Conditioning Allogeneic Hematopoietic Stem Cell Transplantation Research Articles

CD34+ Cell Dose Effects on Clinical Outcomes of Patients with Acute Myeloid Leukemia after T-Replete Haploidentical Allogeneic Hematopoietic Stemcell Transplantation Using Peripheral Blood Stem Cells. a Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

The absolute number of infused CD34+ donor cells represents a critical step towards the achievement of a meaningful marrow engraftment after allogeneic hematopoietic stem cell transplantation (HSCT). Previous observations have reported controversial conclusions regarding the impact of CD34+ donor cell doses and post-transplant clinical end-points. The vast majority of analysis conducted so far have considered myeloablative and reduced-intensity conditioning allogeneic HSCT setting, with HLA-matched sibling and/or unrelated donors. The T-cell replete haploidentical setting has not been extensively studied yet. We conducted a retrospective analysis on 414 adult patients (median age 54 years; range, 18-74) with acute myeloid leukemia (AML) in first (70%) and second (30%) complete remission who had received a T-cell replete allogeneic HSCT from a haploidentical donor, using peripheral blood stem cells (PBSC), between 2006-2018, based on ALWP-EBMT registry data. Median donor age was 37 years (range, 20-71). Time from disease diagnosis to HSCT was 6.3 months (range, 1.3-97.9). Seventy-three (18%) patients had secondary-AML. Eighty-seven patients (21%) had unfavorable cytogenetics. Karnofsky performance-status at the time of HSCT was ≥ 90 in 318 (77%) patients. Graft vs. host disease (GVHD) prophylaxis was post-transplant cyclophosphamide (PT-Cy)-based in 293 (71%) patients and anti-lymphocyte serum (ATG)-based in 121 (29%) patients. Conditioning was myeloablative in 179 (43%) patients and reduced-intensity in 235 (57%) patients. Median number of infused CD34+ cells was 6.58 x 106/kg (range, 2.2-31.2). Thirteen patients (3.2%) experienced graft failure while the remaining 399 (96.8%) engrafted uneventfully. Neutrophils engraftment at day 30 was 91.2% (95% Confidence interval [CI]: 88 - 93.6) while sustained platelets engraftment (>20.000/uL at 6-months) was observed in 83.7% (95% CI: 79.6 - 87). Median time to neutrophils and platelets engraftment were 20 (range, 10-79) and 21 days (range, 1-37) respectively. After a median follow-up of 23.3 months (range, 12.1-41.8) 2-year overall survival (OS) was 64.5 % (95% CI 59.3-69.7) with a leukemia-free survival (LFS) of 57.3 % (95% CI 51.8-62.7) and non-relapse mortality (NRM) of 23.3 % (95% CI: 19.0-27.7). The cumulative incidence of grade II-IV and III-IV acute GVHD at day-100 were 32.3 % (95% CI: 27.8 - 36.9) and 14.6 % (95% CI: 11.3 - 18.2), respectively. Incidence of 2-years chronic GVHD overall and extensive were 36.3 % (95% CI: 30.9 - 41.6) and 14.4 % (95% CI: 10.7 - 18.6), respectively. GVHD-free/relapse-free survival was 43.5 % (95% CI: 38 - 48.9) at 2-years. We found the optimal CD34+/kg threshold defining high-dose (n= 334) versus low-dose (n= 80)to be 4.96 x 106, using the Hothorn and Zeileis method (Hothorn, T. and Zeileis, A. Generalized maximally selected statistics. Biometrics 2008;64(4):1263-1269). Patients in the high-dose group experienced higher rates of engraftment compared to those in the low-dose group both for neutrophils (92.1% vs. 87.3%, p= 0.005) and platelets (86% vs. 73.3%, p= 0.001) while median time to neutrophils engraftment was 19 days (range, 10-79) in the high-dose group and 22 days (range, 14-46) in the low-dose group (p= 0.0001). Recipients of > 4.96 x 106/kg CD34+ cells experienced lower NRM (hazard ratio [HR] 0.48; 95% CI:0.29-0.75) and prolonged LFS (HR 0.62; 95% CI 0.43-0.90) and OS (HR 0.59; 95% CI:0.40-0.87) than recipients of ≤ 4.96 x 106/kg CD34+cell dose. Patients who received ATG as GVHD prophylaxis experienced less grades II-IV acute GVHD respect those in the PT-Cy cohort (HR 0.56; 95% CI: 0.36-0.87) without any differences in grades III-IV acute GVHD incidence at day 100 between the two groups. On Cox analysis, a female donor to male recipient combination was associated with higher extensive chronic GVHD incidence compared to other donor-recipient sex combinations, with CD34+ categorized according to the optimal threshold of 4.96 x 106 (HR 2.21; 95% CI:1.23-3.97; p= 0.008). AML patients who underwent a PBSC T-cell replete HSCT from haploidentical donors receiving ≥ 4.96 x 106CD34+/kg cells experienced a lower NRM and extended survival rates compared to those receiving ≤ 4.96 x 106/kg CD34+. The latter findings may have a significant practical impact and can guide prospective approaches. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise:Molmed: Consultancy, Honoraria; Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria. Chevallier:Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria. Socie:Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Should elderly patients with higher-risk myelodysplastic syndromes undergo allogeneic hematopoietic stem cell transplantation?

