Allogeneic Hematopoietic Cell Transplantation As Curative Therapy for Non-Transformed Follicular Lymphomas

ORIGINAL ARTICLE Allogeneic hematopoietic cell transplantation as curative therapy for non-transformed follicular lymphomas

F Heinzelmann1, W Bethge2, DW Beelen3, M Engelhard4, N Kröger5, P Dreger6, D Niederwieser7, J Finke8, D Bunjes9, J Tischer10, G Kobbe11, E Holler12, M Bornhäuser13, M Stelljes14, H Baurmann15, A Müller1, I Haubitz16, H Schrezenmeier17, C Müller18 and H Ottinger3

Allogeneic hematopoietic cell transplantation (HCT) offers the chance of cure for patients with non-transformed follicular lymphoma (FL), but is associated with the risk of non-relapse mortality (NRM). The aim of this study was to identify subgroups of FL patients who beneﬁt from HCT. The European Society for Blood and Marrow Transplantation (EBMT) Minimum-Essential-A Data of 146 consecutive patients who received HCT for FL between 1998 and 2008 were extracted from the database of the German Registry ‘DRST’. Diagnosis of FL was veriﬁed by contact with the reference pathologists. Estimated 1-, 2- and 5-year overall survivals (OS) were 67%, 60% and 53%, respectively. Day 100 NRM was 15%. Thirteen out of 33 patients (40%) with treatment-refractory disease (RD) at the time of transplantation survived long term. Univariate statistical analysis suggested limited chronic GvHD, donor age ⩽ 42 years and TBI-based conditioning in treatment refractory patients to correlate with favorable OS. Independent prognostic factors for OS were treatment- sensitive disease and limited chronic GvHD for the whole cohort, and additionally TBI-based conditioning for the treatment refractory subgroup. In contrast, patient age ⩾ 55 years had no impact on outcome. Thus, HCT for FL is associated with acceptable NRM, and offers a substantial chance of cure for patients with RD or advanced age. Donors ⩽ 42 years should be preferred if available.

Bone Marrow Transplantation (2016) 51, 654–662; doi:10.1038/bmt.2015.348; published online 8 February 2016

INTRODUCTION published series of HCT for patients with FL myeloablative 20–22 Non-transformed follicular lymphoma (FL), a mature B-cell conditioning protocols (MAC) were used. These studies neoplasm, is the second most common subtype of malignant demonstrated that allogeneic HCT has the potential for cure of lymphoma in adults (~20–25%).1 Conventional treatment options relapsed/chemotherapy-resistant FL. However, owing to the high for FL patients include multiagent chemotherapy combined with non-relapse mortality (NRM) rate of up to 40% this treatment o anti-CD20 monoclonal Abs2,3 or radioimmunotherapy,4,5 leading modality had to be limited to patients 50 years and a Karnofsky ⩾ 23 to an improvement of median overall survival (OS) of 12–14 years performance status 90%. To extend the use of HCT to patients in the last decade.6 High-dose salvage regimens, including with advanced age and comorbidities, reduced intensity con- chemotherapy, rituximab and/or TBI, followed by autologous ditioning (RIC) protocols were developed and became increasingly hematopoietic cell transplantation (HCT) have also clearly popular during the last decade. The results of several, but not all 7–9 clinical trials show low NRM and high OS, and event-free survival improved 5-year PFS and OS. More recently, the type II – (EFS) rates after RIC as compared with MAC in FL.24 31 CD20-Ab obinutuzumab,10,11 bortezomib,12 lenalidomide,13 The present retrospective study enrolled a large cohort of idelalisib,14 ibrutinib,15 bcl-2 inhibitors16 and Car T cells17 have intensively pretreated patients who received HCT for non- potential for further refinement of the clinical outcome in FL transformed histological grades 1–3A FL. The aim of the study patients. However, despite all recent innovative approaches, was to identify prognostic factors for transplantation outcome, cure of FL cannot yet be achieved. Thus, the clinical course of that is, to define subgroups of FL patients who will or will not FL remains to be characterized by a series of subsequent relapses benefit from transplantation. accompanied by an increase of cumulative drug toxicity and finally by a treatment refractory state, resulting in progressive disease (PD). Since the 1990s, there has been increasing interest in PATIENTS AND METHODS evaluating the role of allogeneic HCT to cure patients with Patient enrollment advanced FL by its potential to induce an allo-immune reaction The DRST (German Registry for Stem Cell Transplantation) database was named graft versus lymphoma (GvL) effect.18,19 In the first screened for patients who had received HCT for non-Hodgkin lymphoma

