Investigating Antibiotic Exposure and Risk of Severe Acute Graft Versus Host Disease in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Several studies have shown that alteration of the microbiota, particularly in the gastrointestinal tract, can be associated with graft-versus-host disease (GvHD). Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT) usually get exposed to antibiotics (ATB), mainly in the peri-transplant period. Moreover, ATB, specifically those that target anaerobic bacteria, can alter the microbiota in a variety of body organs. This, in turn, renders several organs vulnerable to injury making them more prone to developing diseases such as GvHD. In this study, we evaluate whether the use of ATB, characterized by duration, timing and type, in the peri-transplant period, is associated with an increased incidence of acute GvHD (aGvHD) and aGvHD-related mortality. In this retrospective study, we included 318 consecutive patients who underwent allo-SCT including haploidentical and cord blood transplantation between December 2012 and June 2018 at a single center. ATB exposure was collected and classified into 3 groups according to the date of initiation of ATB: from the start of conditioning to day - 1 of allo-SCT (early ATB exposure), from day 0 to neutrophil engraftment (late ATB exposure) and a third group of patients who did not receive ATB (no ATB exposure). ATB were only initiated if a patient develop fever or show signs of infection. Patients did not receive any prophylactic ATB. Exposure was further categorized as primary or adjunct. Primary exposure included the use of 4 classes of ATB: carbapenems, anti-pseudomonal penicillin, 4thand 5thgeneration cephalosporins and fluoroquinolones. Adjunct ATB comprised other ATB and was further divided into 2 groups according to anaerobic coverage. The median age at transplant was 55 years. The stem cell source was peripheral blood in 85%, bone marrow in 10% and cord blood in 5% of the patients. Ninety-nine percent of the patients received cyclosporine A as GvHD prophylaxis and 80% and 7% of the patients received (along with cyclosporine A), mycophenolate mofetil and methotrexate, respectively. In addition, 35% and 89% of the patients received post-transplant cyclophosphamide and anti-thymocyte globulin, respectively, as GvHD prophylaxis. The median time to neutrophil engraftment was 16 days post-transplant. The median follow-up was 85 months. 93.7% of the patients received ATB in the peri-transplant period with 64.5% of them in the early ATB exposure group, and 29.2% of them in the late ATB exposure group. The 2-year overall survival and progression free survival were 74.3% and 63.6% in patients with early ATB exposure, compared to 79.5% and 70.8% in patients with late ATB exposure (p=0.11 and p=0.07 respectively). The 2-year cumulative incidence of non-relapse mortality was 16.5% in patients with early ATB exposure, compared to 15.1% in patients with late ATB exposure (p=0.63). The 180-days cumulative incidence of grade 2-4 and 3-4 aGvHD were 23.8% and 12.2% in patients with early ATB exposure, compared to 27.2% and 5.4% in patients with late ATB exposure (p=0.64 and p=0.06 respectively). In multivariate analysis, including the most important parameters associated with GvHD (stem cell source and donors, conditioning regimen, sex mismatch and patients age), early ATB initiation was the only parameter associated with a significantly higher risk of severe grade 3-4 aGvHD [HR 0.51 (0.28-0.90); p=0.02]. In conclusion, in the absence of any ATB prophylaxis, early initiation of ATB, before graft infusion,is associated with a significantly higher risk of severe grade 3-4 aGvHD. Weighing risk of morbidity and mortality associated with infections versus later on risk of developing aGvHD is essential. Hence, new strategies should be developed to risk stratify patients with fever and thus to avoid early non necessary ATB exposure especially in those who develop fever during anti-thymocyte globulin infusion. Studies evaluating such strategies will be necessary in the next years. Disclosures Mohty: Jazz Pharmaceuticals: Honoraria, Research Funding. Malard:Astellas: Honoraria; JAZZ pharmaceutical: Honoraria; Sanofi: Honoraria; Keocyte: Honoraria; Janssen: Honoraria; Therakos/Mallinckrodt: Honoraria.

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Influence of Human Leukocyte Antigen Haplotypes on Acute Graft Versus Host Disease Incidence after Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v108.11.2887.2887 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2887-2887

Author(s):

Sameer Gupta ◽

Charu Aggarwal ◽

Philip L. McCarthy ◽

Swaminathan Padmanabhan ◽

Minoo Battiwalla ◽

...

Keyword(s):

