27%)  
    Relapse-resistant 28 (17%) 22 (15%) 17 (19%)  
    CR2+ 19 (12%) 34 (24%) 30 (34%)  
    Relapse untreated/unknown 2 (1%) 3 (2%) 1 (1%)  
    Missing 8 (5%) 13 (9%) 3 (3%)  
Median interval from diagnosis to alloHCT, mo (range) 17 (4-238) 27 (5-309) 36 (8-198) < .001 
Interval between diagnosis and alloHCT, mo     
    < 12 49 (30%) 18 (13%) 8 (9%) < .001 
    12-24 58 (35%) 44 (31%) 21 (24%)  
    24-36 16 (10%) 24 (17%) 15 (17%)  
    36-60 15 (9%) 25 (17%) 20 (23%)  
    > 60 25 (15%) 29 (20%) 24 (27%)  
Interval from autologous to allogeneic HCT, mo     
    6-12 12 (41%) 15 (29%) 10 (22%) .263 
    12-24 12 (41%) 17 (33%) 17 (38%)  
    24-36 1 (3%) 10 (20%) 4 (9%)  
    36-48 1 (3%) 4 (8%) 4 (9%)  
    48-60 2 (4%) 4 (9%)  
    > 60 3 (10%) 3 (6%) 6 (13%)  
    No prior autologous HCT 136 (82%) 92 (64%) 43 (49%)  

IPI indicates international prognostic index; PIF, primary induction failure; REL, relapse; and CR, complete remission.

Table 2

Characteristics of transplantation in the different conditioning intensity groups