1Department of Radiation Oncology, University Hospital (UH) of Tübingen, Tubingen, Germany; 2Department of Internal Medicine II, UH of Tübingen, Tubingen, Germany; 3Department of Bone Marrow Transplantation, UH of Essen, Essen, Germany; 4Department of Radiotherapy, UH of Essen, Essen, Germany; 5Clinic for Stem Cell Transplantation, UH of Hamburg (UKE), Hamburg, Germany; 6Department of Medicine V, UH of Heidelberg, Heidelberg, Germany; 7Department of Hematology and Oncology, UH of Leipzig, Leipzig, Germany; 8Department of Hematology and Oncology, UH of Freiburg, Freiburg, Germany; 9Department of Internal Medicine III, UH of Ulm, Ulm, Germany; 10Department of Internal Medicine III, UH of Munich (LMU), Munich, Germany; 11Department of Hematology, Oncology and Clinical Immunology, UH of Düsseldorf, Dusseldorf, Germany; 12Department of Hematology and Oncology, UH of Regensburg, Regensburg, Germany; 13Department of Internal Medicine I, UH of Dresden, Dresden, Germany; 14Department of Internal Medicine A, UH of Münster, Munster, Germany; 15Department for Bone Marrow Transplantation, DKD HELIOS Clinic of Wiesbaden, Wiesbaden, Germany; 16Data Processing Center, University of Würzburg, Wurzburg, Germany; 17Institute of Clinical Transfusion Medicine and Immunogenetics, UH of Ulm, Ulm, Germany and 18ZKRD Ulm, Ulm, Germany. Correspondence: Dr F Heinzelmann, Department of Radiation Oncology, University Hospital of Tübingen, Hoppe-Seyler-Str. 3, Tübingen D-72076, Germany. E-mail: [email protected] Received 12 May 2015; revised 3 December 2015; accepted 5 December 2015; published online 8 February 2016 Allogeneic transplant may cure follicular lymphoma F Heinzelmann et al 655 (NHL) between 1998 and 2008. A total of 1342 patients were identified. The data access committee of the German Registry has formally All patients transplanted for lymphomas with a diagnosis other than FL, approved this non-interventional retrospective study. The informed according to the current World Health Organization Classification of consent of all patients with entries in the DRST database has been Tumours of Haematopoietic and Lymphatic Tissues (4th edition, 2008), provided by all cooperating centers. were excluded if an unequivocal translation of formerly used nomencla- tures to the World Health Organization classification was available. The remaining n = 226 patients were accepted as study candidates. Evaluation of engraftment For these patients, local as well as pathologists of the National NHL The day of engraftment was defined as the first of three consecutive days Reference Panel were contacted in order to review the histological post transplantation with a neutrophil count of 4500/μl. Patients with no fi diagnosis according to the WHO classi cation. As a result, 80 study evidence of engraftment who did not survive to day 28 post transplanta- candidates were excluded from the analysis (n = 15: diffuse large tion were excluded from the engraftment analysis. B-cell lymphoma, n = 33: transformed FL, n = 6: FL grade 3B, n = 26: indolent lymphomas other than FL, such as mucosa associated lymphoid tissue lymphoma, chronic lymphocytic leukemia, marginal zone lymphoma Definition of myeloablative, reduced intensity and and mantle cell lymphoma). Of note, no patient was identified among the non-myeloablative conditioning study candidates who proved to have FL on review only. Thus, a total of The authors decided to consider the proposal of Bacigalupo et al. in order fi n = 146 patients with the de nite diagnosis of non-transformed FL to assign a given conditioning regimen to belong to either of three defined (histological grades 1–3A) could finally be enrolled in this study. groups, named MAC, RIC and non-myeloablative conditioning (NMAC). Table 1 shows relevant baseline characteristics and HCT clinical data of — ⩾ ⩾ fi MAC for example, protocols containing TBI 5 Gy (single dose) or 8Gy 146 quali ed patients. All available MED-A data were extracted from the 4 DRST database- irrespective of whether the EBMT data format 31/07/2007 (fractionated dose), or busulfan 8 mg/kg body weight (BW) p.o. or IV — or former versions had been used. equivalent causes irreversible cytopenia requiring stem cell support. In — ⩽ — Local data DRST managers were asked to provide additional patient and contrast, NMAC regimens for example, TBI 2 Gy ± purine analog can donor data (relevant to this study), which were not covered by the be applied without stem cell support. RIC—for example, protocols available MED-A formats, for example: (1) detailed data on conditioning containing reduced dose (at least 30%) of alkylating agents or TBI such regimens (name and cumulative dosages of applied drugs, irradiation as combinations of fludarabine ± alkylating agent/TBI—do not meet the dose in the case of TBI) and (2) evidence for the response to treatment criteria for MAC and NMAC. However, even if cytopenia after RIC is variable, (sensitive/refractory) at the time of HCT (results of computed tomography stem cell support is generally recommended.33 or positron emission tomography scans and biopsies). As data entry of chronic GvHD stages remains difficult even for experienced data managers, data source verification was performed by the Evaluation of response-to-treatment state at the time of HCT medical directors of the transplant units in person according to the Response to prior treatment was assessed using the criteria of the grading system proposed by the Seattle group.32 international working group.34

Table 1. Baseline characteristics of patients (n = 146)

