Abstract

Introduction. The definitive management of R/R FL remains controversial due to various treatment options, including chemoimmunotherapy, pathway inhibitors, and autologous stem cell transplantation (auto-SCT). These options can provide prolonged progression-free survival (PFS). Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the sole curative therapy for FL. Herein, we report the long term outcome of the largest sample of allo-SCT for FL ever studied as well as the identification of patient and disease related factors that were significantly associated with treatment failure.

Patients. Eligible were adult patients with R/R FL having received a first allo-SCT between 2001 and 2011 from an HLA identical sibling donor (SIB) or a well-matched unrelated donor (MUD). Patients with transformed lymphoma were excluded from the analysis as well as planned second transplants, allotransplants from cord blood, mismatched donors, and transplants with ex vivo T cell depletion (TCD).

Results. 1567 patients met the eligibility criteria (EBMT, n = 1115; CIBMTR, n = 452). Demographics separated by data source demonstrate some differences in transplant practices between the two regions. The CIBMTR cohort had a higher proportion of MUD recipients [167 (37%) vs 252 (23%), p < 0.001], more cases with chemoresistant disease [113 (25%) vs 145 (13%), p < 0.001], less patients having received a prior auto-SCT [53 (12%) vs 403 (36%), p < 0.001], more use of myeloablative conditioning (MAC) (145 (32%) vs 220 (20%), p < 0.001) and less use of alemtuzumab in-vivo TCD [29 (6%) vs 201 (18%), p < 0.001] compared to the EBMT cohort. Median (range) follow up of survivors in months was 58 (3 - 130) and 54 (3 - 160) for CIBMTR and EBMT patients, respectively. Cumulative incidence of acute (grades II-IV) graft versus host disease (GVHD) was 20% (18-22) at 100 days and of chronic GVHD 45% (42-48) and 55% (52-58) at 1 and 3 years, respectively for the whole series; this risk was slightly but significantly reduced in the EBMT cohort. All major outcomes [non-relapse mortality (NRM), relapse/progression (R/P), overall survival (OS) and PFS] were comparable between the CIBMTR and EBMT samples (Table 1).

Table 1.
Outcomes CIBMTR EBMT p-value 
NRM
N
@ 1 y
@ 3 y
@ 5 y 
450
21 (17-25)
27 (23-32)
31 (26-35) 
1088
19 (16-21)
24 (21-27)
28 (25-31) 
0.363
0.172
0.114 
R/P
N
@ 1 y
@ 3 y
@ 5 y 
450
13 (10-16)
16 (13-20)
17 (13-21) 
1088
13 (11-15)
18 (15-20)
21 (18-23) 
0.874
0.480
0.114 
PFS
N
@ 1 y
@ 3 y
@ 5 y 
450
66 (62-71)
56 (52-61)
52 (47-57) 
1088
69 (66-72)
58 (55-61)
52 (48-55) 
0.375
0.495
0.792 
OS
N
@ 1 y
@3 y
@ 5 y 
452
74 (70-78)
65 (60-69)
61 (56-65) 
1104
75 (72-78)
67 (64-70)
62 (59-65) 
0.589
0.455
0.695 
Outcomes CIBMTR EBMT p-value 
NRM
N
@ 1 y
@ 3 y
@ 5 y 
450
21 (17-25)
27 (23-32)
31 (26-35) 
1088
19 (16-21)
24 (21-27)
28 (25-31) 
0.363
0.172
0.114 
R/P
N
@ 1 y
@ 3 y
@ 5 y 
450
13 (10-16)
16 (13-20)
17 (13-21) 
1088
13 (11-15)
18 (15-20)
21 (18-23) 
0.874
0.480
0.114 
PFS
N
@ 1 y
@ 3 y
@ 5 y 
450
66 (62-71)
56 (52-61)
52 (47-57) 
1088
69 (66-72)
58 (55-61)
52 (48-55) 
0.375
0.495
0.792 
OS
N
@ 1 y
@3 y
@ 5 y 
452
74 (70-78)
65 (60-69)
61 (56-65) 
1104
75 (72-78)
67 (64-70)
62 (59-65) 
0.589
0.455
0.695 

Multivariate analysis indicated that NRM was significantly affected by age (HR 1.04, 1.02-1.05, p < 0.0001), chemoresistant disease (HR 1.61, 1.28-2.03, p < 0.0001), >= 5 lines of prior CT (vs 3-4) (HR 1.62, 1.20-2.19, p=0.0015) and Karnofsky performance score (KPS) < 80 (HR 2.05 (1.32-3.19, p=0.0014); R/P was significantly affected by grade 3 histology (HR 1.63, 1.16-2.26, p=0.0049) and chemoresistant disease (HR 1.46 (1.07-1.97), p=0.0156); PFS by grade 3 histology (HR 1.42, 1.15-1.76, p=0.0012), chemoresistant disease (HR 1.54, 1.28-1.86, p<0.0001), >= 5 lines of prior CT (vs 3-4) (HR 1.45, 1.13-1.85, p=0.0031), MAC (HR 1.36, 1.14-1.63, p=0.0008) and KPS < 80 (HR 1.78, 1.23-2.58, p =0.0022) and OS by age (HR 1.03, 1.02-1.04, p<0.0001), grade 3 histology (HR 1.44, 1.13-1.83, p=0.0031), chemoresistant disease (HR 1.59, 1.30-1.95, p<0.0001), >= 5 lines of prior CT (vs 3-4) (HR 1.63, 1.25-2.13, p=0.0003), MAC (HR 1.42, 1.16-1.73, p=0.0006) and KPS < 80 (HR 2.23, 1.52-3.25, p<0.0001). Of note, outcomes between SIB and MUD were similar (3y OS 68% and 62%, P=0.114). Moreover a significant impact of TCD and prior auto-SCT could not be detected.

Conclusions. This study represents an example of a fruitful cooperation between two important scientific transplant societies, the EBMT and CIBMTR. Despite significant differences in patient characteristics and transplant strategies between these 2 hitherto largest samples on allo-SCT for R/R FL, long-term disease control was similar and remarkably good with an R/P risk of about only 20% at 5 years. Chemoresistant disease, higher age, multiple pretreatment lines, poor KPS, and MAC all were predictors for an adverse outcome, whereas MUD, TCD, and prior auto-SCT had no impact on any survival endpoint.

Disclosures

Sureda:Takeda: Consultancy, Honoraria, Speakers Bureau. Fenske:Celgene: Honoraria; Millennium/Takeda: Research Funding; Pharmacyclics: Honoraria; Seattle Genetics: Honoraria. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy.

Author notes

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Asterisk with author names denotes non-ASH members.

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