Chimerism in Myeloid Malignancies following Stem Cell Transplantation Using FluBu4 with and without Busulfan Pharmacokinetics versus BuCy

In the era of precision medicine, the impact of personalized dosing of busulfan is not clear. We undertook a retrospective analysis of 78 patients with myeloid malignancies who received fludarabine and busulfan (FluBu4) with or without measuring Bu pharmacokinetics (Bu PK) and those who received busulfan with cyclophosphamide (BuCy). Fifty-five patients received FluBu4, of whom 21 had Bu PK measured, and 23 patients received BuCy. Total donor cell chimerism showed that the percentage of patients maintaining 100% donor chimerism on day 100 was 66.7%, 38.2%, and 73.9% in the FluBu4 with PK, FluBu4 with no PK, and BuCy, respectively (P = .001). Patients who had decreasing donor chimerism by day 100 were 23.8%, 52.9%, and 26.1% in the FluBu4 with PK, FluBu4 with no PK, and BuCy, respectively (P = .04). Bu PK group had fewer patients with less than 95% donor chimerism on day 30, which was not statistically significant, 5% (FluBu4 PK), 31% (FluBu4 with no PK), and 21% (BuCy) (P = .18). Survival distributions were not statistically significant (P = .11). Thus, personalized drug dosing can impact donor chimerism in myeloid malignancies. This will need to be examined in larger retrospective multicenter studies and prospective clinical trials

Update on a pilot study: Flumeltbi peripheral blood HLAhaploidentical stem cell transplantation with post-transplant cyclophosphamide and bortezomib (Cy2Bor3)

Background: Bortezomib (Bor) can inhibit the proliferation of dendritic cells (DCs) and block the expression of co-receptors CD80, CD86 and secretion of cytokines IL-12 and TNF-α and hence the ability of DCs to activate T cells. We started a pilot study incorporating the addition of bortezomib to post-transplant cyclophosphamide (PTCY) in the setting of peripheral blood (PB) HLA-haploidentical stem cell transplantation (Haplo-SCT). Methods: This is a single center open label pilot study. Eligible patients received Fludarabine Melphalan TBI 200 cGy as conditioning followed by haplo-SCT and PTCY. Bor was administered at 1.3mg/m2 on day+1, 4 and 7. Tacrolimus and MMF were started at day+5. Results: Seven patients were enrolled so far, five males and 2 females. Median age was 58 years (26-60). Donors were 3 brothers, 3 sons and 1 mother. Disease risk index was high in 3, intermediate in 3 and low in 1. Three patients had AML, two had ALL and MM, one had ALL and one had CML. CMV recipient status was negative in one and positive in 6. Median HCT-CI was 3(1-4). Median CD34 and CD3 infused were 4.13 x10-6 and 1.7x10-8/ kg recipient respectively, all were cryopreserved except 2. Four patients had CRS before Cy infusion with ASTCT grade of 1. Six patients had grade 3 hypokalemia around day+ 4-5. Five patients had grade 3 mucositis and 2 had grade 1. Four patients had neutropenic fever and one patient had engraftment fever. Median neutrophils and platelets engraftment were 16 and 26 days respectively. Chimerism post SCT was \u3e =99% donor at day 30 for all patients. Six patients are off tacrolimus with median time to be off it was 187.5 days. Five pts had aGVHD with maximum grade of I in 3 patients, II in one patient and III in one patient at a median 50days post SCT. None developed early hematuria, four had late hematuria with highest grade of 4. Two patients were positive for BK virus. One patient had reactivation of CMV, 2 had EBV and one had adenovirus, all resolved. Three pts had HHV6 that resolved. Of the 5 patients who were evaluable, one developed moderate chronic GVHD. So far the median time to follow up is 455 days (70-1239) with relapse and subsequently death in one patient who had high risk AML with 3 different inductions prior to SCT. . At 1 year for 4 evaluable patients IgG were \u3e400 mg/dl and CD4 \u3e 350 cells/ul. Conclusions: Cy2Bor3 post PB Haplo-SCT was well tolerated. Although small number of patients and limited but encouraging results so far. The trial is ongoing

Graft-versus-host disease in recipients of male unrelated donor compared with parous female sibling donor transplants

Optimal donor selection is critical for successful allogeneic hematopoietic cell transplantation (HCT). Donor sex and parity are well-established risk factors for graft-versus-host disease (GVHD), with male donors typically associated with lower rates of GVHD. Well-matched unrelated donors (URDs) have also been associated with increased risks of GVHD as compared with matched sibling donors. These observations raise the question of whether male URDs would lead to more (or less) favorable transplant outcomes as compared with parous female sibling donors. We used the Center for International Blood and Marrow Transplant Research registry to complete a retrospective cohort study in adults with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, who underwent T-cell replete HCT from these 2 donor types (parous female sibling or male URD) between 2000 and 2012. Primary outcomes included grade 2 to 4 acute GVHD (aGVHD), chronic GVHD (cGVHD), and overall survival. Secondary outcomes included disease-free survival, transplant-related mortality, and relapse. In 2813 recipients, patients receiving male URD transplants (n = 1921) had 1.6 times higher risk of grade 2 to 4 aGVHD (P \u3c .0001). For cGVHD, recipient sex was a significant factor, so donor/recipient pairs were evaluated. Female recipients of male URD grafts had a higher risk of cGVHD than those receiving parous female sibling grafts (relative risk [RR] = 1.43, P \u3c .0001), whereas male recipients had similar rates of cGVHD regardless of donor type (RR = 1.09, P = .23). Donor type did not significantly affect any other end point. We conclude that when available, parous female siblings are preferred over male URDs