Evaluation of: Koreth J, Pidala J, Perez WS et al. Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis. J. Clin. Oncol. 31(21), 2662–2670 (2013).Myelodysplastic syndromes (MDS) include a group of hematopoietic malignancies characterized by dysplastic changes, ineffective hematopoiesis and variable risk of leukemic progression. At diagnosis, 86% of MDS patients are ≥60 years. Azacitidine, the only drug that prolongs life in high-risk (HR)-MDS patients, adds a median of only 9.5 months to life. Allogeneic stem cell transplantation (alloSCT) remains the only potentially curative approach. Despite recent improvements including use of reduced intensity conditioning (RIC) that decrease transplant-related mortality, alloSCT continues to be used rarely in elderly MDS. There is paucity of data regarding outcomes of RIC alloSCT in elderly MDS patients, especially in direct comparison with azanucleosides. In this paper, the authors discuss the recent Markov decision analysis by Koreth et al. in which investigators demonstrated superior survival of patients with HR-MDS aged 60–70 years who underwent RIC alloSCT in comparison with those who were treated with azanucleosides.

Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis.

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged ≥ 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk. A Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q- syndrome, unclassifiable, and therapy-related MDS were excluded. Transplantation using T-cell depletion or HLA-mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 132) stratified by IPSS risk was compared with best supportive care for patients with nonanemic low/intermediate-1 IPSS (n = 123), hematopoietic growth factors for patients with anemic low/intermediate-1 IPSS (n = 94), and hypomethylating agents for patients with intermediate-2/high IPSS (n = 165). For patients with low/intermediate-1 IPSS MDS, RIC transplantation LE was 38 months versus 77 months with nontransplantation approaches. QALE and sensitivity analysis did not favor RIC transplantation across plausible utility estimates. For intermediate-2/high IPSS MDS, RIC transplantation LE was 36 months versus 28 months for nontransplantation therapies. QALE and sensitivity analysis favored RIC transplantation across plausible utility estimates. For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk. For low/intermediate-1 IPSS, nontransplantation approaches are preferred. For intermediate-2/high IPSS, RIC transplantation offers overall and quality-adjusted survival benefit.

Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation.

The long-term impact of allogeneic hematopoietic stem cell transplantation (HSCT) on human immunodeficiency virus type 1 (HIV-1) reservoirs in patients receiving combination antiretroviral therapy (cART) is largely unknown. We studied the effects of a reduced-intensity conditioning allogeneic HSCT from donors with wild-type-CCR5(+) cells on HIV-1 peripheral blood reservoirs in 2 patients heterozygous for the ccr5Δ32 mutation. In-depth analyses of the HIV-1 reservoir size in peripheral blood, coreceptor use, and specific antibody responses were performed on samples obtained before and up to 3.5 years after HSCT receipt. Although HIV-1 DNA was readily detected in peripheral blood mononuclear cells (PBMCs) before and 2-3 months after HSCT receipt, HIV-1 DNA and RNA were undetectable in PBMCs, CD4(+) T cells, or plasma up to 21 and 42 months after HSCT. The loss of detectable HIV-1 correlated temporally with full donor chimerism, development of graft-versus-host disease, and decreases in HIV-specific antibody levels. The ability of donor cells to engraft without evidence of ongoing HIV-1 infection suggests that HIV-1 replication may be fully suppressed during cART and does not contribute to maintenance of viral reservoirs in peripheral blood in our patients. HSCTs with wild-type-CCR5(+) donor cells can lead to a sustained reduction in the size of the peripheral reservoir of HIV-1.