ParameterMAC (n = 165)RIC (n = 143)NMAC (n = 88)P
Year of allogeneic HCT     
    Before 2004 (2000-2003) 87 (53%) 46 (32%) 32 (36%) < .001 
    After 2004 (2004-2009) 78 (47%) 97 (68%) 56 (64%)  
HLA match     
    HLA-identical sibling 66 (40%) 37 (26%) 26 (30%) .121 
    Unrelated well HLA-matched 55 (33%) 69 (48%) 44 (50%)  
    Unrelated partially matched 29 (18%) 26 (18%) 13 (15%)  
    Unrelated mismatched 7 (4%) 5 (3%) 1 (1%)  
Unrelated matching to be defined 8 (5%) 6 (4%) 4 (5%)  
Donor/recipient sex match     
    Male/male 59 (36%) 64 (45%) 28 (32%) .359 
    Male/female 37 (22%) 34 (24%) 25 (28%)  
    Female/male 36 (22%) 22 (15%) 15 (17%)  
    Female/female 30 (18%) 21 (15%) 16 (18%)  
Donor/recipient CMV serostatus     
    Positive/positive 42 (25%) 38 (27%) 23 (26%) .753 
    Positive/negative 20 (12%) 17 (12%) 9 (10%)  
    Negative/positive 57 (35%) 36 (25%) 27 (31%)  
    Negative/negative 41 (25%) 48 (34%) 25 (28%)  
    Missing 5 (3%) 4 (3%) 4 (5%)  
Graft source     
    BM 46 (28%) 28 (20%) 13 (15%) .039 
    Peripheral blood stem cells 119 (72%) 115 (80%) 75 (85%)  
Conditioning regimens     
    MAC     
        CY/TBI 90 (55%)  
        BU/CY 38 (23%)  
        Bu/MEL 6 (4%)  
        FLU/MEL 4 (2%)  
        FLU/BU 15 (9%)  
        MEL 200 1 (1%)  
    RIC     
        BU/CY-low dose 2 (1%)  
        FLU/MEL-low dose 44 (31%)  
        FLU/BU-low dose 49 (34%)  
        CY/VP16 ± BU 11 (8%)  
        FLU/ATG 1 (1%)  
        BEAM + similar 17 (12%)  
        TBI based-RIC per center 3 (2%)  
        TBI-low dose-RIC per center 7 (5%)  
    NMAC     
        TBI based 4 (5%)  
        TBI-low dose 29 (33%)  
        FLU/CY 42 (48%)  
    Others     
        Other/unspecified 11 (7%) 9 (6%) 13 (15%)  
TBI in conditioning 90 (55%) 15 (10%) 33 (38%) < .001 
ATG at conditioning regimen or GVHD prophylaxis     
ATG at conditioning regimen 27 (16%) 40 (28%) 21 (24%) .046 
GVHD prophylaxis     
    FK506 + MTX ± other 77 (47%) 50 (35%) 14 (16%) < .001 
    FK506 ± other 22 (13%) 45 (31%) 20 (23%)  
    CsA + MTX ± other 50 (30%) 20 (14%) 5 (6%)  
    CsA ± other 13 (8%) 26 (18%) 45 (51%)  
Median Follow-up of survivors, mo (range) 39 (3-108) 41 (3-87) 59 (12-99)  
ParameterMAC (n = 165)RIC (n = 143)NMAC (n = 88)P
Year of allogeneic HCT     
    Before 2004 (2000-2003) 87 (53%) 46 (32%) 32 (36%) < .001 
    After 2004 (2004-2009) 78 (47%) 97 (68%) 56 (64%)  
HLA match     
    HLA-identical sibling 66 (40%) 37 (26%) 26 (30%) .121 
    Unrelated well HLA-matched 55 (33%) 69 (48%) 44 (50%)  
    Unrelated partially matched 29 (18%) 26 (18%) 13 (15%)  
    Unrelated mismatched 7 (4%) 5 (3%) 1 (1%)  
Unrelated matching to be defined 8 (5%) 6 (4%) 4 (5%)  
Donor/recipient sex match     
    Male/male 59 (36%) 64 (45%) 28 (32%) .359 
    Male/female 37 (22%) 34 (24%) 25 (28%)  
    Female/male 36 (22%) 22 (15%) 15 (17%)  
    Female/female 30 (18%) 21 (15%) 16 (18%)  
Donor/recipient CMV serostatus     
    Positive/positive 42 (25%) 38 (27%) 23 (26%) .753 
    Positive/negative 20 (12%) 17 (12%) 9 (10%)  
    Negative/positive 57 (35%) 36 (25%) 27 (31%)  
    Negative/negative 41 (25%) 48 (34%) 25 (28%)  
    Missing 5 (3%) 4 (3%) 4 (5%)  
Graft source     
    BM 46 (28%) 28 (20%) 13 (15%) .039 
    Peripheral blood stem cells 119 (72%) 115 (80%) 75 (85%)  
Conditioning regimens     
    MAC     
        CY/TBI 90 (55%)  
        BU/CY 38 (23%)  
        Bu/MEL 6 (4%)  
        FLU/MEL 4 (2%)  
        FLU/BU 15 (9%)  
        MEL 200 1 (1%)  
    RIC     
        BU/CY-low dose 2 (1%)  
        FLU/MEL-low dose 44 (31%)  
        FLU/BU-low dose 49 (34%)  
        CY/VP16 ± BU 11 (8%)  
        FLU/ATG 1 (1%)  
        BEAM + similar 17 (12%)  
        TBI based-RIC per center 3 (2%)  
        TBI-low dose-RIC per center 7 (5%)  
    NMAC     
        TBI based 4 (5%)  
        TBI-low dose 29 (33%)  
        FLU/CY 42 (48%)  
    Others     
        Other/unspecified 11 (7%) 9 (6%) 13 (15%)  
TBI in conditioning 90 (55%) 15 (10%) 33 (38%) < .001 
ATG at conditioning regimen or GVHD prophylaxis     
ATG at conditioning regimen 27 (16%) 40 (28%) 21 (24%) .046 
GVHD prophylaxis     
    FK506 + MTX ± other 77 (47%) 50 (35%) 14 (16%) < .001 
    FK506 ± other 22 (13%) 45 (31%) 20 (23%)  
    CsA + MTX ± other 50 (30%) 20 (14%) 5 (6%)  
    CsA ± other 13 (8%) 26 (18%) 45 (51%)  
Median Follow-up of survivors, mo (range) 39 (3-108) 41 (3-87) 59 (12-99)  

CY indicates cyclophosphamide; BU, busulfan; TBI, total body irradiation; Flu, fludarabine; MEL, melphalan; BEAM: carmustine, etoposide, cytarabine, melphalan; VP-16, etoposide; ATG, antithymocyte globulin; MTX, methotrexate; CsA, cyclosporine A; and FK506, tacrolimus.

Study end points and definitions

Outcomes analyzed included engraftment rate, nonrelapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). The intensity of conditioning was categorized based on consensus criteria.16  Neutrophil recovery was defined as the first of 3 subsequent days with absolute neutrophil counts ≥ 0.5 × 109/L without growth factor support. Platelet recovery was defined as the first of 7 subsequent days with platelet counts ≥ 20 × 109/L without platelet transfusions. NRM was defined as death from any cause in the first 28 days or death without evidence of lymphoma progression/relapse. Progression was defined as an increase of ≥ 25% in the sites of lymphoma or development of new sites of lymphoma.17  Relapse was defined as recurrence of lymphoma after a complete response. For PFS, patients were considered treatment failures at the time of relapse/progression or death from any cause. Patients alive without evidence of disease relapse or progression were censored at last follow-up, and the PFS event was summarized by a survival curve. The OS interval variable was defined as the time from date of transplantation to date of death or last contact and summarized by a survival curve.