Stem Cell ◽

Human Leukocyte ◽

Hematopoietic Stem ◽

Hla Alleles ◽

Leukocyte Antigen ◽

Graft Versus Host ◽

Stem Cell Source ◽

Gvhd Prophylaxis ◽

Cell Source ◽

Hla Haplotypes

Abstract There is increasing evidence that the Human Leukocyte Antigen (HLA) alleles may influence the incidence of acute graft versus host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). Differential presentation of recipient antigens to donor-derived T-cells by the respective HLA molecules may be a responsible factor. We have reported a decreased rate of aGVHD in HLA DR15 positive patients (pt) undergoing alloHSCT for myeloid malignancies (Blood, 2006; 107:1970). We investigated the influence of different HLA alleles and the three most common HLA haplotypes in US Caucasians on grade 2–4 acute GVHD (graded using published criteria) in HLA matched alloHSCT. We conducted a retrospective review of 195 related and 70 unrelated consecutive first myeloablative alloHSCT pt treated from 01/1992 to 4/2005 at our center. HLA typing was determined by either molecular (n=176) or serologic (n=89) methods. Pt characteristics included: AML (n=84), CML (n=62), NHL (n=47), ALL (n=41), MDS (n=20), HD (n=7) and CLL (n=4); median age 39 years (range 6–66), < 40 years (n=130); Male (n=168), Female (n=97); Caucasian (>95%); Donor-Recipient Sex Mismatch (n=112); Total Body Irradiation (TBI) conditioning regimens (n=205); Etoposide/Cyclophosphamide(Cy)/TBI (n=122), Busulfan(Bu)/Cy (n=28), Bu/TBI (n=27), Thiotepa/TBI (n=23), Cy/TBI (n=22), Fludarabine/Melphalan (n=8), Thiotepa/Carboplatin (n=8) or other combinations (n=27) and peripheral blood stem cell source (n= 35). HLA Haplotypes analyzed for their effect on aGVHD were A1B8DR3 (n=25), A3B7DR15 (n=20) and A2B44DR4 (n=13). There was no significant difference in the pt characteristics (donor relation, conditioning regimen, donor-recipient sex match, diagnosis, age, gender, performance status, disease status at transplant, stem cell source and GVHD prophylaxis) by each of the three haplotypes. We analyzed prior published HLA alleles that were associated with an increased or decreased risk of aGVHD and pt characteristics for their effect on grade 2–4 aGVHD incidence. By univariate analysis, donor relation (unrelated vs. related, 52% vs. 38%, p=0.0002), HLA A2 (44% vs. 33%, p=0.05) and HLA B8 were associated with increased aGVHD (61% vs. 37%, p=0.005) whereas HLA B18 was associated with decreased aGVHD (19% vs. 43%, p=0.017) in contrast to prior reports using serological typing only. By multivariate analysis, HLA A2 (RR=1.5, 95%CI: 1.0 to 2.2, p=0.04), HLA B8 (RR=1.9, 95%CI: 1.1 to 3.0, p=0.01) and unrelated donor (RR= 1.9, 95%CI: 1.3 to 2.9, p=0.001) were associated with increased aGVHD. HLA haplotype multivariate analysis demonstrated increased risk of aGVHD with haplotypes A1B8DR3 and A2B44DR4 (A1B8DR3: 64% vs. 32%, RR 2.6, 95% CI: 1.1 to 5.9, p=0.012 and A2B44DR4: 61% vs. 39%, RR 3.5, 95% CI: 1.7 to 7.5, p=0.04) whereas haplotype A3B7DR15 had less aGVHD compared to others (18% vs. 42%, RR 0.31, 95%CI: 0.098 to 0.98, p=0.049). This is the first published report of the effect of HLA haplotypes on aGVHD incidence. Results of our haplotype analysis substantiate our findings of single allele effects of HLA A2, HLA B8 and HLA DR15 suggesting a differential effect on aGVHD incidence. The ability to predict aGVHD after alloHSCT using HLA haplotypes may improve outcomes by allowing for individualized GVHD prophylaxis regimens.

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Impact of Cyclosporine a (CsA) Concentration on the Incidence of Severe Acute Graft-Versus-Host Disease (GVHD) after Allogeneic Stem Cell Transplantation (allo-SCT).

Blood ◽

10.1182/blood.v112.11.1150.1150 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1150-1150

Author(s):

Florent Mallard ◽

Eolia Brissot ◽

Patrice Chevallier ◽

Thierry Guillaume ◽

Jacques Delaunay ◽

...

Keyword(s):

