High Peripheral Blood Stem Cell (PBSC) CD34+ Cell Dose Increases the Risk of Chronic Gvhd after Human Leukocyte Antigen (HLA) Matched Sibling Transplantation

Abstract CD34+ cell dose is a critical determinant of outcomes after allogeneic PBSC transplantation, with a CD34 dose ≥2.0 x 10e6/kg shown to positively impact hematopoietic engraftment and survival. However, it is unknown whether additional benefits are observed with even higher CD34 cell doses. Therefore, we further explored the effect of intermediate, high and very high CD34 cell doses on the incidence of engraftment, acute and chronic graft-versus-host disease (GVHD) and transplant related mortality (TRM) and on probability of survival and GVHD-Relapse-free survival (GRFS). Three hundred and five consecutive patients transplanted with GCSF-mobilized PBSC from HLA-matched sibling donors (MSD) were evaluated. Patients were ≥16 years of age, had a hematological malignancy and received a myeloablative or a nonmyeloablative conditioning regimen between 2002 and 2012. The median recipient age was 52 years (r, 19-74 years) with most being male (n=194, 63.8%) diagnosed with leukemia (72%) or lymphoma (22%), and intermediate disease risk index (DRI, n=204, 67%). The median age for the donor were 49 years (r,17-76 years). In 159 patients (52%) the donor and recipient were sex matched with 89 male patients having a female door (29%). The ABO blood type was matched in 195 patients (64%), 153(50%) received a myeloablative (MA) conditioning regimen, and 37 (12%) received a reduce intensity conditioning regimen containing ATG. The median follow up of surviving patients was 793 days (r, 14-4562 days). Patients were divided in four CD34 dose quartiles: first quartile (QT1), ≤4.8 x10e6/kg, QT2 4.8-6.0 x10e6/kg, QT3 6.0-7.5 x10e6/kg, and QT4 ≥ 7.6 x 10e6/kg. Notably, the CD3 doses were similar for all quartiles: QT1 was 3.4 x 10e8/kg (r, 0.3-10.0), QT2 was 2.7 x 10e8/kg (r, 1.1-7.6), QT3 was 2.8 x 10e8/kg (r, 0.8-7.2) and QT4 was 2.8 x 10e8/kg (r, 1.4-7.7); there was no correlation between CD34 and CD3 cell doses. Patient and donor characteristics were similar in the four groups except for shorter median follow-up (P <0.01) in QT1, more sex mismatched grafts (P <0.01) in QT3, and lower median number of cell collections (P <0.01) and more female donor: male recipient pairs (P< 0.01) in QT4. Multivariate analysis results are summarized on the table. Higher CD34+ cell dose was associated with improved platelet recovery with trends toward lower TRM and improved overall survival. Chronic GVHD however was also higher. In summary, additional studies are needed to establish a survival benefit in recipients of higher cell doses >4.8 x 10e6 CD34 cells/kg. Unless survival is positively impacted, the higher risk of chronic GVHD would argue for assigning an upper CD34 cell dose limit to reduce this risk that can significantly impair quality of life. Table Table. Disclosures No relevant conflicts of interest to declare.

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Impact Of Total Nucleated Cell and CD34+ Cell Dose On Transplant Related Outcomes In Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplants

Blood ◽

10.1182/blood.v122.21.2048.2048 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2048-2048 ◽

Cited By ~ 1

Author(s):

Paul Martin ◽

Shuli Li ◽

Edwin P. Alyea ◽

Vincent T. Ho ◽

Corey S. Cutler ◽

...

Keyword(s):