Other outcomes analyzed included acute GVHD (aGVHD)18  and chronic GVHD (cGVHD)19  graded by established criteria and cause of death. “Well matched” was defined as no known disparity between donor and recipient at HLA A, B, C, and DRB1 (8 of 8), partially matched as one known or one likely disparity, and mismatched as ≥ 2 disparities.20 

Statistical analysis

Subject-, disease-, and transplant-related variables for the 3 cohorts based on conditioning intensity (MAC, RIC, and NMAC) were compared using the χ2 test for categorical and the Kruskal-Wallis test for continuous variables. Univariate probabilities of PFS and survival were calculated using the Kaplan-Meier estimator. Probabilities of aGVHD and cGVHD, NRM, and relapse/progression were calculated using cumulative incidence curves to accommodate competing risks. Conditioning regimens were compared using multivariate Cox proportional hazards regression models adjusting for risk factors significantly associated with outcomes. Factors significant at P = .05 level were retained in the final model.

Changing use of pretransplant conditioning regimens

The use of MAC decreased over time (comparing 2000-2003 with 2004-2009; P < .001). In years 2000-2003, proportion of MAC was 53% versus 34% in 2004-2009, whereas RIC increased from 28% in 2000-2003 to 42% in 2004-2009. The proportion of NMAC-transplants was 19% in 2000-2003 versus 24% in 2004-2009.

Subjects

Subject-, disease-, and transplant-related variables of the MAC, RIC, and NMAC cohorts are summarized in Tables 1 and 2. Karnofsky performance score did not differ significantly. MAC subjects were significantly younger (medians 48 vs 54 vs 54 years; P < .001), more often had stage 3/4 disease (72% vs 59% vs 51%; P = .007) and B-symptoms at diagnosis (45% vs 27% vs 25%; P = .003) compared with the RIC and NMAC patients. MAC patients were less likely to receive a prior autotransplant (18% vs 36% vs 51%; P < .001) or radiation before transplantation (32% vs 48% vs 50%; P = .005). MAC subjects had a higher incidence of prior resistant lymphoma to therapy (42% vs 30% vs 26%; P < .001).

MAC regimens were based in most cases (128 of 165) on a combination of cyclophosphamide (120 mg/kg) with total body irradiation (TBI, 12 Gy) or with busulfan (> 9 mg/kg oral or equivalent intravenous). The majority of RIC regimens (118 of 143) were based on combination of fludarabine (150 mg/m2) with busulfan (≤ 9 mg/kg) or melphalan (< 150 mg/m2). NMAC regimens were based on low-dose TBI (2-5 Gy) combined with fludarabine (29 of 88 subjects) or on fludarabine with cyclophosphamide (42 of 88 subjects).

Transplant outcomes

Table 3 summarizes univariate probabilities of all outcomes of interest after transplantation. Supplemental Table 1 (available on the Blood Web site; see the Supplemental Materials link at the top of the online article) displays variables tested in Cox proportional hazards regression models. Table 4 summarizes variables that had an impact on each study outcome.

