Long Term Outcomes of Hematopoietic Stem Cell Transplantation in Patients with Waldenström's Macroglobulinemia. Report from the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (LWP EBMT)
Authors: Kyriakou Charalampia , Fekom Mathilde , Khvedelidze Irma , Moukalled Nour , Serroukh Yasmina I.M. , Castagna Luca , Montoto Silvia , Ossami Saidy Anna , Nguyen Quoc Stéphanie , Wu Ka Lung , Reményi Péter , Nur Erfan , Benakli Malek , Chevallier Patrice , Vucinic Vladan , Broers Annoek E. C. , Einsele Hermann , Tournilhac Olivier , Glass Bertram , Bazarbachi Ali 
Published: December 2024

Waldenström's Macroglobulinemia (WM) is a rare low-grade B- cell non -Hodgkin lymphoma. Novel therapies have achieved prolonged progression-free (PFS) and overall (OS) survivals. The future role of haemopoietic stem cell transplantation (HSCT), autologous (AHSCT) and allogeneic (allo-HSCT) in the era of the new therapeutic advances needs a critical discussion.
The aim of this retrospective analysis was to assess the trends in HSCT for patients with WM and the longer-term survival outcomes.
In the EBMT registry, 772 patients underwent AHSCT between 2000 and 2021 (218 patients were transplanted between 2000-2010, 290 between 2010-2015 and 264 between 2015-2021). The median age was 57 years (IQR: 50-62), 72% were male and the median time from diagnosis to AHSCT was 24 months (IQR: 11-58). The number of prior therapy lines was, 1 in 24%, 2 in 39% and ≥3 in 37% of the patients. Disease status at AHSCT was ≥VGPR in 36%, PR in 52%, primary or relapse refractory disease (PRRD) in 12%. Karnofsky performance status (KPS) was &lt;90 in 24%. Conditioning regimen included BEAM in 54%, Melphalan in 17%, EAM in 7%, FEAM in 4%, BuCy in 4%, BeEAM in 3%, ThioBCNU in 3%, TBI based in 4% and other in 4%. Peripheral hematopoietic stem cells (HSC) source was used in 99% of the cases. The median follow-up was 4.6 years (95%CI: 3.9-5.3). At 2, 5 and 10 years the estimated OS rates were 89.4%, 70.4% and 55.3% and PFS 68.2%, 46.9% and 31.2%. The relapse rates (RR) were 28.8%, 48.6% and 61.8% and the Non-Relapse Mortality (NRM) 3%, 4.5%, 7.1% at 2, 5 and 10 years respectively. From the multivariate analysis, the time from diagnosis to AHSCT was the only significant factor impacting PFS (HR: 1.39, 95% CI:1.03 - 1.87, p= 0.031) and RR (HR: 1.39, 95% CI:1.02-1.90, p= 0.039). Of the 772 patients, 555 (71.89%) were alive. The cause of death was, progressive disease in 143/772 (18.5%) patients, infection in 21 (2.7%), transplant related in 1.16% and secondary malignancy in 1.81%.
In the EBMT registry, 330 patients transplanted with Allo-HSCT between 2000-2021 were identified (117 patients transplanted between 2000-2010, 125 between 2010-2015 and 88 between 2015-2021). The median age was 55years (IQR: 45 -60), 73% were male and the median time from diagnosis to allo-HSCT was 44 months (IQR: 19-95). 11% received 1, 20% had 2 and 68% ≥3 therapy lines prior to allo-HSCT, whilst 21% failed previous AHSCT. Disease status at the allo-HSCT was ≥VGPR in 30%, PR in 45% and PRRD in 26%. KPS was &lt;90 in 25%. Conditioning regimen was TBI based in 61%. Reduced Intensity conditioning (RIC) was administered in 63% and myeloablative conditioning (MAC) in 37%. Stem cell source was peripheral blood in 89% and the donor was matched related in 43%, matched unrelated in 46%, and haploidentical in 9%. With a median follow-up of 8.3years (95% CI: 6.7-9.1) the 2, 5, 10 years estimated OS rates were 62.9%, 54.0%, 47.3% and the PFS 58.7%, 44.6%, 34.7%. The RR were 21.0%, 31.1%, 37.3% and the NRM 20.2%, 24.3% and 27.98% at 2, 5 and 10 years respectively. The incidence of acute graft versus host disease (aGVHD) grade II-IV was 26.7% (grade III-IV, 12,6%) and the cumulative incidence of chronic GVHD (cGVHD) at 1, 2 and 5 years was 33.4%, 42.4%, 45.5%, and that of extensive cGVHD 11.4%, 18.2% and 22.8% respectively. Good KPS &gt;90 (HR:0.59, 95% CI: 0.39-0.87, p= 0.009), was associated with significantly better OS, whilst having PRRD status at allo-HSCT with worse OS (HR: 1.85, 95% CI: 1.12-3.08, p=0.017), PFS ( HR: 1.95, 95%CI: 1.20-3.16, p=0.007) and RR rates (HR: 2.04, 95% CI: 1.11-3.76, p= 0.023). HLA mismatched HSC donor type was associated with significantly higher incidence of cGVHD (HR: 0.26, 95% CI: 0.08-0.87, p=0.029).
In the era of BTK and BCL2 inhibitors, chemo-immunotherapies and forthcoming T cell engagers with bispecific antibodies and CART cell therapies in lymphomas, it is challenging to define the role or timing for-HSCT in WM treatment pathway. This EBMT real world retrospective study showed that, a small group of HSCT eligible patients, transplanted based on local center treatment criteria, have achieved prolong OS and PFS survival with acceptable toxicities.