Disease Risk ◽

Conflicts Of Interest ◽

Risk Index ◽

Chronic Gvhd ◽

Multivariable Analysis ◽

Reduced Intensity Conditioning ◽

Allogeneic Hct ◽

Cell Dose ◽

The Impact ◽

Reduced Intensity

Abstract Background Mobilized peripheral blood (PB) is the most common graft source for allogeneic hematopoietic transplantation (HCT) following reduced intensity conditioning (RIC). The impact, if any, of donor PB graft composition on major transplant outcomes in the RIC allogeneic HCT setting remains incompletely understood. Existing studies have focused primarily on CD34+ cell dose and report conflicting results, especially in relation to survival. The impact of total nucleated cell (TNC) dose has been less frequently evaluated, but limited studies with relatively small cohort sizes have reported higher TNC dose to be associated with improved survival. Methods In order to further explore the relationship between PB donor CD34+ cell dose, TNC dose and RIC HCT outcomes, we assessed 705 adult patients with hematological malignancies who underwent RIC allogeneic HCT at Dana Farber Cancer Institute/ Brigham and Women's Hospital (DFCI/BWH) between 2000 and 2010. The vast majority received a RIC regimen of fludarabine and busulfan (n=698). GVHD prophylaxis was tacrolimus based with or without sirolimus (524 vs. 171, respectively). Recipients of in vivo T-cell depletion (TCD) with antithymocyte globulin or ex-vivo TCD were excluded. The median age was 57 years (range,18-74). Patient's disease risk index (DRI) was categorized as low (n=164), intermediate (n=350), high (n=170) or very high (n=21) per Armand, et al (Blood, 2012). Transplants were categorized as matched (MRD n=273, MUD n=374) or mismatched (MMRD n=4, MMUD n=58). Results There was weak correlation between CD34+ cell dose and TNC (Spearman coefficient 0.25 [0.18-0.32]), and between CD34+/kg and TNC/kg with coefficient 0.25 [0.26, 0.39]. Cell doses for TNC effects were evaluated by quartiles. On multivariable analysis including age, DRI, donor source, gender, and CMV serostatus, higher TNC dose (top quartile, ≥10.8 x 10^10 cells) was independently associated with increased chronic GVHD (HR 1.33 [1.06-1.67], p=0.015) as well as decreased relapse (HR 0.74 [0.58-0.94], p=0.015). There was no effect on acute GVHD, engraftment, or non-relapse mortality. Importantly, higher TNC dose was associated with improved overall survival (HR 0.74 [0.59-0.94], p=0.014, Figure 1) and progression free survival, PFS (HR 0.76 [0.61-0.94], p=0.014). In contrast, although higher doses of CD34+ cells (> 10 x 10^6/kg vs. < 5 x10^6/kg) resulted in faster engraftment for both platelets and neutrophils (data not shown) and a decrease in non-relapse mortality ( HR 0.53 [0.30-0.93], p=0.027), there was no significant effect on acute or chronic GVHD incidence, relapse, PFS or survival. Conclusions These data suggest TNC dose is an important prognostic variable in T-replete RIC HCT with significant impact on survival and should, like CD34+ cell dose, be taken into consideration when planning donor graft infusions. Further studies are needed to confirm these data, and characterize the components of the PB graft that influence survival. Disclosures: No relevant conflicts of interest to declare.

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Impact of Cytopenia Following Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Using Post-Transplant Cyclophoshamide

Blood ◽

10.1182/blood.v128.22.2281.2281 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2281-2281

Author(s):

Villetard Ferdinand ◽

Stefania Bramanti ◽

Samia Harbi ◽

Sabine Fürst ◽

Catherine Faucher ◽

...

Keyword(s):

Bone Marrow ◽

Cell Transplantation ◽

Disease Risk ◽

Conflicts Of Interest ◽

Risk Index ◽

Conditioning Regimen ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Cell Dose ◽

The Impact

Abstract Introduction Allogeneic transplantation from a haploidentical donor (HaploSCT) is an alternative strategy in the treatment of hematologic malignancies in absence of HLA-identical donor. Recent studies reported similar outcome after HaploSCT compared to HLA-identical transplantation in different settings (Bashey, JCO 2013; Wang, Blood 2015; Gosh, JCO 2016). Although survivals seemed promising after HaploSCT, hematopoietic recovery following such a mismatched transplantation could represent a limitation. Thus, our series aims to evaluate hematological recovery after HaploSCT using a post transplantation cyclophosphamide (PT-Cy) platform. Methods This retrospective monocentric study included consecutive patients with following criteria: adults with hematological malignancies; bone marrow or peripheral blood T-replete HaploSCT from 2011 to 2015; non-myeloablative (Baltimore approach) or reduced intensity conditioning (busulfan-based) regimen; PT-Cy as part of GVHD prophylaxis. Patients with primary graft failure were excluded. Absolute neutrophil count (ANC), red cells (RCT) or platelet transfusion (PT) requirements on day 30 (D30) and day 100 (D100) were analyzed among disease-free patients. We first separately evaluated the rate of patients with significant cytopenia in each lineage (defined by ANC < 1 G/L, RCT need, PT need) and searched for impact of pre-transplantation factors on cytopenia (multivariate analyses by binary logistic regression). Then, we evaluated outcome by D30- and D100-landmark analyses according to cytopenia. Results One hundred and forty six patients with a median age of 56 years (range: 19-73) were analyzed: 142 and 117 were evaluable at D30 (4 early deaths) and D100 (17 deaths, 11 relapses), respectively. At D30, 20% of patients had ANC<1G/L, 67% needed RCT and 63% needed PT. Corresponding values at D100 were 20%, 42% and 28%, respectively (Figure 1). At D30: the use of PBSC (HR 9.5, p=0.002) was significantly associated with ANC>1G/L at D30; the use of NMAC Baltimore schema (HR 0.3, p=0.012) and CD34+ cell dose > median (HR 0.4, p=0.041) decreased PT needs while hematopoietic cell transplantation comorbidity index (HCT-CI)≥3 (HR 3.3, p=0.004) was associated with PT needs; no factor was found to significantly influence RCT. At D100: Age>60 years (HR 2.4, p=0.045), female to male HaploSCT (HR 3.3, p=0.020) and HCT-CI≥3 (HR 3.7, p=0.006) were significantly associated with higher risk of RCT need; female to male HaploSCT (HR 3.6, p=0.015) and HCT-CI≥3 (HR 6.9, p=0.001) were associated with PT needs; no factor was found to significantly influence ANC. With a median follow up of 25 months (range: 5-55), cox multivariate model with adjustment by age (continuous), disease risk index (low/intermediate vs high/very high), HCT-CI (0-2 vs ≥3), conditioning regimen (baltimore vs. busulfan-based) and graft source (bone marrow vs PBSC) showed that ANC<1 G/L was strongly associated with higher NRM (HR 2.9, p=0.011) and shorter OS (HR 3.4, p<0.001), overcoming the impact of RCT and PT needs (Figure 2A and 2B). In contrast, D100 analysis showed that PT need was the most determinant factor of increased NRM (HR 13.7, p=0.013) and poor OS (HR 7.3, p=0.003), while both D100 ANC and RCT needs did not impact outcome (Figure 2C and 2D). Discussion We found that cytopenia remain a concern after HaploSCT, leading to increased NRM and OS. The absence of ANC>1G/L at D30 as well as the need of PT at D100 may be considered as a strong post transplantation factor predicting poor outcome. Some pre-transplantation factors of cytopenia have been identified, such as CD34+ cell dose, sex mismatch and graft source. Among them, some may help for donor selection while the optimal donor for HaploSCT is still unknown. Moreover, better neutrophil recovery at D30 is achieved with the use of PBSC. CD34+ optimal cell dose in this setting remains also to be determined. In addition, post transplantation events such GVHD and/or infections should be evaluate to explore their interactions with such cytopenia, aiming to develop early therapeutic interventions. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Allogeneic Hematopoietic Peripheral Blood Stem-Cell Transplantation From HLA-Identical Siblings Versus Allelic-Matched Unrelated Donors (10/10 high resolution) in Patients with Acute Myeloid Leukemia and Myelodyplasic Syndrome After Reduced Intensity Conditioning,