Stem Cell ◽

Blood Concentration ◽

Acute Gvhd ◽

Conditioning Regimen ◽

Solid Organ ◽

Stem Cell Source ◽

Cell Source ◽

Trough Blood ◽

Grade 3 ◽

Severe Grade

Abstract CsA is widely used as the backbone immunosuppressive agent for GVHD prevention after allo-SCT. Previous studies have demonstrated that the immunosuppressive effects of CsA (eg. inhibition of calcineurine in lymphocytes) may be correlated with CsA blood concentration, especially in the context of solid organ transplantation. This report aimed to investigate the impact of CsA concentrations in the early post allo- SCT period, on the incidence of severe acute GVHD, in 85 consecutive patients treated in a single centre between Jan. 2006 and Jan. 2008, and for whom CsA concentrations in the blood were monitored weekly after the start of infusion. 85 patients (45 males) received CsA (usually at 3 mg/Kg/d, 2 or 3 days prior to graft infusion) as a 24-h continuous infusion until hematopoietic recovery and switch to oral formulation. Dose modifications of CsA were performed to maintain adequate trough blood levels and to prevent nephrotoxicity. Patients’ and donors characteristics were as follow: median age: 51 (range, 18–67), 46 (54%) female donors, 33 (39%) myeloid malignancies, 49 (58%) lymphoid malignancies, and 3 cases of SAA. The stem cell source was PBSC in 66 (78%) patients, while bone marrow was used in 19 (22%) patients. 37 (43.5%) were transplanted from a matched related donor, and 48 (56.5%) from a matched unrelated donor. A myeloablative conditioning regimen was used in 24 (28%) patients, and 61 (72%) received a reduced intensity regimen. The median concentrations of CsA in the blood at 1, 2, 3 and 4 weeks after allo-SCT were 348 (range, 172–733), 284 (range, 137–535), 274 (range, 107–649), and 247 (37–695) ng/mL respectively. All patients engrafted at a median of 17 (range, 0–42) days after allo-SCT. With a median follow-up of 16 (range, 5–29) months, grade 2–4 acute GVHD occurred in 36 patients (42%) at a median of 29 (range, 6–100) days after allo-SCT. The incidence of severe grade 3–4 acute GVHD was 23% (95%CI, 14–32%). In this cohort, all acute GVHD risk factors (age, donor-recipient gender, CMV serostatus, ABO compatibility, diagnosis, disease status, stem cell source, donor type, conditioning regimen type, GVHD prophylaxis regimen, CsA concentrations) were assessed. In multivariate analysis, we found that higher whole-blood CsA concentration in the first week following graft infusion, and before onset of acute GVHD was the strongest parameter significantly associated with a reduced the risk of severe grade 3–4 acute GVHD (P=0.01; RR=0.24; 95%CI, 0.08–0.73). Despite its retrospective nature, these data strongly indicate a close relationship between CsA trough blood concentration during the early post allo-SCT period and the severity of acute GVHD. Inadequate or insufficient early exposures of CsA can be a serious risk for developing severe acute GVHD. Therefore, precise monitoring of CsA concentrations and achievement of a high CsA target concentration may be an effective tool to prevent the onset of severe acute GVHD.

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Post Transplant Cyclophosphamide (PTCy) with Anti-Thymocyte Globulin (ATG) Effectively Reduces the Severe (Grade III-IV) Acute Graft-Versus-Host Disease (GVHD) When Compared to ATG Alone in Matched Unrelated Donor (MUD) Allogeneic Hematopoietic Cell Transplants

Blood ◽

10.1182/blood.v128.22.3430.3430 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3430-3430 ◽

Cited By ~ 1

Author(s):

Uday Deotare ◽

David Loach ◽

Fotios V. Michelis ◽

Dennis D. Kim ◽

Santhosh Thyagu ◽

...

Keyword(s):

Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Historical Cohort ◽

Stem Cell Source ◽

Gvhd Prophylaxis ◽

Cell Source ◽

Grade Iii ◽

Severe Grade

Abstract Introduction: Acute Graft-versus-Host Disease (aGVHD) is a frequent complication of Allogeneic Hematopoietic cell transplants (allo-HCT). It can be lethal with increased morbidity and mortality and can occur in upto 40-50% of allo-HCT. Various agents such as calcineurin inhibitors, anti-metabolites and anti T cell antibodies, have been variably used for GVHD prophylaxis. Use of Post-transplant Cyclophosphamide (PTCy) has recently been used extensively in haplo-identical transplant setting with promising results, but has mainly been used in patients with BM as a stem cell source. In those patients receiving PBSC as a stem cell source, PTCy alone could reduce the risk of acute and chronic GVHD significantly. Anti-Thymocyte Globulin (ATG) has been associated with decrease in chronic but not acute GVHD. As most of our patients use PBSC as a graft source, we hypothesized that combination of ATG and PTCy can reduce the incidence of both acute and chronic GVHD. Since we had also used ATG for GVHD prophylaxis in a historical cohort, we compared the results of this approach with the current GVHD prophylaxis regimen. Methods: A total of 28 patients with hematological malignancies, who had an unrelated donor underwent allo-HCT at our center from 1 Oct 2015 to 31 Mar 2016. After interim analysis, when increased non-hematological toxicity was observed with myeloablative conditioning, all patients subsequently received reduced intensity conditioning. Peripheral blood was used as a stem cell source in all patients. The GVHD prophylaxis consisted of a combination of ATG-PTCy-CsA, with rabbit ATG administered on Days -3 (0.5 mg/Kg), -2 (2 mg/Kg) and -1 (2 mg/Kg), PTCy at dose of 50 mg/kg on Days +3 and +4 and CsA from Day+5 onwards. Filgrastim was used from day +7 onwards for 13 patients. Emphasis was given to incidence of acute GVHD, especially Steroid Refractory (SR-GVHD). Results: Out of total of 28 patients, aGVHD was seen in 6 (21.4%) patients, five of which had skin involvement (Grade I- II) and one suspected liver involvement (Grade III), all of which responded rapidly to steroids with no cases of SR-GVHD. Secondary graft failure and EBV reactivations; each were seen in 10% of cases. Primary disease relapse was seen in 3 patients, two of which had minimal residual disease prior to transplantation. These results were then compared to the historical cohort of 27 patients who received a combination of ATG-CsA plus Mycophenolate Mofetil (MMf) (Table 1). The incidence of acute GVHD was 26% vs 22% (p=0.99), with severe Grade III-IV aGVHD of 4% vs 20% (p=0.085) in the ATG-PTCy-CsA and ATG-CsA-MMf cohorts, respectively; both were statistically not signifcant. There were five patients with SR-GVHD in the ATG-CsA-MMf cohort and none in the current GVHD prophylaxis arm. In the historical cohort, the main cause of death in 7 out of 11 patients was severe GVHD as compared to 1 out of 9 in the ATG-PTCy-CsA cohort. Conclusions: Combination of ATG-PTCy-CsA is an effective strategy to reduce aGVHD; especially severe Grade III-IV and doesnot increase the risk of SR-GVHD, in unrelated donor transplants as compared to ATG-CsA-MMf. However, a long term follow up is needed to assess relapse and cGVHD. Disclosures No relevant conflicts of interest to declare.

