Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation (HCT) for Refractory Waldenstrom’s Macroglobulinemia (WM): Evidence for a Graft-Versus-WM Effect.
Authors: Anderson Larry D. , Sandmaier Brenda M. , Maris Michael B. , Niederwieser Dietger , Agura Edward , Maziarz Richard T. , Chauncey Thomas R. , Storb Rainer , Maloney David G. 
Published: October 2019

Abstract
While toxicities and transplant related mortality (TRM) have limited the use of conventional allogeneic HCT to younger patients (pts) without significant medical comorbidities, WM is a disease that affects primarily older pts with a median age of 63 years at diagnosis. Here we examined the safety and efficacy of nonmyeloablative (NM) HCT for patients with refractory WM, where anti-tumor effects are provided by graft-versus-tumor immune responses rather than from conditioning therapy. Twelve pts with refractory WM were treated within the institutions of the Seattle Consortium using HLA-matched related donor (n=7) or unrelated donor (URD) (n=5) HCT. NM conditioning consisted of 2 Gy TBI with (n=8) or without (n=4) fludarabine (30 mg/m2/day x 3 days). Eleven pts received unmodified G-CSF-mobilized peripheral blood mononuclear cells, and 1 pt received URD bone marrow. Post-grafting immunosuppression consisted of mycophenolate mofetil and either cyclosporine or tacrolimus. The median age was 58 (range 44–65) years and median time from diagnosis to allogeneic HCT was 6.6 (range 1.5–20) years. Pts had received a median of 4.5 (2–8) prior regimens. The median follow-up after HCT was 14 (range 1–85) months overall, and median follow-up for surviving pts (n=7) was 17 (range 4–85) months. All pts except 1 have stably engrafted with &gt;95% donor CD3+ T cell chimerism. Acute GVHD grades II, III, IV, and extensive chronic GVHD occurred in 50%, 8%, 0%, and 58% of pts, respectively. TRM was 17%. Responses (4 CR and 6 PR) were seen in 10 of 11 (91%) evaluable pts while 1 had progressive disease. The non-evaluable pt died from early non-relapse causes. The median time to CR was 12 (6–32) months for the 4 CR pts, and 1 of the PR patients still has a declining IgM at 10 months. Only 1 of the 10 responders has had WM progression, though 1 pt in CR died from relapsed diffuse large B-cell lymphoma (DLBCL) 16 months after allografting despite no longer having a monoclonal IgM spike. This pt had been allografted in tandem following an auto transplant with BEAM conditioning for transformation of WM to DLBCL. Of the 7 sibling transplants, all had a response (3 CR and 4 PR). Of 5 pts receiving URD allografts, 1 had a CR, 2 had a PR, 1 was not evaluable due to TRM on day 29, and 1 pt failed to respond and died of progressive IgM myeloma 12 months after HCT. One pt with a PR had heavily pretreated disease (pancytopenic pre-HCT) and died of host-derived AML 10 months after HCT. The Kaplan-Meier estimates of 5 year overall and progression free survival were 59% and 61%, respectively. In summary, graft-versus-tumor effects that develop slowly following NM allogeneic HCT have been observed in the majority of pts with refractory WM. These graft-versus-WM effects occurred in the absence of serious GVHD and with low TRM. NM allogeneic HCT provides a new treatment option for WM pts and may result in long-term disease control.
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