Blood ◽

10.1182/blood.v118.21.4132.4132 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4132-4132

Author(s):

Marie Robin ◽

Raphael Porcher ◽

Lionel Ades ◽

Emmanuel Raffoux ◽

Nicolas Boissel ◽

...

Keyword(s):

Cumulative Incidence ◽

Myeloid Leukemia ◽

Acute Gvhd ◽

Disease Risk ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Sibling Donor ◽

Matched Sibling

Abstract Abstract 4132 Introduction: Although precise matching of the donor/recipient pairs has been made easier by HLA typing at the allelic level, several issues with respect to unrelated transplantation remain to be addressed. In particular, the impacts of allelic HLA matching in patients with Acute Myeloid Leukemia (AML) and myelodysplasic syndrome (MDS) who receive allogeneic Peripheral Blood Stem cells (PBSC) after a reduced intensity conditioning (RIC) regimen is still unclear. In the present study, we aim to compare the impact of the donor type in this setting: HLA identical sibling versus HLA matched 10/10 (high resolution) unrelated donor (MUD). Method and transplantation characteristics: From 01/2001 to 12/2010, 108 consecutive patients with AML (n=63) and MDS (n=45) received PBSC after RIC in our center, either from HLA identical sibling (n=69) or MUD (n=39). Conditioning regimen was fludarabine based in 95% of patients and GvHD prophylaxis consisted in cyclosporine plus mycophenolate in 79% of patients. Engraftment, acute and chronic graft-versus-host disease (GvHD), transplantation-related mortality (TRM), relapse rate and overall survival (OS) at 3 years were compared according to type of donor: HLA identical sibling donor and MUD. Disease characteristics: WHO classification for MDS at time of hematopoietic stem cell transplantation (HSCT) was RAEB1 (24%), RAEB2 (36%), MDS transformed into secondary AML (20%), CMML2 (9%), RA (4%), or other (7%). Disease risk was assumed by cytogenetic (MRC for AML, IPSS for MDS) and EBMT score (good risk: CR1 for AML or MDS or untreated MDS, intermediate risk: CR2 for AML, CR2 or partial remission for MDS, poor risk: all other status). Cytogenetic (no missing data) was poor, intermediate or good for 21, 74 and 5% of AML and 24, 36 and 40% of MDS, respectively. EBMT score at time of HSCT was poor, intermediate or good for 29, 7, 64% of MDS and 11, 21, 68% of AML, respectively. Results of the comparison: Patients characteristics according to type of donor were similar for age (median 57 years), gender and disease distribution. Particularly, disease risks were comparable in 2 groups. Conversely, conditioning regimen (more ATG in MUD: 69 vs. 43%, p=0.016), donor age (younger for MUD: 30 vs. 52 years, p<0.0001) and number of CD34+ cells infused (higher in MUD: 7 vs. 6.5 × 106/kg, p=0.022) were different. The median follow-up was 36 months (range 2 to 72). All patients engrafted. The cumulative incidence of acute GvHD was 40% with HLA matched sibling donor and 44% for MUD (p=0.58). The cumulative incidence of chronic GvHD at 3 years was 49% with HLA matched sibling donor and 45% with MUD (p=0.66). No risk factor was associated with acute GvHD but chronic GvHD was less frequent in patients with AML vs. MDS (41% vs. 59%, p=0.077) and in those patients who received ATG in conditioning regimen (54% vs. 43%, p=0.067). During follow-up, 47 patients died. The 3-year cumulative incidence of TRM was 17% and 22% with HLA matched sibling donor and MUD, respectively (p=0.55). Adjusting for age, MDS was the only factor increasing TRM (HR 3.4; 95% CI 1.2 to 9.5; p=0.02). The 3-year cumulative incidence of relapse was 46% with HLA matched sibling donor and 30% with MUD (p=0.28) knowing that there was no difference between both groups regarding disease risk (cytogenetic and EBMT score). The 3-year OS was 44% with HLA matched sibling donor (95%CI: 33–61) and 50% with MUD (95%CI: 35–71) (Figure 1). Disclosures: Fenaux: Celgene: Honoraria, Research Funding. Peffault de Latour:Alexion: Consultancy, Research Funding.