Parameter Category N Range/percentage

Patient median age at the time of diagnosis of FL (years) 43 18–66 Patient median age at the time of allo-HCT (years) 48 29–71 Patient sex Male 89 61% Female 57 39% Initial stage of FL at the time of diagnosis (Ann Arbor) I-III 49 34% IV 97 66% B symptoms at the time of diagnosis No 93 68% Yes 43 32% Time interval: initial diagnosis—allo-HCT (years) ⩽3.5 71 49% 43.5 75 51% Number of chemotherapy cycles before allo-HCT (except mobilization therapy for auto-HCT) 1–3 88 60% 4–10 58 40% Auto-HCT before allo-HCT No 56 38% Yes 90 62% Time interval: auto-HCT to allo-HCT (months) 23 1.5–164 Response to treatment status of FL at the time of allo-HCT CR1 or CR2 36 25% PR (ﬁrst or subsequent) 74 52% Refractory 33 23% Type of conditioning used before allo-HCT Myeloablativea 39 27% Reduced intensitya 67 46% Non-myeloablativea 40 27% Conditioning protocol for allo-HCT containing TBI Yes 65 45% No 81 55% Donor sex Male 92 63% Female 54 37% Donor median age (years) at the time of allo-HCT 40 21–69 Patient/donor relationship Related 65 45% Unrelated 81 55% Patient/donor HLA match Fully matched 119 82% Partially mismatched 27 18% Sex mismatch (donor female, recipient male) Yes 29 20% No 117 80% Stem cell source Peripheral blood 133 92% Bone marrow 11 8% Abbreviations: allo = allogeneic; auto = autologous; FL = follicular lymphoma; HCT = hematopoietic cell transplantation. aAccording to Bacigalupo et al.33

© 2016 Macmillan Publishers Limited Bone Marrow Transplantation (2016) 654 – 662 Allogeneic transplant may cure follicular lymphoma F Heinzelmann et al 656 Treatment-sensitive disease was defined as first or subsequent CR or PR high-dose chemotherapy alone (n = 66) or a TBI-containing of all sites of disease without occurrence of new lesions after completion of conditioning regimen (n = 24). the recently applied treatment modality (chemotherapy ± antibodies ± local irradiation ± autologous HCT (chemotherapy ± TBI)). Treatment-refractory disease (RD) was defined as a disease status in Disease status at the time of HCT patients, who did not achieve a PR or showed PD after conventional Despite all efforts, the precise disease status at the time of HCT treatment options ± autologous HCT. (sensitive vs refractory) could not be defined in three patients. Thus, HCT outcome analysis focusing on remission status at the Evaluation of disease response to HCT time of HCT was limited to a total of n = 143 patients (cf. Figures 1 Best disease status after HCT was evaluated for all patients surviving day 30 and 2). At the time of HCT, 110 patients (77%) had sensitive using the criteria of the International Working Group (CR continued, disease, whereas 33 patients (23%) had RD. CR achieved, PR and RD). Relapse after HCT was defined as recurrence of FL in patients who were Conditioning regimens in CR at the time of transplantation or had achieved CR after HCT. PD was defined as an increase of persistent lymphoma mass or The distribution of the study patients receiving MAC, RIC or NMAC development of new areas of the disease not previously evident in patients is detailed in Table 1. N = 65 patients (45%) received TBI- without CR before and after the transplantation. containing conditioning, N = 24 patients (37%) were treated with high dose (12 Gy: n = 17, 10 Gy: n = 2 and 8 Gy: n = 5) and 41 patients (63%) with low-dose (4 Gy: n = 11and 2 Gy: n = 30) TBI Early death fi regimens. Of note, only 5 of these 65 patients (7%) had previously Early death post HCT was de ned as the demise of the patient before day received a TBI-containing regimen (n = 4: 2 Gy and n = 1: 4 Gy) in 30 post transplantation. preparation for autologous HCT. HLA typing of donors and recipients Donors HLA typing of unrelated donors and recipients was performed by high-resolution molecular typing of the HLA loci A, B, C, DRB1 and DQB1 Sixty-three percent (92/146) of the enrolled patients had a male as described previously.35 In the related setting, low-resolution molecular and 37% (54/146) a female donor. A donor/recipient sex mismatch HLA-A, B and DRB1 of donors and recipients were accepted if results could (female donor/male patient) was documented in 29/146 cases be confirmed by the segregation analysis of HLA haplotypes (pedigree plot (20%). Sixty-five patients (45%) were transplanted from sibling analysis). donors (HLA identical: n = 62 and partially HLA mismatched: n =3) and 81 patients (55%) from unrelated donors (fully HLA matched: Statistical analysis n = 57 and partially HLA mismatched: n = 24). The mean donor age – Statistical analysis was performed using MEDAS IT software (C Grund, (± s.d.) of related donors was 45.1 years ( ± 11.8; range 22 69 EDV Systems, Margetshoechheim, Germany). Primary end points for years) and of unrelated donors 36.4 years ( ± 9.2; range 20–56 analysis of HCT outcome were OS, EFS and NRM. For the evaluation of years). This difference in age between related and unrelated all aspects of chronic GvHD patients not surviving to day 100 post HCT donors was highly significant (P = 0.0007). were censored. Definitions used: OS was the number of days after HCT to eventually death from any cause. EFS was the time interval from the date Clinical outcome of HCT to the date of relapse/progression of FL or death from any cause. NRM was the time to death of any cause without documented prior OS and EFS. The median follow-up of surviving patients was 9.1 relapse/progression of FL. All clinical baseline parameters, as depicted in years (range 3.6–15.7). The Kaplan–Meier estimates for OS 1, 2, 5 Table 1, were suspected to be risk factors for HCT outcome, and therefore and 10 years after HCT (95% confidence interval) were 67% submitted to statistical analysis for their impact on OS, EFS and NRM, as (63–71), 60% (56–64), 53% (49–58) and 48% (44–52). The was the clinical time dependent outcome parameter of chronic GvHD. The corresponding estimates for EFS were 63% (59–67), 53% (49–58), analysis of the impact of all considered baseline and outcome variables for 47% (42–51) and 40% (36–45). Stable plateaus for OS and OS, EFS and NRM were evaluated using univariate statistical analysis EFS were reached at the 50% and 42% level, respectively (Kaplan–Meier log-normal approximation, log-rank test and U-test), followed by multivariate statistical analysis using established Cox (cf. Figures 3a and b). regression models evaluating changes in treatment or prognostic status (time dependent covariates).36,37 Engraftment. Eight patients not surviving to day 28 post HCT were excluded from analysis. Engraftment was achieved in 99% (137/138) of evaluable patients. The time median for neutrophil RESULTS recovery was 14 days (range: 5-43). Secondary graft failure was Baseline characteristics of study transplantations documented in o2% (2/138) of the cases. The baseline characteristics of the n = 146 study patients are depicted in Table 1. GvHD. A total of 36% of the recipients (n = 51/146) developed clinically relevant (grades II–IV) acute GvHD. Among the patients at risk/surviving day 100 post HCT (n = 123), limited chronic GvHD Pre-treatment was observed in 30% (n = 37/123) and extended chronic GvHD in Before allogeneic HCT, all study patients were intensively 31% (n = 38/123). pretreated with multiple regimens of chemotherapy ± rituximab (median: 3, range 1–10). Thirty study patients received localized Best disease status after HCT. Eight patients died early after radiotherapy at various time points of their disease course. transplant and five patients suffered from fatal failure of multiple Twenty-four patients received 12 Gy TBI-containing conditioning organs, which did not allow for the evaluation of disease status. regimen in preparation for an autologous HCT. In all patients Nevertheless, these patients remained included in our study as an treated with localized radiation and/or additional TBI, the intent-to-treat analysis was performed. cumulative dosage of radiotherapy did not exceed a cumulative The best disease status after HCT was CR in 79% (116/146), PR in dosage of 40 Gy. Thus, for all enrolled patients, a TBI-containing 10% (14/146) and PD in 2% (3/146). In detail, continued CR was conditioning regimen for allogeneic HCT of/or exceeding 4 Gy was documented in all patients (n = 36) transplanted in CR, whereas CR retrospectively regarded to be feasible. Before allogeneic HCT was achieved in 57/74 (85%) of the cases transplanted in PR and in 90/146 patients (62%) had undergone autologous HCT either after 22/33 (67%) of the recipients transplanted for refractory FL.