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Donor Clonal Hematopoiesis Increases Risk of Acute Graft Versus Host Disease after Matched Related Transplantation in AML and MDS Patients

Blood ◽

10.1182/blood-2019-127195 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 47-47 ◽

Cited By ~ 1

Author(s):

Betul Oran ◽

Richard E. Champlin ◽

Feng Wang ◽

Nikeshan Jeyakumar ◽

Guillermo Garcia-Manero ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Hematopoietic Stem ◽

Graft Versus Host ◽

Transplant Outcomes ◽

Stem Cell Source ◽

Gvhd Prophylaxis ◽

Increased Risk ◽

The Impact ◽

Homogenous Population

Background: After the introduction of reduced intensity conditioning (RIC) regimens, older patients became eligible for allogeneic hematopoietic stem cell transplantation (HSCT) with a parallel increase in the use of older sibling donors. Clonal hematopoiesis of indeterminate potential (CHIP) is associated with older age and an increased risk of myeloid malignancies and cardiovascular complications. The impact of using older donors with CHIP on transplant outcomes have not been well-established. In this study, we investigated the association between donor-CHIP and transplant outcomes in acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) patients who underwent HSCT from older donors (age >= 55). Methods: Of 421 AML/MDS patients who underwent their first allogeneic HSCT from an older donor aged ≥55 from 2000- 2018, DNA samples were available from 363 healthy older donors at the time of stem cell donation. We performed targeted deep sequencing of 300 genes on donor blood samples and identified CHIP using modified Mutect and Pindel algorithms. We excluded variants with allele frequency < 2%. After describing the distribution of CHIP among healthy older donors, we investigated the impact of donor CHIP on HSCT outcomes in a more homogenous population. We restricted clinical outcome analyses to 302 patients who underwent first allogeneic HSCT using a matched related donor (MRD), with peripheral blood stem cells (PBSCs) as the hematopoietic stem cell source. In this cohort, 90% of patients received tacrolimus/methotrexate for graft versus host disease (GvHD) prophylaxis. Results: Among 363 donors, 71 (20%) were found to have CHIP. The most frequently mutated genes as CHIP were DNMT3A (32/71, 45%), TET2 (18/71, 25%), PPM1D (8/71, 11%), and SXL1 (7/71, 10%). Of 71 CHIP donors, 63 (89%) had single mutation, while 8 (11%) had two mutations. There were no significant difference in recipients' disease status or transplant characteristics by donor CHIP status (Table 1). The presence of CHIP increased with donor age; the prevalence was 15% in donors aged 55-59, 16% aged 60-64, 32% aged 65-69 and 27% aged ≥70. Transplant outcomes including engraftment rate, time to neutrophil and platelet recovery, progression incidence, progression-free survival (PFS) and overall survival (OS) were comparable by donor CHIP status (Figure) in the 302 patients with older MRDs and PBSCs as the stem cell source. Of note, disease and transplant characteristics were similar for comparison groups. Cumulative incidence (CI) of grade 2-4 and 3-4 acute GvHD (aGvHD) at 6 months after transplant was higher with donor CHIP (HR=2.1, 95%CI=1.4-3.3, p<0.001 and HR=2.9, 95%CI=1.3-6.3, p=0.009) To further investigate the impact of donor CHIP on aGvHD, we investigated the interaction of donor CHIP with older donor age. Within healthy donors aged ≥65, CHIP increased the risk of grade 2-4 and 3-4 aGvHD (HR=2, 95%CI=1.1-3.5, p=0.01 and HR=3.5, 95%CI-1.1-10, p=0.03). The impact was similar in donors aged <65 with increased grade 2-4 and 3-4 aGvHD by CHIP (HR=2.1, 95% CI=1.1-4.4, p=0.04 and HR=2.4, 95%CI=0.6-9.5, p=0.2). Despite the increased aGvHD, we did not observe increased incidence of chronic GvHD by donor CHIP. Conclusion: In this relatively homogenous population of AML/MDS patients who were transplanted after RIC with PBSCs from older matched related donors and who received tacrolimus-based GvHD prophylaxis, donor CHIP was associated with significantly increased risk of grade 2-4 and 3-4 aGvHD. Engraftment, progression risk and overall survival were not affected. Further studies to investigate the molecular mechanism of increased aGvHD and therapeutic interventions to improve aGvHD in the context of donor CHIP are warranted. Disclosures Oran: AROG pharmaceuticals: Research Funding; Astex pharmaceuticals: Research Funding. Champlin:Sanofi-Genzyme: Research Funding; Actinium: Consultancy; Johnson and Johnson: Consultancy. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Jazz Pharma: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Popat:Jazz: Consultancy; Incyte: Research Funding; Bayer: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy.