Table 3

Univariate outcomes after transplantation

Outcome eventnMAC (n = 165)
nRIC (n = 143)
nNMAC (n = 88)
P*
Probability (95% CI)Probability (95% CI)Probability (95% CI)
Time to ANC0.5 × 109/L 164  143  88   
    28 d  86 (80-90)  96 (90-98)  92 (83-96) .012 
    100 d  88 (82-92)  99 (94-100)  97 (90-99) < .001 
aGVHD (II-IV) 164  143  88   
    100 d  43 (36-51)  43 (35-51)  44 (34-55) .970 
cGVHD 163  137  88   
    1 y  35 (28-43)  39 (31-47)  33 (24-43) .641 
    3 y  37 (30-45)  41 (32-49)  37 (27-47) .794 
    5 y  37 (30-45)  42 (34-51)  37 (27-47) .605 
NRM 163  142  86   
    100 d  32 (25-39)  24 (17-31)  17 (10-26) .029 
    1 y  47 (39-54)  31 (24-39)  29 (20-39) .004 
    3 y  55 (47-63)  42 (34-50)  34 (24-45) .003 
    5 y  56 (48-64)  47 (38-56)  36 (26-46) .007 
Relapse/progression 163  142  86   
    1 y  23 (17-30)  32 (25-40)  37 (27-48) .043 
    3 y  26 (19-33)  35 (27-43)  38 (28-49) .078 
    5 y  26 (19-33)  38 (30-46)  40 (30-50) .031 
PFS 163  142  86   
    1 y  30 (23-38)  37 (29-45)  34 (24-44) .487 
    3 y  19 (13-25)  23 (16-31)  27 (18-37) .309 
    5 y  18 (12-24)  15 (9-23)  25 (16-34) .309 
OS 165  143  88   
    1 y  38 (31-45)  46 (37-54)  45 (35-56) .315 
    3 y  21 (15-28)  27 (20-35)  29 (20-39) .302 
    5 y  18 (12-25)  20 (13-29)  26 (17-36) .365 
Outcome eventnMAC (n = 165)
nRIC (n = 143)
nNMAC (n = 88)
P*
Probability (95% CI)Probability (95% CI)Probability (95% CI)
Time to ANC0.5 × 109/L 164  143  88   
    28 d  86 (80-90)  96 (90-98)  92 (83-96) .012 
    100 d  88 (82-92)  99 (94-100)  97 (90-99) < .001 
aGVHD (II-IV) 164  143  88   
    100 d  43 (36-51)  43 (35-51)  44 (34-55) .970 
cGVHD 163  137  88   
    1 y  35 (28-43)  39 (31-47)  33 (24-43) .641 
    3 y  37 (30-45)  41 (32-49)  37 (27-47) .794 
    5 y  37 (30-45)  42 (34-51)  37 (27-47) .605 
NRM 163  142  86   
    100 d  32 (25-39)  24 (17-31)  17 (10-26) .029 
    1 y  47 (39-54)  31 (24-39)  29 (20-39) .004 
    3 y  55 (47-63)  42 (34-50)  34 (24-45) .003 
    5 y  56 (48-64)  47 (38-56)  36 (26-46) .007 
Relapse/progression 163  142  86   
    1 y  23 (17-30)  32 (25-40)  37 (27-48) .043 
    3 y  26 (19-33)  35 (27-43)  38 (28-49) .078 
    5 y  26 (19-33)  38 (30-46)  40 (30-50) .031 
PFS 163  142  86   
    1 y  30 (23-38)  37 (29-45)  34 (24-44) .487 
    3 y  19 (13-25)  23 (16-31)  27 (18-37) .309 
    5 y  18 (12-24)  15 (9-23)  25 (16-34) .309 
OS 165  143  88   
    1 y  38 (31-45)  46 (37-54)  45 (35-56) .315 
    3 y  21 (15-28)  27 (20-35)  29 (20-39) .302 
    5 y  18 (12-25)  20 (13-29)  26 (17-36) .365 

n indicates number of patients; and ANC, absolute neutrophil count.

*

Probabilities of neutrophil recovery, platelet recovery, aGVHD, cGVHD, NRM, and progression/relapse were calculated using the cumulative incidence estimate. PFS and OS were calculated using the Kaplan-Meier product limit estimate.

Table 4

Multivariate analysis

Reference groupNRM
Relapse/PD
Treatment failure/PFS
Mortality/OS
PHRPHRPHRPHR
Main effect .71*/.58 0.069*/0.026 1.45*/2.14 0.096*/0.003 1.05*/1.05 0.740*/0.788 .96*/.84 0.761*/0.301 
Karnofsky 1.51 0.011 — — 1.43 0.004 1.48 0.002 
Donor type§ 2.32 < 0.001 — — — — — — 
Disease status 2.79/1 < 0.001/— 2.06/3.23 0.006/0.002 2.49/1.47 < 0.001/0.056 2.37/— < 0.001/— 
No rituximab before alloHCT# — — 1.69 0.008 — — — — 
Year of alloHCT** .49 < 0.001 — — .61 < 0.001 .60 < 0.001 
Reference groupNRM
Relapse/PD
Treatment failure/PFS
Mortality/OS
PHRPHRPHRPHR
Main effect .71*/.58 0.069*/0.026 1.45*/2.14 0.096*/0.003 1.05*/1.05 0.740*/0.788 .96*/.84 0.761*/0.301 
Karnofsky 1.51 0.011 — — 1.43 0.004 1.48 0.002 
Donor type§ 2.32 < 0.001 — — — — — — 
Disease status 2.79/1 < 0.001/— 2.06/3.23 0.006/0.002 2.49/1.47 < 0.001/0.056 2.37/— < 0.001/— 
No rituximab before alloHCT# — — 1.69 0.008 — — — — 
Year of alloHCT** .49 < 0.001 — — .61 < 0.001 .60 < 0.001 

— indicates not applicable; and PIF, primary induction failure.

*

RIC-resistant versus MAC (reference group).

NMAC versus MAC (reference group).

< 90% versus ≥ 90% (reference group).

§

Other versus sibling MRD (reference group).

Relapse-resistant versus sensitive (reference group).

PIF-resistant versus sensitive (reference group).

#

Versus used.

**

After 2004 vs before 2004 (reference group).

Engraftment

Cumulative incidence of neutrophil recovery at days 28 and 100 after transplantation was significantly higher after RIC (day 28: 96%, 95% CI, 90%-98%; day 100: 99%, 95% CI, 94%-100%) and NMAC (day 28: 92%, 95% CI, 83%-96%; day 100: 97%, 95% CI, 90%-99%) compared with MAC regimens (day 28: 86%, 95% CI, 80%-90%; P = .012; day 100: 88%, 95% CI, 82%-92%; P < .001).