Bone Marrow Transplantation (2016) 654 – 662 © 2016 Macmillan Publishers Limited Allogeneic transplant may cure follicular lymphoma F Heinzelmann et al 657 a The remaining 65 casualties were due to NRM such as 100 infectious complications/extensive GvHD (n = 40), acute GvHD 90 P = 0.30 (n = 7), cerebral bleeding (n = 2), myocardial infarction (n = 3), pneumothorax (n = 1), pneumonitis (n = 1), encephalitis (n = 1), 80 leukoencephalopathy (n = 1) and secondary malignancies 70 Sensitive (n = 9; laryngeal carcinoma (n = 1), gastric cancer (n = 2); secondary 60 AML (n = 1), bronchial carcinoma (n = 2), post-transplant-related lymphoproliferative disease (n = 1), malignant melanoma (n = 1), 50 cancer of unknown origin (n = 1)), respectively. OS [%] 40

30 Refractory Risk factors for HCT outcome

20 Results of univariate statistical analysis Patient age. Our uni- and multivariate statistical analysis included 10 patient age as a continuous as well as a discrete variable 0 (age median: 48 years, 55 years vs ⩾55 years). We found that 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 age in general had no impact on outcome irrespective of which Time post transplantation [years] type of variable was employed in our analysis. OS results for Time post transplantation Day 0 1 year 2 years 5 years 10 years patients o55 (n = 108) and ⩾ 55 years (n = 38) are depicted in Number of patients at risk Sensitive 110 77 69 62 25 Figure 4a, as this cutoff is frequently used in clinical studies to Number of patients at risk Refractory 33 18 15 13 7 separate younger from elderly patients. b Donor age. Donor age was found to have an impact on HCT 100 outcome. A donor age of ⩽ 42 years was found to be the best P = 0.27 cutoff value for predicting a favorable OS (P = 0.0088, cf. Figure 4b) 90 and EFS (P = 0.0070). The median ages of the young and elderly 80 donor groups were 34 (range: 21–42) and 51 (range 43–69) years, 70 respectively. Furthermore, in the case of chronic GvHD, young