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Does Polyoma (BK) Virus Contribute to Development of Hemorrhagic Cystitis (HC) in Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation (UD HSCT) Recipients? A Prospective Evaluation.

Blood ◽

10.1182/blood.v108.11.5282.5282 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5282-5282

Author(s):

Poliana A. Patah ◽

Nicholas A. Szewczyk ◽

Lisa Gilman ◽

Alison Gulbis ◽

Joyce Neumann ◽

...

Keyword(s):

Stem Cell ◽

Hemorrhagic Cystitis ◽

Bk Virus ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Stem Cell Source ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Grade 3 ◽

Hodgkin's Lymphomas

Abstract BK virus infection is highly prevalent in humans, and has been associated with development of HC after HSCT. Previously we determined that UD HSCT is independently associated with higher prevalence of HC (El-Zimaity et al. Blood 2004). In order to further investigate the association of BK with HC, we hypothesized that patients who have positive urine PCR for BK virus before UD transplant have a higher incidence of HC. Methods: we studied 62 consecutive patients transplanted from 09/05 to 05/06. Preparative regimens were ablative (n=26) or reduced intensity (n=36); 15 patients (23%) received cyclophosphamide-containing regimens. GVHD prophylaxis was tacrolimus and mini-methotrexate. Stem cell source was bone marrow (n=28), peripheral blood (n=25) or umbilical cord (n=9). BK virus quantitative PCR was performed on urine samples collected upon admission. Results: Median age was 53 years (range, 19–67). Diagnoses were leukemias (n=36), multiple myeloma (n=2), Hodgkin’s disease (n=4), non-Hodgkin’s lymphomas (n=16), and other (n=4). Median time to platelet engraftment was 16 days (range, 0–62; n=51). Median follow-up is 97 days. BK PCR was positive in 28 patients (45%). Number of viral copies ranged from 300 to > 200 million copies. Eleven patients (18%) developed HC, at a median of 25 days after HSCT. HC was of grade 1 (n=1), grade 2 (n=4), grade 3 (n=5), grade 4 (n=1; required bilateral nephrostomies). In the PCR positive group, 7 patients (25%) had HC, versus 4 (12%) in the PCR-negative group (hazard ratio = 3.4 for a positive PCR; log-rank p = 0.057). 100-day cumulative incidence of HC is shown in the figure. 45% of CB recipients developed HC. Incidence of HC was not statistically significantly increased among recipients of ablative or cyclophosphamide-containing regimens. Likewise, development of grade II-IV acute GVHD (n=18, 29%) was not associated with higher rates of HC. Six patients developed HC before platelet engraftment. Viral load did not correlate with development of HC. Four patients had viruria of 50–200million/mL; only one developed HC. Conclusion: BK viruria pre-HSCT may be a risk factor for development of HC; further study is needed in a large cohort of patients. Figure Figure

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Antithymocyte Globulin and Role Of Stem Cell Source On Outcome In Myeloablative Conditioning Of Allogeneic Hematopoietic Stem Cell Transplantation With Identical Sibling and Matched Unrelated Donors - A Retrospective Study Of French Society Of Bone Marrow Graft Transplantation and Cellular Therapy -

Blood ◽

10.1182/blood.v122.21.3382.3382 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3382-3382

Author(s):

Aurélie Ravinet ◽

Aurélie Cabrespine ◽

Regis Peffault de la Tour ◽

Mauricette Michallet ◽

Ibrahim Yakoub-Agha ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Antithymocyte Globulin ◽