NRM

MAC regimens were associated with higher NRM compared with RIC and NMAC regimens (100-day NRM: 32% vs 24% vs 17%; P = .029; 1-year NRM: 47% vs 31% vs 29%; P = .004; 5-year NRM: 56% vs 47% vs 36%; P = .007; Figure 1). In multivariate analysis, NMAC (HR = 0.58, 95% CI, 0.36-0.97; P = .026) and RIC (HR = 0.71, 95% CI, 0.49-1.03; P = .069) were associated with lower NRM compared with MAC. Significant covariates associated with a higher NRM included Karnofsky performance score < 90% (HR = 1.51, 95% CI, 1.10-2.08; P = .011), and HLA-mismatched unrelated donor status (HR = 2.32, 95% CI, 1.57-3.43; P < .001). Transplants performed after year 2004 (HR = 0.49; P < .001) and chemotherapy-sensitive relapse before transplantation (HR = 0.5; 95% CI, 0.31-0.81; P = .005) were associated with lower NRM.

Figure 1

Illustration of PFS, progression/relapse, and NRM in the different conditioning groups. NST indicates nonmyeloablative stem cell transplantation; Prog, progression; and Rel, relapse.

Figure 1

Illustration of PFS, progression/relapse, and NRM in the different conditioning groups. NST indicates nonmyeloablative stem cell transplantation; Prog, progression; and Rel, relapse.

Close modal

Relapse/progression

Cumulative incidence of relapse/progression at 1, 3, and 5 years after alloHCT was higher after NMAC and RIC than MAC regimens (at 1 year: 37% vs 32% vs 23%; P = .043; at 3 years: 38% vs 35% vs 26%; P = .078; at 5 years: 40% vs 38% vs 26%; P = .031; Figure 1). NMAC regimens (HR = 2.14, 95% CI, 1.29-3.54; P = .003) and RIC (HR = 1.45, 95% CI, 0.94-2.26; P = .096) were associated with a higher risk of relapse/progression in multivariate analysis compared with MAC. Significant covariates associated with a higher risk of relapse/progression were no therapy with rituximab before transplant (HR = 1.69, 95% CI, 1.15-2.48; P = .008), chemoresistant primary induction failure (HR = 3.23, 95% CI, 1.55-6.69; P = .002), and chemotherapy resistant relapse before transplant (HR = 3.6, 95% CI, 1.72-7.55; P < .001).

PFS

PFS was similar at 1, 3, and 5 years after transplantation between MAC, RIC, and NMAC regimens (at 1 year: 30% vs 37% vs 34%; P = .487; at 3 years: 19% vs 23% vs 27%; P = .309; at 5 years: 18% vs 23% vs 25%; P = .309; Figure 1). In multivariate analysis, PFS was similar for patients from RIC (HR = 1.05, 95% CI, 0.79-1.39; P = .74) and NMAC cohorts (HR = 1.05, 95% CI, 0.75-1.47; P = .788) compared with the MAC cohort. Significant covariates associated with lower PFS included lower Karnofsky performance status (HR = 1.43, 95% CI, 1.12-1.83; P = .004) and chemotherapy-resistant relapse (HR = 2.49, 95% CI, 1.74-3.57; P < .001). Transplantation performed in year 2004 or later was associated with superior PFS and lower risk of treatment failure (HR = 0.61, 95% CI, 0.48-0.78; P < .001).

Survival

Survival at 1, 3, and 5 years did not differ significantly between MAC, RIC, and NMAC regimens (at 1 year: 38% vs 46% vs 45%; at 3 years: 21% vs 27% vs 29%; at 5 years: 18% vs 20% vs 26%). Covariates significantly correlated with lower survival and higher mortality included Karnofsky performance score < 90 (HR = 1.48, 95% CI, 1.16-1.90; P = .002) and chemotherapy-resistant relapse (HR = 1.70, 95% CI, 1.14-2.56; P = .010). Transplants performed in 2004 or later were associated with lower mortality (HR = 0.60; 95% 0.47-0.76; P < .001).

Secondary outcomes

The incidence of grade ≥ 2 aGVHD (43%; 95% CI, 36%-51% both for MAC and RIC, 44%; 95% CI, 34%-55% for NMAC), and cGVHD at 5 years (37%; 95% CI, 30%-45% both for MAC and NMAC, 42%; 95% CI, 34%-51% for RIC) did not differ significantly between the cohorts.

Cause of death

The main cause of death among all 3 cohorts was relapsed/progressive lymphoma (MAC, 38%; RIC, 39%; NMAC, 48%). Other leading causes of deaths were sepsis/severe infection (MAC, 21%; RIC, 16%; NMAC, 16%), organ failure (MAC, 14%; RIC, 13%; NMAC, 6%), and GVHD (MAC, 11%; RIC, 8%; NMAC: 6%).