Sensitive donor age was found to be linked to limited and advanced donor 60 age to extended disease (U-test: P = 0.06). The observed effect of 50 donor age on HCT outcome and chronic GvHD could mainly be EFS [%] 40 attributed to the unrelated donor transplant setting (unrelated donors: median age 36.4 ± 9.2 years, related donors: median age: 30 Refractory 45.1 ± 11.8 years, P = 0.0007). 20 Response-to-treatment state at the time of HCT. If all study 10 patients (n = 146) were included in the statistical analysis, results 0 for OS and EFS did not differ significantly for patients with 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 sensitive and RD as shown in Figures 1a and b. However, if Time post transplantation [years] statistical analysis was confined to the largest subgroup of study Time post transplantation Day 0 1 year 2 years 5 years 10 years patients who had received chemotherapy-only based condition- Number of patients at risk Sensitive 110 73 63 55 20 Number of patients at risk Refractory 33 16 13 12 7 ing (n = 80), the treatment-sensitive cohort showed a trend towards better OS (P = 0.087) and EFS (P = 0.058) rates as Figure 1. (a, b) Overall survival (OS, a) and event-free survival b = compared with patients with RD. (EFS, ) after HCT for all (N 146) study patients according to the The impact of TBI-containing conditioning protocols on HCT response state to pre-treatment at the time of HCT (Kaplan–Meier plots and corresponding 95% confidence intervals, for details outcome for patients with sensitive and RD was analyzed by direct see text). comparison with the corresponding subgroups of patients conditioned with chemotherapy alone. Relapse. Overall, of the n = 116 patients with documented CR For patients with sensitive disease, the type of conditioning was after HCT only n = 17 (15%) relapsed. Fifteen of these relapses found to have no influence on OS (P = 0.59) and EFS (P = 0.48). occurred during the first 3 years after HCT (first year: n = 6; second In contrast, for patients with RD, TBI-containing conditioning year: n = 4; and third year: n = 5). Notably, only two late relapses regimens resulted in improved OS and EFS rates. As shown in (beyond year 3) were diagnosed among the 77 patients with a Figures 2a and b, the corresponding 95% confidence interval of follow-up 45 years and occurred 5.1 and 9.1 years after HCT. the two subcohorts did not overlap and the level of significance Eight out of 17 relapsed patients (47%) achieved a subsequent for superiority of TBI-containing conditioning was almost reached CR, which proved to be stable in all cases until the end of the for OS (P = 0.061) and EFS (P = 0.070) despite the small number of period of this study (median follow-up: 76 months, range refractory patients treated by TBI (n = 14). 61–139 months). Reinduction treatment included application of Beside the baseline parameters listed in Table 1, the influence of donor lymphocyte infusions, rituximab, bendamustine and/or the outcome parameter chronic GvHD on OS and EFS was localized radiotherapy. analyzed after stratification according to the degree of the disease, that is, absent, limited or extended. NRM. Cumulative NRM rates as calculated at days 30, 100 and at Patients with chronic GvHD (irrespective of stage) had a lower 24 months post transplantation were 4%, 15% and 35%, risk of relapse, if transplanted in CR, and a higher chance to respectively (Supplementary figure 1). achieve CR, if transplanted in PR or with PD (no chronic GvHD: 19/48, chronic GvHD: 11/75, P = 0.0019, χ2 test). Causes of death. None of the patients with PD (n = 8) after HCT Patients with limited chronic GvHD reached better OS and EFS survived 42 years. Six study patients who relapsed also died, rates compared with the two other study cohorts, whereas the despite intensive multimodal treatment, due to progressive outcome for patients with absent or extended disease was found disease (Supplementary figure 2). to be similar as evidenced by log-rank tests (OS: limited vs absent:

90 90 P = 0.061 80 80 TBI 70 70

60 60

50 50 OS [%] OS [%] OS 40 40

30 30

20 20

10 Chx 10

0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time post transplantation [years] Time post transplantation [years]

Time post transplantation Day 0 1 year 2 years 5 years 10 years Time post transplantation Day 0 1 year 2 years 5 years 10 years Number of patients at risk TBI 14 11 10 8 4 Number of patients at risk 146 98 87 77 32 Number of patients at risk Chx 19 7 5 53 b b 100 100 90 90 P = 0.070 80 80 70 TBI 70 60 60 50