Myeloablative Conditioning ◽

Hematopoietic Stem ◽

Stem Cell Source ◽

Gvhd Prophylaxis ◽

Cell Source

Abstract Objectives Allogeneic hematopoietic stem cell transplantation (AHSCT) is an effective treatment modality for a number of hematological malignancies. Several retrospective studies demonstrate that the addition of antithymocyte globulin (ATG) to standard GvHD prophylaxis in myeloablative conditioned AHSCT resulted in a reduction of the incidence of acute and chronic GvHD. However the impact of rabbit ATG incorporated within a standard myeloablative conditioning regimen (MAC) prior to AHSCT on overall survival (OS) has never been clearly assessed. The purpose of this study is to evaluate retrospectively the long term influence of ATG on OS in a large cohort. Methods All AHSCT with matched sibling donor (MSD) and matched unrelated donor (MUD) performed between 2001-2010 in France and reported to Promise database were retrospectively studied. Patients fulfilling the requirements for this study had received a MAC such as total body irradiation (TBI)-cyclophosphamide or busulfan-cyclophosphamide (Bu-Cy) with or without ATG. Results 1980 AHSCT were reported in 32 transplant centers. One hundred and fifty (8%) patients received ATG (25 with MSD and 125 with MUD), whereas 1830 (92%) did not receive ATG (1441 with MSD and 389 with MUD). Diagnosis were 1452 acute leukemia (73%), 340 myelodysplasia (MDS) and/or myeloproliferative syndrome (MPS) (17%), 157 lymphoma (8%), 9 myeloma and 21 chronic lymphocytic leukemia (CLL) (2%). 1385 patients received a TBI 12 Gy based regimen with cyclophosphamide whereas 595 patients received Bu-Cy. Bone marrow (1468 patients) or peripheral blood stem cells (512 patients) were infused 24-48h after the last cyclophosphamide administration (day 0). Median age at transplantation was 37.5 years in the ATG group and 39.2 years in the non ATG group. Median follow-up was of 79.8 months [19.2-138.8]. Using multivariable analysis, OS was adversely significantly influenced by age of recipient older than 39.1 years, bone marrow stem cell source, MUD, non-complete remission status before HSCT, GvHD grade 2-4, age of donor older than 38.3 years and the use of GvHD prophylaxis other than cyclosporine and methotrexate. ATG was not an independent variable influencing OS. The use of different model of multivariate analyses including propensity score trends to demonstrate that the influence of ATG on OS remain strongly correlated to donor type (MSD vs MUD). According to our results, patient with MSD presented better OS (not reached) than patient with MUD (37 months) (p<0.01). Interestingly, OS rates were lower in the ATG group compared to the non ATG group for patients who received bone marrow (median OS 81 months vs 112 months p=0.033). In this group, in the long term, patients who received ATG trend to have more relapse (median PFS 22 months vs 69 p=0.015). This difference is not observed for patient who received peripheral blood (PB), probably because PB induces more GvHD (49% vs 41%, p=0.001), which is usually correlated with less relapse. In this group, the use of ATG or not has no impact on OS. Conclusion The use of ATG does not influence OS. However, this use is strongly influenced by stem cell source with a negative impact of ATG for the group of patients who received BM. Its usefulness should be discussed. Disclosures: No relevant conflicts of interest to declare.

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Refined Graft-Versus-Host Disease-Free, Relapse-Free Survival after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Intermediate and Unfavorable Prognosis Acute Myeloid Leukemia Ttransplanted in First Complete Remission from HLA-Identical Related or Unrelated Donors: A Retrospective Study on Behalf of the ALWP of the EBMT

Blood ◽

10.1182/blood.v128.22.4643.4643 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4643-4643

Author(s):

Giorgia Battipaglia ◽

Annalisa Ruggeri ◽

Myriam Labopin ◽

Liisa Volin ◽

Didier Blaise ◽

...

Keyword(s):

