Long-Term Outcome of Allogeneic Stem Cell Transplantation (allo-SCT) in Patients with Waldenstrom Macroglobulinemia (WM)-a Retrospective Study of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT)
Authors: Kyriakou Charalampia , Boumendil Ariane , Finel Herve , Schmitz Norbert , Sengeloev Henrik , Mackinnon Stephen , Blaise Didier , Chevallier Patrice , Browne Paul , Craddock Charles , Niederwieser Dietger W. , Schetelig Johannes , Lenhoff Stig , Fegueux Nathalie , Montoto Silvia , Dreger Peter 
Published: October 2019

Abstract
WM is an indolent lymphoma that has benefited from the introduction of novel agents with the achievement of higher response rates. However, WM remains incurable with conventional treatment. In addition, patients with high risk disease have either transient short lived responses or are refractory to conventional treatments. Although international treatment recommendations suggest considering allo-SCT in late relapses or in refractory younger patients, the place and timing of allo-SCT in the treatment algorithm of WM remains unclear. The aim of the present study was to analyse the long-term outcome of allo-SCT in WM.
Patients and methods: Eligible for this retrospective study were patients aged 18 years or older who had a first reduced intensity (RIC) or myeloablative (MAC) conditioning allo-SCT (10/10 matched donor, sibling or unrelated) for WM between 2001 and 2013 and were registered with the EBMT. Baseline patient, disease and transplant data were collected from MED-A forms. Centers were requested to provide additional diagnostic, treatment and follow-up information. Statistical analysis used log rank test to assess the impact of baseline characteristics on survival endpoints. In multivariate analysis, prognostic factors for survival were estimated using Cox regression models and for relapse incidence (IR) and non-relapse mortality (NRM) by Fine and Gray models.
Results: 260 patients (72% male) fulfilling the inclusion criteria of this study were identified in the database. The median age was 52 (range 19-72) years. Disease status at allo-SCT was sensitive in 78% and refractory in 22% of the patients. Conditioning was reduced-intensity (RIC) in 66%, with PBSC (92%) being the predominant stem cell source (bone marrow 7%, cord blood 1%). Patients receiving RIC were significantly older and had a longer interval between diagnosis and transplant but were otherwise comparable to patients with myeloablative conditioning (MAC). Donors were related in 65% and unrelated in 35% of the transplants. The median number of treatment lines prior to alloSCT was 3. Pretreatment details were available for 118 patients. Of these, first-line treatment was alkylator-based in 80%, purine analogue (PA)-based in 17%, and contained rituximab in 23%; for 2nd-line treatment, these figures were 50%, 36%, and 34%; and for 3rd-line treatment 41%, 32%, and 44%. Less than 10% of the patients had received bortezomib or imide-based regimens in any pretreatment line.
At 100 days the cumulative incidence of acute graft versus host disease (aGVHD) grade I-II was 35%, and grade III-IV was 12%. At 2 years the cumulative incidence of chronic GVHD (cGVHD) was 41%. The development of cGVHD did not significantly impact on any outcome on a landmark analysis.
After a median follow-up for living patients of 57 months (IQR 31-97), 5-year NRM, IR, progression-free survival (PFS) and overall survival (OS) were 29%, 24%, 47% and 55%. Risk factor analyses considering age, sex, performance status (PS), disease status, pretreatment lines, rituximab exposure, year of transplant, donor, and conditioning identified PS for NRM, disease status for IR, and PS and MAC for OS as significant predictors of an adverse outcome after multivariable adjustment. Although RIC patients tended to have a lower NRM and a better PFS than MAC patients, this was not statistically significant, suggesting that RIC patients had a better survival after relapse. 45 patients were treated with donor lymphocyte infusions (DLI) and results of DLI were reported in 22 patients. Of these, a response was observed in 60%, which was complete in 55%.
Conclusions: This large study demonstrates that allo-SCT can effectively induce long-term disease control in heavily pre-treated patients with WM, suggesting that graft-versus-lymphoma effects are active and stable in WM. Accordingly, DLI seems to be a promising treatment option in case of post-transplant disease recurrence. Additional studies are needed to elaborate the place of allo-SCT in the treatment algorithm of WM in the era of novel agents.

Disclosures
No relevant conflicts of interest to declare.