50 EFS [%] 40 EFS [%] EFS 40 30 30 20 20 10

10 Chx 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time post transplantation [years] Time post transplantation [years] Time post transplantation Day 0 1 year 2 years 5 years 10 years 1 year 2 years 5 years 10 years Time post transplantation Day 0 Number of patients at risk 146 92 78 67 27 Number of patients at risk TBI 14 9 8 84 Number of patients at risk Chx 19 7 5 4 3 Figure 3. (a, b) Overall survival (OS, a) and event-free survival b = fi a b (EFS, ) for n 146 study patients after rst allogeneic hematopoie- Figure 2. ( , ) Overall survival (OS) and event-free survival (EFS) tic cell transplantation for non-transformed follicular lymphoma after HCT for study patients with pre-treatment-refractory disease – fi a b fi (Kaplan Meier plots and corresponding 95% con dence intervals, ( , OS, , EFS) at the time of HCT strati ed according to the for details see text). employed conditioning regimen. TBI containing (darkly shaded), Chx, chemotherapy-only based (brightly shaded), (Kaplan–Meier plots and corresponding 95% confidence intervals, for details factors for improved EFS and OS after HCT. In contrast, see text). multivariate statistical analysis could not establish donor age as an independent risk factor for HCT outcome due to the P = 0.0067, limited vs extended: P = 0.0011 and extended vs above-mentioned association of young donor age and limited absent: P = 0.56; EFS: limited vs absent: P = 0.0038, limited vs chronic GvHD. extended: P = 0.0036 and extended vs absent: P = 0.99). As the results for patients with absent and extended chronic GvHD did DISCUSSION not differ, the two subgroups were compiled for the final analysis. As depicted in Figures 5a and b, patients showing limited GvHD This retrospective multicenter study enrolled n = 146 consecutive had significantly better EFS (P = 0.0016) and OS (P = 0.0016) rates patients who underwent allogeneic HCT after intensive pre- as compared with the combined group of patients with absent or treatment (cf. Table 1). The aim of the study was to identify extended chronic GvHD. subgroups of FL patients who benefited from HCT. In contrast, previous autologous HCT (Supplementary figures 3 Review of pathology and retrospective data source verification and 4), performance of allogeneic HCT less than 1 year after for all data on chronic GvHD were part of the study. As only 25% autologous HCT (Supplementary figures 5 and 6) and type of of the patients were in CR at the time of HCT, the median conditioning played no role for outcome. follow-up time of 9.1 years for surviving patients appears to be adequate for the purpose of our evaluation. Results of multivariate statistical analysis. As detailed in Table 2, The main finding of this study is that HCT offers a substantial chemo-sensitive disease at the time of transplantation, use of chance of cure for patients with non-transformed FL (cf. Figure 3), TBI-containing conditioning protocols for patients with RD, and irrespective of whether presenting with treatment-sensitive or RD. the presence of limited chronic GvHD are independent prognostic The curative potential of HCT for sensitive and refractory FL is

Bone Marrow Transplantation (2016) 654 – 662 © 2016 Macmillan Publishers Limited Allogeneic transplant may cure follicular lymphoma F Heinzelmann et al 659 a a 100 100 P = 0.0016 90 P = 0.44 90 Limited

80 80

70 70

60 60 50 < 55 years 50 OS [%] OS [%] 40 40

30 30 ≥ 55 years 20 20 Other (absent or extended)

10 10

0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time post transplantation [years] Time post transplantation [years]

Time post transplantation Day 0 1 year 2 years 5 years 10 years Time post transplantation Day 100 1 year 2 years 5 years 10 years Number of patients at risk < 55 years 108 74 66 58 29 Number of patients at risk Limited 37 33 31 28 10 Number of patients at risk ≥ 55 years 38 24 21 19 3 Number of patients at risk Other 86 59 54 47 19

b 100 b 100 P = 0.0088 P = 0.0016 90 90 80 Limited 80 70 ≤ 42 years 70 60 60 50 50 OS [%]

40 EFS [%] 40 30 30 20 20 > 42 years Other (absent or extended) 10 10 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time post transplantation [years] Time post transplantation [years]

Time post transplantation Day 0 1 year 2 years 5 years 10 years Time post transplantation Day 100 1 year 2 years 5 years 10 years Number of patients at risk Donor age ≤ 42 years 77 57 52 47 17 Number of patients at risk Limited 37 32 30 26 10 Number of patients at risk Donor age > 42 years 46 26 22 18 9 Number of patients at risk Other 82 52 47 39 14 Figure 4. (a, b) Impact of patient age (a) and donor age (b)on a b a overall survival (OS) after HCT for non-transformed follicular Figure 5. ( , ). Overall survival (OS, ) and event-free survival b lymphoma (Kaplan–Meier plots and corresponding 95% confidence (EFS, ) after HCT for study patients surviving to day 100 post HCT intervals, for details see text). The cutoff point (o55 years) for according to the occurrence (yes/no) of limited chronic GvHD. patient age was selected according to the definition of patients OS and EFS data for patients without and with extended chronic regarded to be ‘elderly’ in numerous clinical studies. In contrast, the GvHD were compiled as they did not differ according to log-rank – fi cutoff point for donor age ⩽ 42 years was identified to be the best test (Kaplan Meier plots and corresponding 95% con dence discriminator for the clinical outcome of HCT. intervals, for details see text).