In contrast to autologous HCT, which represents a standard second-line approach for relapsed/refractory patients with DLBCL, alloHCT that is performed in some centers as third-line approach is no standard option for this disease entity. A limited number of studies evaluating the outcomes of alloHCT in DLBCL have been published, and the heterogeneity of patients in these reports does not allow definite conclusions to be drawn regarding this approach.10,21-25  The current study is the largest report comparing outcomes after conditioning regimens of different intensity (including 164 MAC, 143 RIC, and 88 NMAC) in DLBCL patients. Patient-, disease-, and transplant-related differences observed between the different conditioning groups reflect the expected effect of patient selection, with the MAC cohort having lower median age, higher incidence of advanced and chemorefractory disease, and less use of radiotherapy or autotransplantation before allotransplantation. The patients in the 3 conditioning groups were different regarding disease characteristics as those patients with poor prognosis (eg, with chemorefractory disease) underwent more aggressive MAC transplantations. In this setting, the potential of the alloHCT based on the graft-versus-lymphoma effect might be insufficient because of still increased tumor burden after the conditioning.

In one major aspect, conditioning intensity affected the outcomes. Both the short- and long-term NRM was higher for MAC compared with the RIC and NMAC patients: The MAC cohort had a higher day-100 NRM (> 30%), and also 5-year NRM. Similarly, in an EBMT analysis studying 101 DLBCL patients, van Kampen et al observed a 3-year NRM of 41% after MAC compared with 20% in RIC.5  Lazarus et al reported a high NRM of 45% at 5 years in 79 DLBCL patients who received related donor alloHCT with MAC, primarily combinations of cyclophosphamide with 12 Gy TBI or with busulfan as second-line approach after initial chemotherapy.26  Regarding the RIC/NMAC transplants, we found a similar NRM rate compared with previous studies reporting on NRM rates between 23% and 28%.12,15,27  A lower Karnofsky performance status, a history of chemotherapy resistant relapse before alloHCT, or the use of unrelated donors impacted adversely on NRM in our study.

On the other hand, the cumulative incidence of relapse/progression at 5 years was higher after NMAC and RIC with 40% and 38% compared with MAC with 26% (P = .031) in our study. This is also similar to previous studies reporting relapse rates of 33%-41% after RIC regimens for DLBCL patients.12,14,15  After MAC alloHCT, Doocey et al documented a 5-year relapse rate of 32% in patients with different aggressive lymphoma entities, including DLBCL,8  and Lazarus et al observed a relapse rate of 33% at 5 years for DLBCL patients.26  Besides the negative impact of RIC regimens, nonreceipt of rituximab before transplantation and chemoresistant disease adversely impacted on relapse.

Finally, we found no difference in survival between the 3 conditioning groups. Although the OS and PFS after MAC (18% each at 5 years) were comparable with other studies,26  survival outcomes after RIC (5-year OS, 20%; PFS, 15%) and NMAC (5-year OS, 26%; PFS, 25%) in our study was lower compared with other studies (OS, 45%-52%; PFS, 35%-48%).5,12,14,15  Thomson et al observed a 4-year PFS of 48% after RIC,14  whereas Lazarus et al observed a 5-year PFS of 22% after MAC alloHCT.26  These differences between the results in this study and the previous literature are probably the result of different patient selection criteria. Karnofsky performance status, disease status before alloHCT, and year of transplantation were significant predictors regarding the PFS and OS.

As the present study was based on a retrospective multicenter registry analysis, limitations regarding the patients' demographics between 3 conditioning groups with possible bias should be taken into account. Nevertheless, the present data and the previous studies clearly demonstrate that allogeneic HCT may be curative for selected patients with relapsed, poor-risk DLBCL. The higher NRM after use of MAC regimens and the association of the relapse with the conditioning intensity provide an orientation for selecting the most appropriate conditioning strategies. The use of rituximab before HCT according to our study may reduce the relapse/progression rate after transplantation; however, it needs to be further investigated in large prospective studies. In summary, younger DLBCL patients and patients with little comorbidity may receive additional reduction in relapse risk from MAC regimens, whereas elderly patients or those with severe comorbidities may be selected for RIC regimens that are associated with lower NRM.

The online version of this article contains a data supplement.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

The authors thank Asad Bashey, Maria L. Delioukina, James L. Gajewski, Brandon M. Hayes-Lattin, Roger Herzig, Osman Ilhan, Philip L. McCarthy, Alan M. Miller, Gustavo A. Milone, Silvia Montoto, Reinhold Munker, Gordon L. Phillips, and David A. Rizzieri for their helpful comments and insights as members of the study committee.

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, or any other agency of the US government.