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Similar Outcomes of Allogeneic Hematopoietic Cell Transplantation from Matched Sibling Donor and Haploidentical Donor for Refractory/Relapsed Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.5511.5511 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5511-5511

Author(s):

Dai-Hong Liu ◽

Li Yu ◽

Wenrong Huang ◽

Liping Dou ◽

Honghua Li ◽

...

Keyword(s):

Cohort Study ◽

Stem Cell ◽

Cell Transplantation ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematopoietic Stem ◽

Platelet Recovery ◽

Sibling Donor ◽

Matched Sibling

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only effective, even curative treatment for refractory/relapsed AML patients. Unmanipulated haploidentical HCT (haplo-HCT) resulted in encouraging outcomes for treatment of hematologic malignancies and become an alternative option in case of lacking HLA matched sibling donor (MSD). Unmanipulated haplo-HCT from G-CSF mobilized bone marrow and peripheral blood stem cell (PBSC) has shown similar results as that from MSD-HCT in leukemia. Here, we report the results of a cohort study on the efficacy and toxicity of haplo-PBSCT compared with MSD-PBSCT for treatment of refractory/relapsed AML. PATIENTS AND METHODS Among 419 newly diagnosed AML patients, 69 patients relapsed during CR1 and were planned to receive allo-HCT after re-induction. The order of preference of donors was MSD, matched unrelated (HLA 10/10 or 9/10 loci matched), or haploidentical donor. Thirty patients received haplo-PBSCT and 13 patients MSD-HCT (July, 2007 ~ June, 2014) at our unit. There was no difference of the characteristics of demography, disease or transplantation between these two groups (Table 1). High-resolution DNA techniques were used to evaluate the HLA-A, B, DRB1, DQB1, and C loci. Donors were treated with rhG-CSF (5 mg.kg-1.day-1) for consecutive days. The PBSCs were collected on day 5 - 6 and infused on the day of collection. The conditioning regimen consisted of Bu (9.6 mg.kg-1, intravenously, days -10 ~ -8), Carmustine, (250 mg.m-2, day -5), cytarabine (8 g.m-2, days -7 ~ -6), CY (120 mg kg-1, days -4 ~ -3), and ATG (rabbit; 10 mg.kg-1, days -5 ~ -2). MSD-HCT patients had the same conditioning regimen without ATG. All transplant recipients received cyclosporine A, mycophenolate mofetil, and short-term methotrexate for GVHD prophylaxis. The endpoint of the last follow-up for all surviving patients was June 30, 2015. RESULTS Sustained myeloid engraftment with full donor chimerism was achieved in both groups (100%) at a median of 16 (10 - 26) days. Twenty-six patients (86.7%) in haplo-PBSCT group and all patients in MSD-PBSCT group achieved platelet recovery. There was no difference of the cumulative incidence of acute GVHD grade 2-4 (Fig. 1), chronic GVHD (20% vs 33.3%, P=0.581), transplantation-related mortality (TRM) (16.7% vs 0%, P = 0.121), relapse (33.3% vs 38.5%, P = 0.578, Fig 2) between haplo-PBSCT and MSD-PBSCT group. Donor age of 41yr and older was an independent risk factor for inferior leukemia-free-survival (27.8% vs 37.2%, P = 0.004). CONCLUSION In this cohort study, haplo-PBSCT showed similar outcomes in patients with refractory/relapsed AML compared with MSD-PBSCT. It suggested the feasibility of G-CSF-primed PBSC as a graft source in unmanipulated haplo-HCT under myeloablative conditioning, which was effective and tolerable for treatment of poor risk leukemia. Table 1. Characteristics of patients and donors Haploidentical donor Matched sibling donor P value Cases % Cases % Gender, n (%) Receipt Male 22 73.3 8 61.5 0.485 Donor Male 22 73.3 7 53.8 0.292 Age,y, median(range) Patient ≤40 y, n (%) 21 70 6 46.2 0.178 Donor ≤41 y, n (%) 13 43.3 5 38.5 1.000 AML, n (%) 1.000 CR2 5 16.7 2 15.4 NR/beyond CR2 25 83.3 11 84.6 Time to transp 0.51 ≥7m 14 46.7 8 61.5 Conditioning Regimen, n (%) 0.675 BuCy 22 73.2 9 69.2 TBIcy 4 13.3 1 7.7 FB 4 13.3 3 23.1 CD34+ in graft (106/kg) 0.499 ≥4.77 17 56.7 5 41.7 Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures No relevant conflicts of interest to declare.

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Comparable Outcomes Among Adult Patients Allotransplanted for Myelodysplastic Syndrome Using Haploidentical, Matched Unrelated or Matched Sibling Donors: A Single-Center Study

Blood ◽

10.1182/blood-2021-146826 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4914-4914

Author(s):

Alice Garnier ◽

Maxime Jullien ◽

Thierry Guillaume ◽

Pierre Peterlin ◽

Amandine Le Bourgeois ◽

...