study patients (n = 80) who received chemotherapy-only based suggested by the stable OS and EFS plateaus reached after conditioning, the subcohort of 61 patients with sensitive disease transplantation (cf. Figures 1a and b). had better OS (P = 0.087) and EFS (P = 0.058) rates than the The results reported for the chemorefractory group are better 19 patients with RD. than those outlined in most other publications.29,38,39 A possible To evaluate the impact of TBI-containing conditioning on HCT explanation might be the higher percentage of patients treated by outcome the above-mentioned two subcohorts were used as TBI-based conditioning. reference. In patients with sensitive disease, OS and EFS rates did Multivariate statistical analysis (cf. Table 2) revealed three not differ, irrespective of whether a chemotherapy-only based parameters as independent risk factors for a beneficial OS and EFS: (n = 61) or a TBI-containing (n = 49) regimen were used. In contrast, treatment-sensitive disease at the time of HCT, as suggested by for patients with RD, use of TBI-containing conditioning (n = 14) – numerous previous studies,21,29 31,38,40,41,39 use of a TBI-containing resulted in improved OS and EFS rates as compared with regimens conditioning regimen in patients with RD and the occurrence of based on chemotherapy alone (n = 19). Despite the small number limited chronic GvHD. of patients, the levels of significance for superiority of the TBI Univariate statistical analysis of the entire study population group were almost reached for OS (P = 0.061) and EFS (P = 0.070), could not reveal a significant difference in HCT outcome for and corresponding 95% confidence interval did not overlap at all patients with sensitive and RD despite the sparse overlap of (cf. Figures 2a and b). Thus, univariate statistics support the results the corresponding 95% confidence intervals for OS and EFS of our multivariate analysis that—beside the disease status in (cf. Figures 1a and b). However, this analysis was confounded by general—the use of TBI-containing conditioning in treatment the type of conditioning regimen used. If analysis was confined to refractory patients has an impact on HCT outcome.

Table 2. Results of multivariate statistical analysis for OS and EFS after HCT

Risk factor End point HR CI (68%) P-value

(A)a

Treatment-sensitive disease (yes/no) at the time of HCT OS 0.522 0.392–0.695 0.023c EFS 0.493 0.376–0.645 0.0086c TBI-based conditioning (yes/no) in case of refractory disease at the time of HCT OS 0.406 0.251–0.656 0.060 EFS 0.355 0.222–0.567 0.027c (B)b

Treatment-sensitive disease (yes/no) at the time of HCT OS 0.376 0.262–0.538 0.0064c EFS 0.348 0.249–0.486 0.0016c TBI-based conditioning (yes/no) in case of refractory disease at the time of HCT OS 0.185 0.095–0.359 0.011c EFS 0.157 0.081–0.301 0.0045c Limited chronic GvHD (yes/no) OS 0.279 0.190–0.408 0.00082c EFS 0.286 0.202–0.404 0.00030c Abbreviations: CI = confidence interval; EFS = event-free survival; HCT = hematopoietic cell transplantation; HR = hazard ratio; OS = overall survival. aFinal model: independent risk factors for OS and EFS after testing the influence of all baseline variables depicted in Table 1. bFinal model: independent risk factors for OS and EFS after testing the influence of all baseline variables plus the outcome variable occurrence of limited chronic GvHD (yes/no) for patients surviving day +100 after HCT. clevel of significance (Po0.05) reached (for details see text).

As the results for TBI represent a subset analysis of a very GvHD correlated with an increment of NRM, affecting OS and limited number of patients, the authors cannot formally EFS rates. recommend the use of TBI-based conditioning in patients with Once established, the GvL effect might contribute to cure. The RD. However, the possible benefits of TBI for patients with vast majority of the documented relapses (88%) occurred within chemorefractory disease at the time of HCT are at hand: (1) FL is a the first 3 years after HCT in accordance with previously published 23,40 radiosensitive entity,42,43 (2) TBI employs different death signal studies, whereas only 2 of the 77 patients with a follow-up pathways than chemotherapy; and (3) TBI can reach inadequately 45 years had a late relapse. perfused tissues as well as the subarachnoid space without The final items to be discussed are the impact of patient and 44–46 21,47 donor age on HCT outcome. As observed in numerous previous limitations. Interestingly, two large retrospective analyses 23,51–56 provided evidence for superiority of TBI-based conditioning studies, OS was found to be slightly lower in patients ⩾ fi compared with chemotherapy-only based conditioning in FL 55 years without reaching any statistical signi cance in uni- and patients in multivariate analyses. Moreover, a recently published multivariate analysis. However, of greater clinical interest is that (1) the documented difference was so small that neither univariate trial from the EBMT Working Party also support superiority of fi TBI-based conditioning for FL patients in the autologous setting.48 nor multivariate analysis could reveal a signi cant impact of The third identified independent risk factor for HCT outcome is patient age on OS; and (2) stable plateaus for OS were reached for the occurrence of limited chronic GvHD. both subgroups, suggesting potential cure rates of 50% for With the exception of the small subgroup of patients (n = 14) younger and 42% for elderly patients (cf. Figure 4a). These with RD who received TBI-containing conditioning, the contribu- promising results for elderly patients can be easily explained. The vast majority of elderly patients were not treated with MAC known tion of the conditioning regimen to cure FL appears to be modest to be associated with an increased NRM risk. Furthermore, the for two reasons: (1) all study patients were intensively pretreated, beneficial action of the GvL effect is not limited by recipient age as including 90/146 patients who received an autologous HCT before it is mediated by the donor immune system. allogeneic HCT; and (2) neither uni- nor multivariate statistical The results of univariate analysis on donor age were clear-cut analysis could demonstrate a superior EFS for the subgroup of the (cf. Figure 4b): usage of a donor aged ⩽ 42 years is associated with 39 study patients treated with MAC. significantly better OS after HCT (P = 0.0088). Numerous clinical Our data suggest that the potential of HCT to cure FL relies studies focusing on other entities support the use of young much more on the so-called GvL effect than on conditioning. donors.57–60 It is well established that transplanted donor immune cells can This finding remains valid even if multivariate analysis could not react against healthy as well as residual malignant cells of the fi 49,50 con rm donor age as an independent risk factor for HCT outcome. recipient. Both reactions are guided by a common immuno- Donor age could not figure as a further independent risk factor, as logical mechanism, named allo-reactivity. Thus, the occurrence of young donor age was found to be linked with the established risk GvHD is correlated with the GvL effect, as evidenced by numerous factor of limited chronic GvHD (U-test: P = 0.06). clinical studies. On the other hand—in contrast to limited chronic Interestingly, in contrast to published studies in FL patients,61–63 GvHD—extended chronic GvHD often is a life-threatening disease. preceding autologous HCT included as a variable in uni- and These two facts explain why patients with limited chronic GvHD multivariate statistical analysis could not be identified as a risk show better OS and EFS rates than patients without chronic GvHD factor for inferior outcome after allogeneic HCT. or patients with extended chronic GvHD (cf. Table 2, Figures 5a In summary, this study demonstrates that a substantial number and b). The presence of chronic GvHD, irrespective of stage, was of patients with non-transformed FL have a realistic chance of found to be correlated with a lower risk of relapse/a higher chance cure,64 even if presenting with RD state and/or advanced age to achieve CR, whereas extended in contrast to limited chronic (⩾ 55 years), and suggests that (1) patients with RD and/or