Stem Cell ◽

Myeloid Leukemia ◽

Relapse Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Graft Versus Host ◽

Stem Cell Source ◽

Cell Source ◽

Grade Ii

Abstract The refined endpoint of graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) represents an important measure of outcomes of allogeneic hematopoietic stem cell transplant (HSCT) including both clinical results and quality of life without ongoing morbidity. We analyzed the refined GRFS in 5059 patients with de novo acute myeloid leukemia (AML) with intermediate and unfavorable cytogenetics in first complete remission (CR1), undergoing HSCT from a matched sibling (MSD, n=3731) or unrelated donor (UD, n=1328). HSCT were performed between 2000 and 2015 and reported to EBMT. Median age for the whole population was 49 years (range 18-76) There were statistical differences between the 2 groups: compared to MSD, UD recipients were younger (60 vs 32 years, p<0.01), had more often a male donor (54% vs 69%, p<0.01), had a longer interval from diagnosis to HSCT (140 vs 168 days, p<0.01) and were more often transplanted from a CMV negative donor (62% vs 41%, p<0.001). UD recipients received more often reduced intensity conditioning regimen (59% vs 47%, p<0.01), in vivo T-cell depletion (TCD) (72% vs 26%, p<0.01) and peripheral blood stem cells (PBSC) (79% vs 74%, p<0.01). Median follow up was longer for MSD recipients (60 vs 32 months, p<0.01) In univariate analysis, cumulative incidence (CI) of relapse (RI) was 25% in both groups (p=0.89); UD recipients experienced a higher CI of grade II-IV acute GVHD (aGVHD, 26% vs 23%, p<0.01), of extensive chronic GVHD (cGVHD, 23% vs 19%, p<0.01), non-relapse mortality (NRM, 12% vs 15%, p<0.01) and had a lower probability of leukemia-free survival (LFS, 60% vs 63%, p<0.01) and of overall survival (OS, 65% vs 69%, p<0.01). Probability of GRFS at 4 years was not different, being 44% in both groups (p=0.9). Regardless the donor type, probability of 4-year GRFS was higher in patients receiving in-vivo TCD (48% vs 41%, p<0.01), with the use of myeloablative conditioning (45% vs 40%, p<0.01), in patients aged less than median age (47% vs 40%, p<0.01), in patients with intermediate risk cytogenetics (47% vs 33%, p<0.01), when interval from diagnosis to HSCT was higher than 5 months (45% vs 41%, p<0.03), when bone marrow was used as stem cell source (49% vs 41%, p<0.01), in female recipients (46% vs 41%, p<0.01). In a multivariate analysis adjusted for the differences between the 2 groups, UD was associated with lower GRFS (HR 1.19, CI 1.07-1.31, p<0.01), higher risk of grade II-IV aGVHD (HR 1.79, CI 1.53-2.09, p<0.01) and extensive cGVHD (HR 1.42, CI 1.19-1.69, p<0.01), higher NRM (HR 1.64, CI 1.34-1.99, p<0.01) and OS (HR 1.13, CI 1.00-1.28, p<0.01). The other factors independently associated with GRFS were unfavorable cytogenetics (HR 1.42, p<0.01), time from diagnosis to HSCT (HR 0.96, p<0.01), male recipients from female donors (HR 1.23, p<0.01), PBSC as stem cell source (HR 1.22, p<0.01), use of in-vivo TCD (HR 0.73, p<0.01). Unfavorable cytogenetics was associated with lower LFS (HR 1.64, CI 1.50-1.81, p<0.01) and OS (HR 1.68, CI 1.53-1.86, p<0.01) and higher RI (HR 1.94, CI 1.73-2.17, p<0.01). When performing a subgroup analysis according to the use (n=1955) or not (n=3104) of in-vivo TCD, GRFS was not different in the two groups (47% vs 48%, p=0.54). GRFS was lower in UD recipients not receiving in-vivo TCD (37% vs 41%, p<0.02). In multivariate analysis, a lower GRFS was observed in UD versus MSD when in-vivo TCD was not used (HR 1.23, CI 1.05-1.43, p<0.01), while no significant differences were found for those receiving in-vivo TCD. Unfavorable cytogenetics was associated to a worse GRFS in both groups. In conclusion, UD transplant is associated with lower GRFS, probably due to higher incidence of GVHD and NRM. Importantly, in-vivo TCD might improve outcomes of UD recipients, leading to a GRFS comparable to MSD recipients. Moreover, in AML in CR1, unfavorable cytogenetics remains a strong predictor of worse outcomes either in MSD and UD recipients as compared to intermediate cytogenetics. Disclosures Maertens: Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Amgen: Consultancy; Gilead: Consultancy, Honoraria, Speakers Bureau.

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Family Mismatched Donor Transplantation for Myelofibrosis: A Retrospective Analysis of the EBMT Chronic Leukaemia Working Party

Blood ◽

10.1182/blood.v128.22.4655.4655 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4655-4655 ◽

Cited By ~ 1

Author(s):

Kavita Raj ◽

Eduardo Olavarria ◽

Diderik-Jan Eikema ◽

Liesbeth C de Wreede ◽

Linda Koster ◽

...

Keyword(s):

Stem Cell ◽

Cumulative Incidence ◽

Graft Failure ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Stem Cell Source ◽