Keyword(s):

Stem Cells ◽

Myelodysplastic Syndrome ◽

Peripheral Blood ◽

Risk Index ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Peripheral Blood Stem Cells ◽

Blood Stem Cells ◽

Matched Sibling

Abstract Introduction: Allogeneic stem cell transplantation (allo-SCT) remains the only curative option for patients with myelodysplastic syndrome (MDS). If recent data have shown encouraging results with haploidentical (haplo) donors in this context, no comparison with allo-SCT using other source of graft (matched sibling [MSD] or unrelated [MUD] donors) has been reported so far. Methods: We retrospectively considered 102 consecutive adults transplanted for MDS between March 2010 and August 2020 in our Department, comparing outcomes between those receiving a graft from a MSD, a MUD or a haplo-donor. Results : Thirty-three, 48 and 21 patients respectively received a graft from a MSD, MUD or haplo donor. Peripheral blood stem cells (PBSC) were the source of graft for all patients. The median age of the whole cohort was 63 years old (range: 20-74) and the median follow-up was 23 months (range: 0-125). The three groups shared similar characteristics (gender, type of MDS, disease status, disease risk index, CMV status, ABO compatibility, peripheral blood stem cells graft count, conditioning regimen) except median recipient age which was younger in matched patients ( 61 vs 65 MUD vs 65 Haplo, p=0,04) and median donor age which was older in matched transplant ( 61 vs 34 MUD vs 42 Haplo, p< 0,001) (Table 1). With a median follow-up of 46,4 months, the 4-year OS (Figure 1) was comparable between the three groups (haplo: 60.1 % ± 11,0 % , MSD: 59,0 % ±9,4 % and MUD: 61.2 % ± 7,2 %, p = 0.88) as well as the 4-year DFS (Figure 2) (55.9 % ± 11,1 % vs 51,2 % ±9,2 % vs 59.6 % ± 7,2 %, p = 0.78) and the cumulative incidence (CI) of NRM (34.6 % ±12,4 % , 15,4% ± 6,4% and 23.8 % ± 6,4 %, p = 0.21). Also, the 4-year CI of acute grade 3-4 GVHD (14,3% vs 15,2% vs 20,8%, p=0.79) and of moderate/severe chronic GVHD (14,3% vs 24.2% vs 27,1%, p=0.56) were not significantly different. The 4-year GRFS seemed better with haplo (Figure 3) but this was not statistically significant (56,1 % ± 11,0% vs 28,1% ±9,2 % vs 32,8 % ± 7,4%,p=0 .41). Conclusions: These data suggest that haplo-identical donors represent a valid alternative in MDS patients lacking a MSD or a MUD for allo-SCT. Figure 1 Figure 1. Disclosures Moreau: Oncopeptides: Honoraria; Amgen: Honoraria; Celgene BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria.

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HLA-Haploidentical HSCT with Post-Transplant Cyclophosphamide for Severe Aplastic Anemia

Blood ◽

10.1182/blood.v120.21.4510.4510 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4510-4510

Author(s):

Yuelin He ◽

Chunfu Li ◽

Xuedong Wu ◽

Xiaohui Zhou ◽

Xiaoqin Feng ◽

...

Keyword(s):

Aplastic Anemia ◽

Acute Gvhd ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Donor Lymphocyte Infusion ◽

Severe Aplastic Anemia ◽

Platelet Recovery ◽

Graft Versus Host

Abstract Abstract 4510 Objective To investigate the effect of pretransplantation donor lymphocyte infusion (DLI) and posttransplantation cycolphosphamide (CY) to prevent graft rejection and graft-versus-host disease (GVHD) after bone marrow transplantation plus peripheral blood stem cell transplantation from HLA-haploidentical mismatched related donors. Methods Four patients (median age, 11 years; range, 8–15 years) with severe aplastic anemia and all of them had HLA-haploidentical donors more than or equal to 2/8 HLA (HLA-A, B, C and DRB1) mismatched at antigen level. The conditioning regimen consisted of pretransplantation DLI (Lymphocytes, 1×10e7/kg at day -9); 40mg/m2/day of fludarabine (day-6 to -2); 3.2mg/kg/day of Busulfex (day-6 and -5); 10mg/kg/day of Thiotepa (day -4) and 50mg/kg/day of Cy on day -7, 14.5mg/kg on day-3,-2 and 40mg/kg on day +3,+4, respectively. The prophylaxis of acute GVHD consisted of tacrolimus and mycophenolate mofetil. The median follow-up time is 5 (rang: 3–6) months. Results The median times to neutrophil (>500/ÌL) and platelet recovery (>20,000/ÌL) were 21 and 23.5 days, respectively. No acute GVHD and Chronic GVHD were, so far, observed for all patients and were survive without SAA. Conclusion Posttransplantation cyclophosphamide for the prophylaxis of acute GVHD was safe and effective. Disclosures: No relevant conflicts of interest to declare.