Bone Marrow Transplantation (2016) 654 – 662 © 2016 Macmillan Publishers Limited Allogeneic transplant may cure follicular lymphoma F Heinzelmann et al 661 advanced age are candidates for HCT; (2) donors aged ⩽42 years Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol are preferred; and (3) TBI-containing conditioning regimen might 2013; 31:2920–2926. be a good option in patients with RD. Whether novel drugs such 11 Radford J, Davies A, Cartron G, Morschhauser F, Salles G, Marcus R et al. 14 16 Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular as PI3 kinase inhibitors and bcl-2 inhibitors or chimeric Ag 122 – 17— lymphoma: results of the GAUDI study (BO21000). Blood 2013; :1137 1143. receptor-enhanced T cells (CAR T cells) either alone or in 12 Fowler N, Kahl BS, Lee P, Matous JV, Cashen AF, Jacobs SA et al. combination—will finally erase or reduce the present role of Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory allogeneic HCT in FL remains speculative today and has to be follicular lymphoma: the phase II VERTICAL study. J Clin Oncol 2011; 29: evaluated by future clinical studies. 3389–3395. 13 Fowler NH, Davis RE, Rawal S, Nastoupil L, Hagemeister FB, McLaughlin P et al. Safety and activity of lenalidomide and rituximab in untreated indolent CONFLICT OF INTEREST lymphoma: an open-label, phase 2 trial. Lancet Oncol 2014; 15: 1311–1318. 14 Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ et al. The authors declare no conflict of interest. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014; 370: 1008–1018. ACKNOWLEDGEMENTS 15 Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity We would like to thank Franziska Strehle, Helga Neidlinger and Karin Fuchs, who are in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 2013; 31: the data managers of the DRST and to all local data managers of the participating 88–94. transplant units. Last but not least, thanks to all local as well as reference pathologists 16 Davids MS, Roberts AW, Anderson MA, Pagel JM, Kahl BS, Gerecitano JF et al. The for their valuable support of this study. The DRST is supported by grants from the BCL-2-specific BH3-Mimetic ABT-199 (GDC-0199) is active and well-tolerated in Deutsche Krebshilfe eV, Deutsche Jose-Carreras Leukämie Stiftung eV, DKMS and patients with relapsed non-Hodgkin lymphoma: interim results of a phase I study. Alfred and Angelika Gutermuth-Stiftung. This study is based on data provided by the Blood (Annu Meet Abstr) 2012; 120: abstract 304. German Registry for Stem Cell Transplantation. 17 Ramos CA, Heslop HE, Brenner MK. CAR-T Cell Therapy for Lymphoma. Ann Rev Med. 2016; 67:165–183. 18 Jones RJ, Ambinder RF, Piantadosi S, Santos GW. Evidence of a graft-versus- AUTHOR CONTRIBUTIONS lymphoma effect associated with allogeneic bone marrow transplantation. Blood 77 – FH and HO were involved in all aspects of planning, execution, data evaluation 1991; :649 653. 19 Sorror M, Storer B, Sandmaier BM, Maloney DG, Chauncey TR, Langston A et al. of the study and writing of the manuscript. IH performed the statistical analyses Hematopoietic cell transplantation-comorbidity index and Karnofsky performance of our data. Dr C. Müller facilitated the contact with the local data managers of status are independent predictors of morbidity and mortality after allogeneic DRST in case of queries and supervised the quality of their answers. 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