Transplant Outcomes in Patients with Ph+ Chronic Myeloid Leukemia: Haploidentical Donors Compared to Matched Sibling Donors and Matched/Mismatched Unrelated Donors: A Retrospective Analysis from the EBMT Chronic Malignancies Working Party (EBMT-CMWP)

Abstract Introduction: The role of allogeneic hematopoietic cell transplantation (allo-HCT) in Philadelphia-positive chronic myeloid leukemia (Ph+ CML) changed profoundly after the introduction of tyrosine kinase inhibitors (TKIs). Nevertheless, allo-HCT still represents the preferred treatment option for selected high-risk patients in Europe, with TKI resistance as the most common indication in first chronic phase (CP1). Reported survival outcomes for patients transplanted in CP1 with matched related (MRD), matched unrelated (MUD) and mismatched unrelated donors (MMUD) are generally good, but there are no published data on transplants from haploidentical donors (HD). In this retrospective study, we aimed to compare HD outcomes with those using MRD/MUD/MMUD. Patients and Methods: Patients who had received a first allo-HCT for Ph+ CML between 2012 and 2019 were selected from the EBMT database. Following the exclusion of patients transplanted using MRD, MUD, or MMUD and who received post-Cy GvHD prophylaxis, 1686 patients were included in the analysis. The impact of donor type on overall survival (OS) and relapse-free survival (RFS) was assessed using the Kaplan-Meier method; the cumulative incidence of relapse (REL) and non-relapse mortality (NRM) were estimated as competing events. Univariate comparisons were tested by log-rank or Gray's test, as appropriate. Cox proportional hazard models were applied to compare the risk of OS, RFS, REL and NRM in patients transplanted from MRD, MUD, MMUD and HD, adjusted for baseline disease and transplant characteristics, and to analyze the cause-specific hazard of NRM and REL. Two-sided p values of p<0.05 were considered statistically significant. Results: Overall, the median age at transplant was 46 years (range 18-74). 62% were male. The median interval from diagnosis to transplant was 17.5 months. Disease status at transplant was CP1 in 43%, CP2 or later in 27%, accelerated phase (AP) in 12%, and blast phase (BP) in 18%. Karnofsky Performance Status (KPS) was ≥90 in 78% of patients. Donor was MRD in 661 patients (39.2%), MUD in 677 (40.2%), MMUD in 212 (12.6%) and HD in 136 (8%). The stem cell source was peripheral blood (PB) in 84% (52% in HD, p<0.001). Reduced intensity conditioning (RIC) was used in 33%. Median time to neutrophil engraftment was 18 days in HD, and 16 days in MRD/MUD/MMUD transplants. Median time to platelet (>20 x 10 9/L) engraftment was 25 days in HD, 14 days in MRD/ MUD and 15 days in MMUD transplants. 53% of patients were serologically CMV positive pre-transplant. The cumulative incidence of grade II-IV acute GvHD at Day +100 was 25%, 27%, 31% and 39% in HD, MRD, MUD and MMUD, respectively (p=0.008). Chronic GvHD at +60 months was observed in 36%, 49%, 40% and 48% in HD, MRD, MUD and MMUD transplants (p=0.006), respectively. With regard to transplant outcomes at 60 months in HD, MRD, MUD and MMUD, OS was 51%, 51%, 62% and 58% (p=0.22), RFS was 42%, 46%, 51% and 45% (p=0.03, Fig.1), REL was 37%, 35%, 28% and 31% (p=0.064), NRM was 21%, 20%, 21% and 24% (p=0.34), and GVHD-free/relapse-free survival (GRFS) was 23%, 22%, 32% and 26% (p<0.001, Fig.2), respectively. By multivariable analyses (1,482 patients included), poorer OS was associated with older age (HR per 10 year increase 1.12, 95% CI 1.03-1.21, p=0.008), KPS <90 (HR vs ≥90 1.83, 1.51-2.23, p<0.0001), CMV+ status (HR 1.27 1.04-1.55, p=0.02), more advanced disease vs CP1 (p<0.0001); shorter RFS associated with KPS <90 (HR vs ≥90 1.51 1.27-1.80, p<0.0001), RIC (HR vs MAC 1.25, 1.05-1.50, p=0.01), disease status at transplant other than CP1 (overall p<0.0001), and BP vs AP (HR 1.33, 1.01-1.75, p=0.04); higher REL was predicted by KPS <90 (HR 1.54, 1.23-1.93, p<0.0001), RIC (HR vs MAC 1.31, 1.04-1.64, p=0.02) and disease status at transplant ≥CP2 vs CP1 and BP vs AP (p<0.0001); higher NRM was associated with older age (HR per 10 year increase 1.17, 1.05-1.31, p<0.005), KPS <90 (HR 1.47, 1.10-1.96, p<0.001), and PB as stem cell source (HR 1.61, 1.04-2.50, P=0.03). Table 1 shows the hazard ratio of OS, RFS, REL and NRM after transplants in MRD, MUD and MMUD compared to HD. Conclusions: Apart from confirming the stage of disease at transplant as being a major prognostic factor, this study identified a trend to better RFS and GRFS in patients with Ph+ CML transplanted using MUD when compared to MRD/HD/MMUD. These results should be interpreted with caution given the limited number of patients who had HD. Figure 1 Figure 1. Disclosures Byrne: Incyte: Honoraria. Apperley: Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau; Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ganser: Novartis: Honoraria; Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria. Hayden: Amgen: Honoraria; Jansen, Takeda: Other: Travel, Accomodation, Expenses. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.