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Comparison of Peripheral Blood Stem Cells (PBSC) to Bone Marrow (BM) for T-Replete HLA-Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood.v128.22.683.683 ◽

2016 ◽

Vol 128 (22) ◽

pp. 683-683 ◽

Cited By ~ 3

Author(s):

Asad Bashey ◽

MeiJie Zhang ◽

Shannon R. McCurdy ◽

Stefan O. Ciurea ◽

Andrew St. Martin ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Disease Risk ◽

Risk Index ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Advisory Committees ◽

Mortality Risks ◽

Post Transplant

Abstract T cell-replete haploidentical donor transplants (HAPLO-HCT) using post-transplant cyclophosphamide for control of alloreactivity is now being increasingly utilized. HAPLO-HCTs were originally performed using BM grafts. However, recently, a few single center studies have reported good outcomes using G-CSF mobilized PBSC grafts for HAPLO-HCT. No prospective randomized comparisons of BM to PBSC grafts for HAPLO-HCT have been performed. Therefore, we analyzed outcomes for 687 adults (496 BM, 191 PBSC) who received HAPLO-HCT for hematologic malignancies using post-transplant cyclophosphamide + mycophenolate + calcineurin inhibitor for GVHD prophylaxis between 2009 and 2014 in the United States. The primary outcome was overall survival. The characteristics of recipients of BM and PBSC were similar except BM recipients were older, more likely to have a performance score ≥90, HCT-CI index ≤2, be CMV seronegative, have a lymphoid malignancy and receive reduced-intensity conditioning. Most PBSC transplants occurred between 2012 and 2014. The median follow-up was 35 and 20 months for recipients of BM and PBSC grafts, respectively. Cox regression models were built to study the effect of graft type adjusted for other significant factors on overall mortality, non-relapse mortality, relapse and graft-versus-host disease (GVHD) and outcomes censored at 2-years to accommodate differential follow-up between treatment groups (Table 1). After adjusting for age, CMV serostatus, disease risk index (disease type/disease status for myeloid and lymphoid malignancy and cytogenetic risk for acute leukemia and myelodysplastic syndrome) and transplant conditioning regimen there were no significant differences in risks for overall mortality (HR 1.00, p= 0.98; 2-year overall survival: 54% and 57%) or non-relapse mortality (HR 0.92, p=0.74; 2-year non-relapse mortality: 17% and 16%) after transplantation of BM compared to PBSC, respectively. However, relapse risks were higher after transplantation of BM compared to PBSC (HR 1.49, p=0.009; 2-year relapse: 45% and 28%). Subset analyses explored the effect of graft type separately for myeloablative and reduced intensity conditioning regimen adjusting for age, CMV serostatus and disease risk index. Consistent with the main analysis there were no differences in overall or non-relapse mortality risks and relapse risks were higher with BM compared to PBSC with myeloablative regimens (Table 1). Although this may in part be explained by lower chronic GVHD risks with transplantation of BM grafts, chronic GVHD was not significantly predictive of relapse risk when modeled as a time-dependent covariate (HR= 0.73, p=0.49). Grade II-IV acute GVHD risks (HR 0.45, p<0.001; 22% and 37%), adjusted for conditioning regimen were lower after transplantation of BM compared to PBSC. Chronic GVHD risks adjusted for age and performance score were also lower after transplantation of BM compared to PBSC (HR 0.35, p<0.001; 20% and 41%) but rates of moderate and severe chronic GVHD were not significantly different (28% and 32%). There were no differences in incidence of hematopoietic recovery by graft type. In conclusion, compared to BM grafts HAPLO-HCT with PBSC are associated with similar overall survival and non-relapse mortality risks but lower relapse risks with myeloablative conditioning regimens. Longer follow up is needed to ascertain whether survival differences may occur later. The observed adverse effect of BM grafts on relapse with myeloablative regimens must be studied further in the setting of carefully controlled trials. Table 1. Table 1. Disclosures Ciurea: Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board. Hamadani:Takeda: Research Funding. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees. Wingard:Ansun: Consultancy; Gilead: Consultancy; Astellas: Consultancy; Fate Therapeutics: Consultancy; Merck: Consultancy.

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Incorporation of Posttransplant Cyclophosphamide (PCy) As Part of Standard Immunoprophylaxis (IP) for All Allogeneic Transplants: A Retrospective, Single Institution Study

Blood ◽

10.1182/blood-2019-130598 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4485-4485

Author(s):

Dennis Cooper ◽

Jackie Manago ◽

Vimal Patel ◽

Dale Schaar ◽

Tracy Krimmel ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Transplantation ◽