The CIBMTR is supported by the National Cancer Institute, the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (Public Health Service Grant/Cooperative Agreement U24-CA76518); NHLBI and National Cancer Institute (Grant/Cooperative Agreement 5U01HL069294); Health Resources and Services Administration (contract HHSH234200637015C); the Office of Naval Research (grants N00014-06-1-0704 and N00014-08-1-0058); and the following: Allos Inc; Amgen Inc; Angioblast; anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Children's Leukemia Research Association; Fresenius-Biotech North America Inc; Gamida Cell Teva Joint Venture Ltd; Genentech Inc; Genzyme Corporation; GlaxoSmithKline; HistoGenetics Inc; Kiadis Pharma; Leukemia & Lymphoma Society; Medical College of Wisconsin; Merck & Co Inc; Millennium: Takeda Oncology Co; Milliman USA Inc; Miltenyi Biotec Inc; National Marrow Donor Program; Optum Healthcare Solutions Inc; Osiris Therapeutics Inc; Otsuka America Pharmaceutical Inc; RemedyMD; Sanofi; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix Inc; StemCyte, A Global Cord Blood Therapeutics Co; Stemsoft Software Inc; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Teva Neuroscience Inc; THERAKOS Inc; and Wellpoint Inc.

National Institutes of Health

Contribution: U.B., E.K., and P.N.H. designed the study, interpreted data, prepared the manuscript, and gave approval of the final manuscript; J.C. and J.L.-R. performed the statistical analysis; and P.A., M.R.B., C.N.B., M.S.C., T.S.F., C.O.F., R.P.G., J.G., L.M.I., D.J.I., G.G.L., H.M.L., R.T.M., P.H.W., H.C.S., S.S., S.M.S., J.M.V., and E.K.W. participated in interpretation of data, manuscript preparation, and approval of the final manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Ulrike Bacher, Department for Stem Cell Transplantation, University of Hamburg, Martinistrasse 52, 20246 Hamburg, Germany; e-mail: [email protected].

1
Coiffier
 
B
Lepage
 
E
Briere
 
J
et al. 
CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.
N Engl J Med
2002
, vol. 
346
 
4
(pg. 
235
-
242
)
2
Sehn
 
LH
Donaldson
 
J
Chhanabhai
 
M
et al. 
Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia.
J Clin Oncol
2005
, vol. 
23
 
22
(pg. 
5027
-
5033
)
3
Micallef
 
IN
Maurer
 
MJ
Wiseman
 
GA
et al. 
Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma.
Blood
2011
, vol. 
118
 
15
(pg. 
4053
-
4061
)
4
Philip
 
T
Guglielmi
 
C
Hagenbeek
 
A
et al. 
Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma.
N Engl J Med
1995
, vol. 
333
 
23
(pg. 
1540
-
1545
)
5
van Kampen
 
RJ
Canals
 
C
Schouten
 
HC
et al. 
Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin's lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry.
J Clin Oncol
2011
, vol. 
29
 
10
(pg. 
1342
-
1348
)
6
Bishop
 
MR
Dean
 
RM
Steinberg
 
SM
et al. 
Clinical evidence of a graft-versus-lymphoma effect against relapsed diffuse large B-cell lymphoma after allogeneic hematopoietic stem-cell transplantation.
Ann Oncol
2008
, vol. 
19
 
11
(pg. 
1935
-
1940
)
7
Dhedin
 
N
Giraudier
 
S
Gaulard
 
P
et al. 
Allogeneic bone marrow transplantation in aggressive non-Hodgkin's lymphoma (excluding Burkitt and lymphoblastic lymphoma): a series of 73 patients from the SFGM database. Societ Francaise de Greffe de Moelle.
Br J Haematol
1999
, vol. 
107
 
1
(pg. 
154
-
161
)
8
Doocey
 
RT
Toze
 
CL
Connors
 
JM
et al. 
Allogeneic haematopoietic stem-cell transplantation for relapsed and refractory aggressive histology non-Hodgkin lymphoma.
Br J Haematol
2005
, vol. 
131
 
2
(pg. 
223
-
230
)
9
Kim
 
SW
Tanimoto
 
TE
Hirabayashi
 
N
et al. 
Myeloablative allogeneic hematopoietic stem cell transplantation for non-Hodgkin lymphoma: a nationwide survey in Japan.
Blood
2006
, vol. 
108
 
1
(pg. 
382
-
389
)
10
Robinson
 
SP
Goldstone
 
AH
Mackinnon
 
S
et al. 
Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation.
Blood
2002
, vol. 
100
 
13
(pg. 
4310
-
4316
)
11
Kusumi
 
E
Kami
 
M
Kanda
 
Y
et al. 
Reduced-intensity hematopoietic stem-cell transplantation for malignant lymphoma: a retrospective survey of 112 adult patients in Japan.
Bone Marrow Transplant
2005
, vol. 
36
 
