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Outcomes of two-step haploidentical allogeneic stem cell transplantation in elderly patients with hematologic malignancies

ABSTRACT: Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the best curative option for the majority of patients with hematologic malignancies (HM); however, many elderly patients are excluded from transplant and outcome data in this population is still limited. The novel two-step graft engineering approach has been the main platform for allo-SCT at Thomas Jefferson University since 2006. Following administration of the preparative regimen, we infuse donor lymphocytes, followed by cyclophosphamide to induce bidirectional tolerance, then infusion of CD34-selected cells. A total of 76 patients ≥ 65 years old with HM underwent haploidentical (haplo) allo-SCT on the two-step transplant platform between 2007 and 2021. The median time to neutrophil engraftment was 11 days and platelet engraftment was 18 days. With a median follow up of 44 months, the 3-year overall survival (OS) and progression-free survival (PFS) were 36.3% and 35.6%, respectively. The cumulative incidences of non-relapse mortality (NRM) and relapse at 3 years were 43.5% and 21.0% at 3 years, respectively. The cumulative incidence of grade III-IV acute graft-versus-host-disease (GVHD) was 11.1% at 6 months, and chronic GVHD requiring treatment was 15.1% at 2 years. The two-step haplo allo-SCT is a novel alternative platform for high-risk older HM patients, achieving fast engraftment, low relapse rates and promising survival.

SUBMITTER: Bi X

PROVIDER: S-EPMC9388981 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Project description:In the context of allogeneic transplant platforms, human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents one of the latest and most promising curative strategies for patients affected by high-risk hematologic malignancies. Indeed, this platform ensures a suitable stem cell source immediately available for virtually any patents in need. Moreover, the establishment in recipients of a state of immunologic tolerance toward grafted hematopoietic stem cells (HSCs) remarkably improves the clinical outcome of this transplant procedure in terms of overall and disease free survival. However, the HLA-mismatch between donors and recipients has not been yet fully exploited in order to optimize the Graft vs. Leukemia effect. Furthermore, the efficacy of haplo-HSCT is currently hampered by several life-threatening side effects including the onset of Graft vs. Host Disease (GvHD) and the occurrence of opportunistic viral infections. In this context, the quality and the kinetic of the immune cell reconstitution (IR) certainly play a major role and several experimental efforts have been greatly endorsed to better understand and accelerate the post-transplant recovery of a fully competent immune system in haplo-HSCT. In particular, the IR of innate immune system is receiving a growing interest, as it recovers much earlier than T and B cells and it is able to rapidly exert protective effects against both tumor relapses, GvHD and the onset of life-threatening opportunistic infections. Herein, we review our current knowledge in regard to the kinetic and clinical impact of Natural Killer (NK), γδ and Innate lymphoid cells (ILCs) IRs in both allogeneic and haplo-HSCT. The present paper also provides an overview of those new therapeutic strategies currently being implemented to boost the alloreactivity of the above-mentioned innate immune effectors in order to ameliorate the prognosis of patients affected by hematologic malignancies and undergone transplant procedures.

Project description:A minimally toxic nonmyeloablative regimen was developed for allogeneic hematopoietic cell transplantation (HCT) to treat patients with advanced hematologic malignancies who are older or have comorbid conditions.To describe outcomes of patients 60 years or older after receiving minimally toxic nonmyeloablative allogeneic HCT.From 1998 to 2008, 372 patients aged 60 to 75 years were enrolled in prospective clinical HCT trials at 18 collaborating institutions using conditioning with low-dose total body irradiation alone or combined with fludarabine, 90 mg/m(2), before related (n = 184) or unrelated (n = 188) donor transplants. Postgrafting immunosuppression included mycophenolate mofetil and a calcineurin inhibitor.Overall and progression-free survival were estimated by Kaplan-Meier method. Cumulative incidence estimates were calculated for acute and chronic graft-vs-host disease, toxicities, achievement of full donor chimerism, complete remission, relapse, and nonrelapse mortality. Hazard ratios (HRs) were estimated from Cox regression models.Overall, 5-year cumulative incidences of nonrelapse mortality and relapse were 27% (95% CI, 22%-32%) and 41% (95% CI, 36%-46%), respectively, leading to 5-year overall and progression-free survival of 35% (95% CI, 30%-40%) and 32% (95% CI, 27%-37%), respectively. These outcomes were not statistically significantly different when stratified by age groups. Furthermore, increasing age was not associated with increases in acute or chronic graft-vs-host disease or organ toxicities. In multivariate models, HCT-specific comorbidity index scores of 1 to 2 (HR, 1.58 [95% CI, 1.08-2.31]) and 3 or greater (HR, 1.97 [95% CI, 1.38-2.80]) were associated with worse survival compared with an HCT-specific comorbidity index score of 0 (P = .003 overall). Similarly, standard relapse risk (HR, 1.67 [95% CI, 1.10-2.54]) and high relapse risk (HR, 2.22 [95% CI, 1.43-3.43]) were associated with worse survival compared with low relapse risk (P < .001 overall).Among patients aged 60 to 75 years treated with nonmyeloablative allogeneic HCT, 5-year overall and progression-free survivals were 35% and 32%, respectively.

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Outcomes of two-step haploidentical allogeneic stem cell transplantation in elderly patients with hematologic malignancies

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