Disease Risk ◽

Conflicts Of Interest ◽

Risk Index ◽

Chronic Gvhd ◽

Number Of Patients ◽

One Year ◽

Disease Free

Background: The incorporation of PCy in IP has allowed transplantation of stem cells from haploidentical (HI) family members such that nearly all patients have a potential donor. Thus far, HI stem cell transplantation with PCy appears to yield comparable results to matched unrelated (MUD) and matched sibling donors (MSD) who have been treated with conventional GVHD regimens, but with less chronic GVHD (cGVHD). Particularly in light of the low incidence of cGVHD, which has not been achieved with other IP strategies after T cell-replete products, PCy is being investigated after MUD and MSD transplantation where complications from cGVHD remain the major cause of non-relapse mortality. A recent study from the BMTCTN showed that in patients conditioned with reduced intensity regimens and who received MSD and MUD stem cells, the addition of PCy to standard IP (SIP) was superior to either bortezomib or maravoric in the composite endpoint of graft-versus-host disease-free, relapse-free survival (GRFS). However, this study did not include patients who received ablative conditioning regimens and did not report on the percentage of patients who were disease-free and off immunosuppression (DFOI) at 1 year after transplant. In the present study, we have compared our experience with the addition of PCy for essentially all allogeneic stem cell transplants treated over a 2 year period with the results of patients treated with SIP in the prior two year span. Outcomes of interest included one-year overall survival (OS) and one-year GRFS as well as the percentage of patients DFOI at one year. Methods: With the exception of patients receiving umbilical cord blood transplants, beginning in April 2016, all but two patients who received allogeneic transplants were given mobilized peripheral blood stem cells and then treated with PCy on days +3 and +4 followed by tacrolimus and mycophenolate on day 5. In the absence of GVHD, mycophenolate was stopped at days +35-50 and tacrolimus was tapered beginning after day +100 unless there was low donor chimerism or a suspicion of relapse in which case tacrolimus could be tapered sooner. In order to have at least one-year follow-up, the last patient included in the study was treated before April 2018. During this time period, MSD were prioritized over MUD which in turn were chosen over haploidentical donors. For comparison, we looked at the prior 2 year period (2014-2016) in which patients were treated with SIP (including ATG in patients who received MUD stem cells). Because of a higher percentage of patients with an advanced disease risk index (DRI) in the years 2014-2016, we restricted our analysis in the SIP cohort to those patients with low and intermediate risk disease but included all patients in the more recent period who received PCy. Results: There were 68 patients treated in the PCy group, including 2 patients who received PCy after HI transplants in the years 2014 and 2015. After eliminating patients with high DRI there were 40 patients in the earlier SIP cohort of patients. The resulting patient groups were similar with respect to median age (53) and diagnosis (approximately 80% of patients with AML and ALL). There was a slightly higher percentage of patients in the SIP group with hematopoietic cell transplantation-comorbidity index scores of 3 or more (52.5 vs 48.5). In the PCy group the number of patients with early, intermediate and advanced DRI were 2, 53 and 13, whereas in the (modified) SIP category 2 patients had a low DRI and 38 had intermediate DRI. In the PCy group, HI donors comprised 26.5% of the total compared to 19.1% MSD and 54.4% MUD donors. In the SIP group, MSD and MUD donors accounted for 30% and 70% of the donors. One-year percentages of OS, GRFS and DFOI were 79.4, 47.1 and 44.1 in the PCy group compared to 72, 45 and 35 in the SIP cohort. If the analysis of the PCy group is limited to the 50 patients with MSD and MUD donors (as in the SIP cohort), the one-year OS, GRFS and DFOI are 88, 52 and 52. Conclusions: PCy in combination with SIP resulted in at least comparable results as SIP despite the inclusion of 19% of patients with a high DRI and 26.5% HI donors. The results with the addition of PCy are excellent in patients with MSD and MUD donors with more than half of the patients GRFS and DFOI at one year. Future studies on GVHD prophylaxis should report DFOI as the latter status may be the best platform for posttransplant strategies aimed at eliminating minimal residual disease and for improving QOL. Disclosures No relevant conflicts of interest to declare.

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Umbilical Cord Blood Transplant after Reduced Intensity Conditioning Provides Outcomes Comparable HLA-Matched Siblings for Patients with High Risk and Advanced Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v108.11.606.606 ◽

2006 ◽

Vol 108 (11) ◽

pp. 606-606 ◽

Cited By ~ 4

Author(s):

Claudio G. Brunstein ◽

Daniela Setubal ◽

Marcie Tomblyn ◽

Todd DeFor ◽

Mukta Arora ◽

...

Keyword(s):

