Low Risk of Chronic Graft-versus-Host Disease and Relapse Associated with T Cell–Depleted Peripheral Blood Stem Cell Transplantation for Acute Myelogenous Leukemia in First Remission: Results of the Blood and Marrow Transplant Clinical Trials Network Protocol 0303

Abstract

Graft versus host disease (GVHD) is most effectively prevented by ex vivo T cell depletion (TCD) of the allograft but its role in the treatment of patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) in complete remission (CR) remains unclear. We therefore performed a Phase 2 single arm multi-center study to evaluate the role of TCD in AML patients in CR1 or CR2 up to the age of 65 years. The primary objective was to achieve a disease-free survival (DFS) rate at 6 months post transplant that exceeded 75%. 44 patients with AML in CR1 (N=37) or CR2 (N=7) with a median age of 48.5 years (range 21–59) received myeloablative chemotherapy and fractionated total body irradiation (TBI, 1,375cGy) followed by immunomagnetically selected CD34-enriched, T-cell depleted allografts from HLA-identical siblings. No pharmacological GVHD prophylaxis was given. All patients engrafted. The incidence of acute GVHD grades 2–4 was 22.7%. The incidence of extensive chronic GVHD was 6.8% at 24 months. The relapse rate for patients in CR1 at 36 months was 17.4%. With a median follow up of 34 months, disease free survival (DFS) for all patients at 6 months was 82%. DFS for pts in CR1 was 72.8% and 58% at 12 and 36 months, respectively. HCT following myeloablative chemoradiotherapy can be performed in a multi-center setting using a uniform method of TCD resulting in a low risk of extensive chronic GVHD and relapse for pts with AML in CR1.

ATG in allogeneic stem cell transplantation: standard of care in 2017? Counterpoint

“…For instance, dose intensity appears to be more important for early-stage, good-risk AML in which GVL seems less necessary. 22 This was also recently demonstrated in a randomized study of reduced vs myeloablative conditioning for patients with acute myeloid leukemia or myelodysplastic syndrome, in which the relapse rate was unacceptably high in the reduced intensity arm, closing the trial down earlier than expected. 23 It may be even more complicated than just reduced vs myeloablative conditioning.…”

“…Another T-cell depletion approach that has effectively reduced GVHD rates is CD34 selection, which removes T cells from the graft before stem cell infusion into the patient. 22,30 This strategy again offers a reduction in acute and chronic GVHD, but does not improve survival because of the increased infectionrelated deaths. Although ATG has been compared with standard GVHD prophylaxis strategies that include a calcineurin inhibitor and methotrexate, it is unclear if ATG is a better prophylactic strategy in comparison with these other T-cell depletion strategies.…”

Prolonged sirolimus administration after allogeneic hematopoietic cell transplantation is associated with decreased risk for moderate-severe chronic graft-versus-host disease

“…Finally, we acknowledge that other approaches may decrease risk for chronic GvHD and promote immune tolerance. Ex vivo T-cell depletion and post-transplantation cyclophosphamide hold promise, 11,13 as do in vivo T-cell depletion strategies such as ATG. 12,46 Furthermore, the use of marrow versus peripheral blood is associated with less chronic GvHD.…”

“…5 This represents a major obstacle to the success of HCT, as chronic GvHD remains a major source of late HCT-associated morbidity and death, [7][8][9] and is associated with prolonged immune suppressive therapy. 10 In contrast, ex vivo and in vivo T-cell depletion strategies (including ATG and post-transplant cyclophosphamide) are associated with lower risk of chronic GvHD, [11][12][13] and merit ongoing study. The optimal type and duration of immune suppressive therapy to mitigate risk for serious chronic GvHD and effectively induce tolerance remains unknown.…”

Is there really a specific graft-versus-leukaemia effect?

“…Two small phase-2 non-randomized studies reported grafts of CD34-positive cells decrease the likelihood of being diagnosed with chronic and possibly acute GvHD without increasing leukaemia relapse compared with historic controls. 13,14 Because most or all immune cells were removed from the graft post transplant, anti-leukaemia activity was either mediated by other mechanisms (such as cytokines) or by immune cells developing from the graft (or both). A retrospective, non-pre-specified analysis of a phase-2 study of umbilical cord blood cell transplants reported a lower leukaemia relapse risk without more diagnosed acute or chronic GvHD.…”