Dose-Adjusted EPOCH-Rituximab Combined With Fludarabine Provides an Effective Bridge to Reduced-Intensity Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Lymphoid Malignancies

There is currently no standard chemotherapy regimen for patients with lymphoid malignancies being considered for reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation (RIC-alloHSCT). The ideal regimen would provide disease control and result in lymphocyte depletion to facilitate engraftment. To this end, we developed a novel regimen by adding fludarabine to dose-adjusted continuous-infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus with or without rituximab (DA-EPOCH-F/R). One hundred forty-seven patients with lymphoid malignancy (median age, 50 years) who had heavily pretreated (median prior regimens, three) and chemo-refractory (47%) disease were treated with DA-EPOCH-F/R before RIC-alloHSCT. Patients received one to three consecutive cycles until achieving lymphocyte depletion (CD4(+) count < 200/μL) or progressive disease. Overall response rate was 41%; 39% of patients had stable disease. Toxicity included grade 4 neutropenia in 65% and thrombocytopenia in 25% of patients. DA-EPOCH-F/R resulted in lymphocyte depletion (P < .001), which was inversely associated with serum interleukin (IL) 7 and IL-15 levels. Of 147 patients, 143 patients proceeded to RIC-alloHSCT. Patients with lower CD3(+) (P < .001), CD4(+) (P < .001), and CD8(+) (P < .001) T-cell counts after DA-EPOCH-F/R were more likely to achieve full donor lymphoid chimerism by day +14 after transplant. Relative to nonresponders to DA-EPOCH-F/R, patients with complete and partial response had increased event-free survival (77.4 v 4.8 months; P < .001) and overall survival (98.5 v 16.2 months; P < .001). DA-EPOCH-F/R safely provides tumor cytoreduction and lymphocyte depletion, thereby offering a bridge to RIC-alloHSCT in patients with aggressive lymphoid malignancies.

Cyclosporine a and Mycophenolate Mofetil Vs Cyclosporine a and Methotrexate as Gvhd Prophylaxis in Reduced Intensity Conditioning Hematopoietic Stem Cell Transplantation from HLA-Identical Sibling Donor.

J.L.Piñana is supported by grants from the Instituto de Salud Carlos III (expedient CM06/00139, Ministerio de Sanidad)Background: Cyclosporine A (Csa) with methotrexate (MTX) is the most common prophylactic regimen against acute graft versus host disease (aGVHD). Although some studies show that Mycophenolate Mofetil (MMF) in combination with Csa for patients undergoing allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is associated with early hematologic recovery, less toxicity as mucositis and no diferencies in terms of aGVHD. Limited data is available comparing these two combinations in reduced intensity conditioning Allo-HSCT (Allo-RIC). In this case-control study from two Spanish BMT centers, we retrospectively analyzed the introduction of MMF as GVHD prophylaxis in comparison with a short course of MTX in a large series of patients who underwent HLA identical sibling donor Allo-RIC.Patients and methods: We include 145 consecutive Allo-RIC patients, who received peripheral blood (PB) as source of stem cells, between April 2000 and August 2007. The median follow-up for the whole group was 514 days (8 to 3170 days). The study group included 91 males and 54 females. Median age was 55 years (range 18 to 71 years). Diagnoses were acute leukemia/myelodisplastic syndrome/myeoloproliferative disorders) (n=37/15/13), multiple myeloma (n= 32), Hodgkin lymphoma (n= 6), chronic lymphocytic leukemia (n=15) and non-Hodgkin lymphoma (NHL) (n= 27). GVHD prophylaxis consisted of CsA/MMF in 52 and CsA/MTX in 93 patients. The conditioning regimen was based on fludarabine in combination with busulfan (59 recipients) or melphalan (86 cases).Results: The occurrence of mucositis grade 2–4 was higher in the CsA/MTX group than in the CsA/MMF group (57% vs 23% p= 0.001). No significant differences were found between CsA/MMF and CsA/MTX groups in time to neutrophil recovery (15 +/−3 days vs 15 +/− 2days) (p= 0.5). Cumulate incidence of acute GVHD were 50% (95% C.I., 38–65) for CsA/MMF group and 48% (95% C.I. 39–60%) for CsA/MTX group (p= 0.9). Although chronic GVHD was also similar [71% (95% C.I. 58–86%) in CsA/MMF group vs 68% (95% C.I. 57–80%) in Csa/MTX group (p= 0.7)], we observed that the development of chronic GVHD was delayed in the CsA/MMF group [174 days (range 100–365) vs 134 days (range 84–302) p= 0.008)]. Non relapse mortality (NRM) at 100 days was higher in MTX group (6% vs 18%, p=0.04). However, relapse and overall survival at median follow-up were still similar between groups (25% vs 18%, p= 0.4 and 52% vs 51%, p=0.7, respectively).Conclusion: We conclude that the combination Csa/MMF appears to be at least equivalent to the standard Csa/MTX GVHD prophylaxis in HLA identical sibling donor Allo-RIC. The toxicity profile of Csa/MMF was better, reflected by a significantly less incidence of mucositis.