3
(pg. 
205
-
213
)
12
Rezvani
 
AR
Norasetthada
 
L
Gooley
 
T
et al. 
Non-myeloablative allogeneic haematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: a multicentre experience.
Br J Haematol
2008
, vol. 
143
 
3
(pg. 
395
-
403
)
13
Maloney
 
D
Allogeneic transplantation following nonmyeloablative conditioning for aggressive lymphoma.
Bone Marrow Transplant
2008
, vol. 
42
 
suppl 1
(pg. 
S35
-
S36
)
14
Thomson
 
KJ
Morris
 
EC
Bloor
 
A
et al. 
Favorable long-term survival after reduced-intensity allogeneic transplantation for multiple-relapse aggressive non-Hodgkin's lymphoma.
J Clin Oncol
2009
, vol. 
27
 
3
(pg. 
426
-
432
)
15
Sirvent
 
A
Dhedin
 
N
Michallet
 
M
et al. 
Low nonrelapse mortality and prolonged long-term survival after reduced-intensity allogeneic stem cell transplantation for relapsed or refractory diffuse large B cell lymphoma: report of the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire.
Biol Blood Marrow Transplant
2010
, vol. 
16
 
1
(pg. 
78
-
85
)
16
Bacigalupo
 
A
Ballen
 
K
Rizzo
 
D
et al. 
Defining the intensity of conditioning regimens: working definitions.
Biol Blood Marrow Transplant
2009
, vol. 
15
 
12
(pg. 
1628
-
1633
)
17
Cheson
 
BD
Pfistner
 
B
Juweid
 
ME
et al. 
Revised response criteria for malignant lymphoma.
J Clin Oncol
2007
, vol. 
25
 
5
(pg. 
579
-
586
)
18
Glucksberg
 
H
Storb
 
R
Fefer
 
A
et al. 
Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors.
Transplantation
1974
, vol. 
18
 
4
(pg. 
295
-
304
)
19
Filipovich
 
AH
Weisdorf
 
D
Pavletic
 
S
et al. 
National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and Staging Working Group Report.
Biol Blood Marrow Transplant
2005
, vol. 
11
 
12
(pg. 
945
-
956
)
20
Weisdorf
 
D
Spellman
 
S
Haagenson
 
M
et al. 
Classification of HLA-matching for retrospective analysis of unrelated donor transplantation: revised definitions to predict survival.
Biol Blood Marrow Transplant
2008
, vol. 
14
 
7
(pg. 
748
-
758
)
21
Nagler
 
A
Slavin
 
S
Varadi
 
G
Naparstek
 
E
Samuel
 
S
Or
 
R
Allogeneic peripheral blood stem cell transplantation using a fludarabine-based low intensity conditioning regimen for malignant lymphoma.
Bone Marrow Transplant
2000
, vol. 
25
 
10
(pg. 
1021
-
1028
)
22
Morris
 
E
Thomson
 
K
Craddock
 
C
et al. 
Outcomes after alemtuzumab-containing reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma.
Blood
2004
, vol. 
104
 
13
(pg. 
3865
-
3871
)
23
Escalón
 
MP
Champlin
 
RE
Saliba
 
RM
et al. 
Nonmyeloablative allogeneic hematopoietic transplantation: a promising salvage therapy for patients with non-Hodgkin's lymphoma whose disease has failed a prior autologous transplantation.
J Clin Oncol
2004
, vol. 
22
 
12
(pg. 
2419
-
2423
)
24
Dean
 
RM
Fowler
 
DH
Wilson
 
WH
et al. 
Efficacy of reduced-intensity allogeneic stem cell transplantation in chemotherapy-refractory non-Hodgkin lymphoma.
Biol Blood Marrow Transplant
2005
, vol. 
11
 
8
(pg. 
593
-
599
)
25
Rodriguez
 
R
Nademanee
 
A
Ruel
 
N
et al. 
Comparison of reduced-intensity and conventional myeloablative regimens for allogeneic transplantation in non-Hodgkin's lymphoma.
Biol Blood Marrow Transplant
2006
, vol. 
12
 
12
(pg. 
1326
-
1334
)
26
Lazarus
 
HM
Zhang
 
MJ
Carreras
 
J
et al. 
A comparison of HLA-identical sibling allogeneic versus autologous transplantation for diffuse large B cell lymphoma: a report from the CIBMTR.
Biol Blood Marrow Transplant
2010
, vol. 
16
 
1
(pg. 
35
-
45
)
27
Rigacci
 
L
Puccini
 
B
Dodero
 
A
et al. 
Allogeneic hematopoietic stem cell transplantation in patients with diffuse large B cell lymphoma relapsed after autologous stem cell transplantation: a GITMO study.
Ann Hematol
2012
, vol. 
91
 
6
(pg. 
931
-
939
)

Author notes

*

U.B. and E.K. contributed equally to this study.

Sign in via your Institution