Association between the choice of the conditioning regimen and outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (Fludarabine/busulfan=166, Fludarabine/melphalan=327) and 379 using MAC (Fludarabine/busulfan=247, Busulfan/cyclophosphamide=132). In multivariable analysis with RIC, Fludarabine/melphalan was associated with inferior overall survival (HR 1.80, 95% CI 1.15-2.81, p=0.009), higher early non-relapse mortality (HR 1.81, 95% CI 1.12-2.91, p=0.01) and higher acute graft versus host disease (GVHD) (grade II-IV- HR 1.45, 95% CI 1.03-2.03, p=0.03; grade III-IV HR 2.21, 95%CI 1.28-3.83, p=0.004) compared to Fludarabine/busulfan. In the MAC setting, Busulfan/cyclophosphamide was associated with a higher acute GVHD (grade II-IV HR 2.33, 95% CI 1.67-3.25, p\u3c0.001; grade III-IV HR 2.31, 95% CI 1.52-3.52, p\u3c0.001) and inferior GVHD-free relapse-free survival (GRFS) (HR 1.94, 95% CI 1.49-2.53, p\u3c0.001) as compared to Fludarabine/busulfan. Hence, our study suggests that Fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GVHD) and MAC (lower acute GVHD and better GRFS) in myelofibrosis

Choice of Unmanipulated T Cell Replete Graft for Haploidentical Stem Cell Transplant and Posttransplant Cyclophosphamide in Hematologic Malignancies in Adults: Peripheral Blood or Bone Marrow—Review of Published Literature

Allogeneic hematopoietic stem cell transplantation (SCT) is often the only curative option for many patients with malignant and benign hematological stem cell disorders. However, some issues are still of concern regarding finding a donor like shrinking family sizes in many societies, underrepresentation of the ethnic minorities in the registries, genetic variability for some races, and significant delays in obtaining stem cells after starting the search. So there is a considerable need to develop alternate donor stem cell sources. The rapid and near universal availability of the haploidentical donor is an advantage of the haploidentical SCT and an opportunity that is being explored currently in many centers especially using T cell replete graft and posttransplant cyclophosphamide. This is probably because it does not require expertise in graft manipulation and because of the lower costs. However, there are still lots of unanswered questions, like the effect of use of bone marrow versus peripheral blood as the source of stem cells on graft-versus-host disease, graft versus tumor, overall survival, immune reconstitution, and quality of life. Here we review the available publications on bone marrow and peripheral blood experience in the haploidentical SCT setting

Choice of Unmanipulated T Cell Replete Graft for Haploidentical Stem Cell Transplant and Posttransplant Cyclophosphamide in Hematologic Malignancies in Adults: Peripheral Blood or Bone Marrow-Review of Published Literature

Allogeneic hematopoietic stem cell transplantation (SCT) is often the only curative option for many patients with malignant and benign hematological stem cell disorders. However, some issues are still of concern regarding finding a donor like shrinking family sizes in many societies, underrepresentation of the ethnic minorities in the registries, genetic variability for some races, and significant delays in obtaining stem cells after starting the search. So there is a considerable need to develop alternate donor stem cell sources. The rapid and near universal availability of the haploidentical donor is an advantage of the haploidentical SCT and an opportunity that is being explored currently in many centers especially using T cell replete graft and posttransplant cyclophosphamide. This is probably because it does not require expertise in graft manipulation and because of the lower costs. However, there are still lots of unanswered questions, like the effect of use of bone marrow versus peripheral blood as the source of stem cells on graft-versus-host disease, graft versus tumor, overall survival, immune reconstitution, and quality of life. Here we review the available publications on bone marrow and peripheral blood experience in the haploidentical SCT setting

Choice of Unmanipulated T Cell Replete Graft for Haploidentical Stem Cell Transplant and Posttransplant Cyclophosphamide in Hematologic Malignancies in Adults: Peripheral Blood or Bone Marrow-Review of Published Literature

Allogeneic hematopoietic stem cell transplantation (SCT) is often the only curative option for many patients with malignant and benign hematological stem cell disorders. However, some issues are still of concern regarding finding a donor like shrinking family sizes in many societies, underrepresentation of the ethnic minorities in the registries, genetic variability for some races, and significant delays in obtaining stem cells after starting the search. So there is a considerable need to develop alternate donor stem cell sources. The rapid and near universal availability of the haploidentical donor is an advantage of the haploidentical SCT and an opportunity that is being explored currently in many centers especially using T cell replete graft and posttransplant cyclophosphamide. This is probably because it does not require expertise in graft manipulation and because of the lower costs. However, there are still lots of unanswered questions, like the effect of use of bone marrow versus peripheral blood as the source of stem cells on graft-versus-host disease, graft versus tumor, overall survival, immune reconstitution, and quality of life. Here we review the available publications on bone marrow and peripheral blood experience in the haploidentical SCT setting