Treatment of McLeod Phenotype Chronic Granulomatous Disease with Reduced-Intensity Conditioning and Unrelated-Donor Umbilical Cord Blood Transplantation

Patients with chronic granulomatous disease (CGD) complicated by antimycotics-refractory invasive aspergillosis have an extremely poor prognosis if they cannot undergo allogeneic hematopoietic stem cell transplantation from a suitable related donor while in good clinical condition. We successfully treated a 20-year-old man with very rare McLeod phenotype CGD with reduced-intensity conditioning and unrelated-donor umbilical cord blood transplantation. We postulate that reduced-intensity conditioning-allogeneic hematopoietic stem cell transplantation is a promising therapeutic strategy for patients with CGD even if only unrelated-donor umbilical cord blood is available.

Reduced Intensity Conditioning Hematopoietic Stem Cell Transplantation (HSCT) with Mesenchymal Stem Cells (MSC) Infusion for Treatment of Metachromatic Leukodystrophy (MLD): A Case Report.

Background: Patients (pts) with MLD have neurological and musculo-skeletal defects with a limited survival. HSCT has been reported as an effective treatment to stabilize or improve defects associated with this disease. Koç and colleagues reported that donor allogeneic MSC infusion is safe and may be associated with reversal of the disease pathophysiology in some tissues (Bone Marrow transplant, 2002). We decide thus to perform a non myeloablative familial HSCT in adult pt with a symptomatic MLD in order to evaluate the safety and the benefit allogeneic HSCT with MSC infusion in a patient with MLD. An informed consent was obtained from the pt.Patient: a 23 years old women who presented an adult form of MLD for three years was admitted in our department. The most important symptoms associated with the disease were dizziness, proximal weakness of the lower limbs, difficulty to walk, disorder of the memory and urinary incontinence. The reduced intensity conditioning was preferred to decrease the morbidity and mortality of the procedure. MSC were isolated and amplified from the BM-mononuclear cells of the HSC donor. MSC expansion was made in a commercial serum-free medium (UltraCulture, Cambrex, Walkersville, MD) supplemented with a serum substitute (Ultroser, Pall Biosepra, Cergy-Saint-Christophe, France) as previously reported by our group (Eur J Haematol, 2006). Ex vivo expanded allogeneic MSC were intravenously infused at the dose of 1×106 MSC/kg of recipient body weight. The conditioning regimen of the HSCT consisted in Fludarabine and ATG combination and 5× 106 CD34 cells were infused concomitantly with 1.106 MSC cells. We did not observed any immediate or delayed side effects after the MSC infusion. The patient did not presented any complications after the HSCT. At day 8 of the transplantation she had an normal hematological recovery. The platelet nadir was 72.000/mm3 and she did not need any transfusion. With regards of her neurological status, since 22 months the patient had no new deterioration and we observed a stabilisation of the clinical manifestations.Conclusions: This case report suggests the feasibility and the potential efficacy of reduced intensity conditioning allogeneic HSCT with MSC infusion for patient with MLD. A larger trial is required to confirm this observation.