High Risk ◽

Disease Risk ◽

Conditioning Regimen ◽

Disease Status ◽

P Value ◽

Limiting Factor ◽

Hematopoietic Stem ◽

Cell Dose ◽

Matched Sibling ◽

Total Body

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is a standard treatment for patients with high risk or advanced AML. However, older age and of co-morbidities frequently limit its use due to high risk of regimen related toxicities (RRT) after a myeloablative regimen. While the inception of RIC regimens has been very successful at reducing RRT, lack of available HLA matched sibling or unrelated donors has become the principal limiting factor. We hypothesized that UCB would increase the utilization of HSCT in patients with AML who lacked a HLA-matched, medically suitable sibling donor. Therefore, we evaluated the various transplant outcomes in 64 AML patients treated with RIC followed by transplantation with HLA-matched sibling PBSC (n=21) and 4–6/6 HLA matched UCB (n=43). All pts received Fludarabine (Flu, 200 mg/kg) and total body irradiation (TBI 200 cGy) with either cyclophosphamide (Cy 50 mg/kg, n=49) or Busulfan (Bu 8 mg/kg, n=15). All pts received cyclosporine A and mycophenolate mofetil GVHD prophylaxis. UCB grafts were composed of 1 (n=15) or 2 (n=28) units to achieve the minimum cell dose. Patients with good and intermediate risk cytogenetics in first complete remission (CR1) were classified as standard risk; others were classified as high risk. Multivariate models considered: donor type, age, disease status, weight, CMV serostatus, cytogenetic risk, disease risk, acute GVHD, conditioning regimen, and time from diagnosis to HSCT. The proportion of engraftment (88% vs. 100%, p=0.10), the incidence of grade II–IV GVHD at day 100 (51% vs. 62%, p=0.85) and TRM at 1 year (28% vs 38%, p=0.43) did not differ between UCB and PBSC recipients. Similarly, relapse at 2 years (UCB 35% vs SIB 35%, p=0.72) and 2 year survival (UCB 31% vs SIB 32%, p=0.62) were comparable. In multivariate analysis, only disease risk group was associated with increased relative risk (RR) of relapse (RR 2.9, 95%CI, 1.3–6.2, p<0.01) and death (RR 2.6, 95%CI, 1.1–5.5, p=0.02). These results demonstrate that partially HLA matched UCB after RIC markedly extends the availability of HSCT with results comparable to those observed with PBSC from HLA matched sibling donors. Variable UCB (n=43) SIB PBSC (n=21) p value * Cell doses of double UCB grafts=combined cell dose. Age in years - median (range) 53 (22–68) 54 (19–69) 0.77 Weight in kg - median (range) 75 (53–120) 72 (51–112) 0.24 Recipient/Donor CMV + 20 (47%)/− 13 (62%)/8 (38%) <0.01 HLA-match 6/6* 5 (7%) 21 (100%) HLA-match 4–5/6* 66 (93%) Zero Disease status CR1 18 (43%) 14 (67%) Cytogenetics good/intermediate 32 (84%) 10 (48%) 0.31 Cytogenetics poor risk 7 (16%) 10 (48%) TNC X10 7/kg median (range)* 3.6 (1.6–5.9) 93.4 (64.8–212.3) CD34 X105/kg median (range)* 4.9 (1.1–18.8) 52.2 (14.1–153.7) Median follow-up in years 2.7 (0.7–5.5) 1.3 (0.7–6.1)

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Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Patients with Haematological Lymphoid Malignancies: Long Term Follow-up in a Single Centre Series.

Blood ◽

10.1182/blood.v114.22.4326.4326 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4326-4326

Author(s):

Malek Benakli ◽

Redhouane Ahmed nacer ◽

Amina Talbi ◽

Rachida Belhadj ◽

Farih Mehdid ◽

...

Keyword(s):

Complete Remission ◽

Hodgkin Lymphoma ◽

Median Time ◽

Conflicts Of Interest ◽

Late Onset ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Lymphoid Leukaemia ◽

Autologous Transplant

Abstract Abstract 4326 Background Patients (pts) with recurrent and refractory haematological lymphoid malignancy (HLM) have a very limited survival expectance. RIC allo-SCT has been proposed as a strategy for retaining the graft versus malignancy effect of allo-SCT while decreasing transplant related mortality (TRM). Here, we retrospectively studied a series of 32 pts treated by RIC allo-SCT. Patients and methods Between April 2001 and November 2007, 32 pts with HLM underwent RIC allo-SCT with an HLA-identical sibling donor. Fifteen pts with multiple myeloma, 7 pts with Non-Hodgkin lymphoma, 6 pts with Chronic lymphoid leukaemia, 3 pts with Hodgkin lymphoma and 1 pt with Waldenstrom disease. At time of allo-SCT, 10 pts were in complete remission (3 received prior autologous transplant) and 22 in refractory/progressive disease (6 received prior autologous transplant). Median age was 38 years (range, 28-60) and the sex-ratio (M/F) 2,2. Median time from diagnosis to RIC allo-SCT was 18 (range,6-76) months. The conditioning regimen included Fludarabine 150mg/m2 and Melphalan 140mg/m2. GVHD prophylaxis consisted of association cyclosporine (cSA) and mycophenolate (MMF). All pts received G-CSF mobilised peripheral blood stem cells, with a median CD34+ cell count: 6,2.106/kg (range, 1.9-13,6). Results Neutropenia occurred in all pts (100%) and the median duration of aplasia was 9 (range, 5-16) days. Only 10 pts (31 %) required red blood cells transfusions and 23 pts (71 %) needed platelets transfusions. Acute GVHD was observed in 15 cases (47 %) including 10 cases of grade II-IV. Fifteen pts (75 %) had chronic GVHD, of whom 9 with an extensive form. Four pts (12 %) had CMV reactivation at a median time 60 (range, 52-80) days after transplantation. Six pts (18 %) had late onset relapse at a median time of 13 (range, 4-45) months. TRM was 43 % at one year after RIC allo-SCT. With a median follow-up of 60 (range 18-97) months, 12 pts (37,5 %) are still alive in complete remission with full donor chimerism. Twenty pts (62,5 %) have died (5 early severe infections, 10 GVHD, 3 after relapse, one myocardial infarction, and one accident). Overall and progression-free survivals at 8 years are 31 % and 30 % respectively. Conclusion This study, after a large follow-up, suggests that RIC allo-SCT is a potential therapy for refractory or progressive HLM. However, TRM is still high likely due to the inclusion of refractory and heavily pretreated pts with many comorbid conditions. Disclosures: No relevant conflicts of interest to declare.

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