Gvhd Prophylaxis ◽

Cell Source ◽

Mismatched Donor

Abstract Background: Allogeneic stem cell transplantation is a treatment option for patients with advanced myelofibrosis. Problems encountered include an increased risk of delayed or poor engraftment and in the mismatched unrelated donor setting a higher rate of GVHD and particularly poor outcomes. As for other indications for allogeneic stem cell transplants, patients for whom either a matched sibling or matched unrelated donor is not available are considered for either a double umbilical cord blood, a mismatched unrelated donor or haploidentical stem cell transplant. Data on the latter option are limited and we reviewed registry data on all family mismatched donor transplants performed between 2001 and 2015 and reported to the EBMT registry. Results: Records retrieved 69 patients with myelofibrosis transplanted between November 2001 and November 2015. 44 (64%) were male. 50 (74%) had primary myelofibrosis,18 (27%) had secondary myelofibrosis (6 from ET, 5 from PRV and 7 others) and unknown 1(2%). Of 25 patients for whom the JAK2 V617F mutation status was known, 15 (22%) harboured the mutation. Patient Karnofsky performance status was > 70% in 98%. Of the mismatched family donors, 47 (68%) were male and 22 (31%) female. Donors were HLA mismatched at 1 locus in 12 (17%) and 2 or more loci in 48 (69%). Donor-recipient serology combinations were CMV -/- in 8 (12%), +/- in 4 (6%), -/+ in 15 (22%) and +/+ in 34 (49%) missing 8 (12%). Bone marrow was the stem cell source in 34 (49%) and peripheral blood in 35 (51%). The median total nucleated cell count (TNC) infused was 7.5x108/kg (range 2.3-21x108/kg) from data available in 17 patients. The median CD34+ cell dose was 6.9x106/kg (range 1.9-18.18x106/kg) from data available in 19 patients. Conditioning was myeloablative in 48 (70%) and RIC in 21 (30%) The conditioning regimes were varied but the predominant ones were Fludarabine, Busulphan, ATG (FBATG) and Thiotepa, Busulphan, Fludarabine (TBF). TBI was administered in 8 (12%) and in vivo T cell depletion in 22 (32%), ex-vivo T cell depletion in 5 (7%) patients. GVHD prophylaxis varied with post transplant Cyclophosphamide administered in 34/67 (49%) and ATG in 19/67 patients (28%). Neutrophil engraftment was established in 53 (82%) at a median of 20 days (range 11-83). Primary graft failure occurred in 8 (12%) and secondary graft failure in 4 (6%). This occurred at a median of 12 months (range 4.5-35 months). Eleven of these patients had a second allograft at a mean interval of 6.4 months. Responses to the first allograft (censoring for patients who had a second allograft) with data available in 45 patients, showed that complete remission was achieved in 35 patients (78%), 6 (13%) were never in CR and 4 (9%) were not evaluable. The cumulative incidence of grade II-IV acute GvHD at 100 days was 12% (95% CI 4-21%) and for grade III-IV acute GvHD at 100 days it was 5% (95% CI 3-11%). Data for chronic GVHD was valid in 49 patients. The cumulative incidence of chronic GvHD at 2 years was 62% (95% CI 47-76%). The cumulative incidence of limited cGvHD was 45% (95% CI 31-59%) whereas the cumulative incidence of extensive cGvHD was 10% (95% CI 2-19%). The median follow up was 24 months (95% CI 13-35 months). The 2-year OS was 51% (95% CI 37-76%) and the 5-year OS was 38% (95% CI 21-55%). The 2-year RFS was 44% (95% CI 30-59%) and the 5-year RFS was 31% (95% CI 15-48%). The 2 year cumulative incidence of relapse was 14% (95% CI 5-24%). The 2 year NRM was 41% (95% CI 28-55%), which increased to 54% (95% CI 37-72%) at 5 years. The main causes of death were infection (16, 24%), GVHD (7, 10%) organ damage or failure (3, 5%), relapse/disease progression (1, 2%) and secondary malignancy or PTLD (1, 2%). On univariate analysis there was no significant effect of recipient gender, donor gender, degree of HLA mismatch 1 vs >1 Ag MM, CMV matching between donor and recipient, primary or secondary MF, disease stage at transplant (chronic versus advanced phase), conditioning intensity, conditioning regimen, GVHD prophylaxis with ATG or post transplant cyclophosphamide or stem cell source on overall survival. Conclusion: Concerns regarding engraftment and secondary graft failure have excluded patients with myelofibrosis from clinical trials of mismatched related donor transplant. The data suggest that engraftment is feasible, and PFS and OS can be attained with limited severe chronic GVHD with family mismatched donors in this setting. Disclosures Ciceri: MolMed SpA: Consultancy.

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A consideration for efficient unrelated hematopoietic stem cell source acquisition—from an experience of Japan

Bone Marrow Transplantation ◽

10.1038/s41409-019-0542-0 ◽

2019 ◽

Vol 55 (3) ◽

pp. 657-660

Author(s):

Satoshi Nishiwaki ◽

Koichi Miyamura ◽

Yoshinobu Kanda ◽

Minoko Takanashi ◽

Naoyuki Uchida ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Hematopoietic Stem ◽

Stem Cell Source ◽

Cell Source

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ORAL CYCLOSPORINE AS AN ALTERNATIVE FOR INITIAL STANDARD PROPHYLAXIS IN ALLOGENEIC STEM CELL TRANSPLANTATION WHEN INTRAVENOUS FORMULATION IS UNAVAILABLE

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i12.27049 ◽

2018 ◽

Vol 11 (12) ◽

pp. 108

Author(s):

Eucario Leon-rodriguez ◽

Monica M Rivera-franco

Keyword(s):

Stem Cell ◽

Care Center ◽

Tertiary Care ◽

Gender Disparity ◽

Hematopoietic Stem ◽

Entire Cohort ◽

Graft Versus Host ◽

Gvhd Prophylaxis ◽

Oral Group ◽

Acute Graft

Objective: The objective of the study was to compare the incidence of acute graft versus host disease (aGVHD) between oral and intravenous (IV) initial standard cyclosporine A (CsA) prophylaxis in a tertiary care center in Mexico.Methods: A total of 117 consecutive patients who underwent allogeneic hematopoietic stem cell transplantations (HSCT) were retrospectively analyzed. GVHD prophylaxis consisted of CsA and methotrexate (MTX). CsA was administered IV, until 2005, when it was withdrawn from the market, and CsA was administered orally.Results: Most of the patients were male (55%), with a median age of 33 years (range, 15–63). 92 patients (79%) received CsA orally, and 25 (22%) intravenously. There were no significant differences in CsA concentrations during weeks 1, 2, 3, and 4 between the oral and IV group. From the entire cohort, 1 patient (4%) from the IV group and 16 (17%) from the oral group developed aGVHD, respectively. Sex, gender disparity, and HSCT source were statistically associated with aGVHD in the multivariate analysis.Conclusions: Using oral instead of IV CsA for aGVHD prophylaxis is feasible and could be financially efficient; nonetheless, our results showed a higher incidence of aGVHD in the oral group; however, our study has limitations and further prospective studies including a larger cohort are encouraged.

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