Download Full-text

Allogeneic Stem Cell Transplantation for Blast Crisis Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors — a Retrospective Study By the EBMT Chronic Malignancies Working Party

Blood ◽

10.1182/blood-2018-99-114592 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3465-3465

Author(s):

Aleksandar Radujkovic ◽

Henric-Jan Blok ◽

Arnon Nagler ◽

Francis Ayuketang Ayuk ◽

Jürgen Finke ◽

...

Keyword(s):

Stem Cell ◽

Prognostic Factors ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Blast Crisis ◽

Disease Status ◽

Advisory Committees ◽

Stem Cell Source ◽

Cell Source

Abstract Introduction: The prognosis of patients diagnosed with blast crisis (BC) chronic myeloid leukemia (CML) is dismal. Allogeneic stem cell transplantation (alloSCT) represents the only curative treatment option. In the current tyrosine kinase inhibitor (TKI) era, however, data on transplant outcomes in patients with BC CML, particularly those with active BC at transplant, are scarce. We hereby report on a multicentre, EBMT-registry based retrospective study of adult patients allografted for BC CML focusing on patients with active disease at transplant and pre-transplant prognostic factors. Patients and methods: Patients with BC CML at transplant (i.e. prior to the start of the conditioning) who underwent alloSCT after the year 2004 within the EBMT database were identified. Next, transplant centers were asked to report the exact disease status at transplant (including blood count, blast count in peripheral blood and bone marrow, achievement and type of remission with corresponding assessment dates, and the reason to proceed with alloSCT in BC CML). A total of 170 patients allografted for BC CML between 2004 and 2016 had complete data for analysis. Overall survival (OS) and leukemia-free survival (LFS) were calculated from date of alloSCT to the appropriate endpoint. For multivariable analysis of predictors of OS and LFS, Cox proportional hazard regression models were performed. Confounding prognostic factors (full models) were: age, disease status prior to alloSCT, Karnofsky performance status (KPS) prior to transplant, interval from diagnosis to transplant, year of transplant, stem cell source, conditioning intensity, donor type, and donor/recipient sex match. All patients provided informed consent for data collection and analysis. Results: Median age at alloSCT was 45 years (range [r], 18-75). Median time from diagnosis to alloSCT was 13.9 months (r, 1.6-367.4). Median follow-up time was 54.7 months (r, 0.1-135.2). Stem cell source was peripheral blood, bone marrow and cord blood in 145 (85%), 18 (11%) and 7 (4%) patients, respectively. Donor types were: unrelated (UD), matched related, and mismatched related in 91 (54%), 64 (38%), and 15 (9%) patients, respectively. Conditioning was myeloablative in 108 (64%) of patients. KPS at alloSCT was ≤80% in 31% of patients. Information on BCR-ABL mutations was available for 41 patients; T315I was present in 28 patients. After thorough analysis of disease parameters, a total of 95 patients had any kind of remission of BC CML (including secondary chronic phase) prior to transplant (termed BC in remission); 75 patients had active BC CML prior to transplant (termed BC active). Main reason for proceeding with alloSCT despite active disease was resistance/refractoriness towards TKI in combination with polychemotherapy. Extramedullary disease was documented in 4 patients. In uni- and multivariable analyses of the entire cohort, besides low KPS, only disease status prior to transplant was significantly associated with shorter OS and LFS (for BC active: HR 2.00, 95%CI 1.35-2.96, p=0.001 and HR 1.80 95%CI 1.27-2.57, p=0.001, respectively). Accordingly, for patients allografted for active BC estimated 3-year OS and LFS was rather short (23.8% 95%CI 13.6-34.0 and 11.6% 95%CI 3.0-20.2, respectively) and significantly lower as compared to patients allografted for BC in remission (3-year OS and LFS: 51.1% 95%CI 40.5-61.7 and 33.8% 95% CI 23.6-44.0, respectively) (Figure 1A and B). Consequently, prognostic factors for survival were analyzed separately according to disease status at alloSCT (slim models, Table 1). For patients with BC in remission at transplant advanced age, lower KPS, shorter interval from diagnosis to transplant, myeloablative conditioning, and UD transplant were risk factors for inferior survival, whereas in patients allografted for active BC, only UD transplant was associated with prolonged LFS and with a trend towards improved OS (Table 1). Conclusion: Survival of BC CML patients after alloSCT in the TKI era remains poor unless disease remission could be achieved. In patients who achieve remission prior to alloSCT, conventional prognostic indicators remain the determinants of transplant outcomes. In patients with active BC CML, UD transplantation appears to be associated with a survival advantage in our study. Disclosures Finke: Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding. Tischer:Jazz Pharmaceuticals: Other: Jazz Advisory Board. Mayer:Eisai: Research Funding; Roche: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding. Byrne:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

Download Full-text

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.

Download Full-text

Conditioning with 8 Gy Total Body Irradiation and Fludarabine for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia: Projected 4-Year Update.

Blood ◽

10.1182/blood.v108.11.3016.3016 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3016-3016

Author(s):

Matthias Stelljes ◽

Martin Bornhaeuser ◽

Matthias Kroger ◽

Joerg Beyer ◽

Maria C. Sauerland ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Myeloid Leukemia ◽

Dna Typing ◽

Relapse Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Unrelated Donors ◽

Total Body ◽

Acute Myeloid

Abstract Seventy-one patients with acute myeloid leukemia (AML), most of them (63/71) considered ineligible for conventional allogeneic hematopoietic stem cell transplantation (HSCT), were enrolled into a phase II study on reduced intensity myeloablative conditioning with fractionated 8 Gy total body irradiation (TBI) and fludarabine (120 mg/m2) (Blood. 2005 Nov 1;106(9):3314–21). Patients received mobilized peripheral blood stem cells (n=68) or bone marrow (n=3) from siblings (n=39) or unrelated donors (n=32). HLA-typing was performed for HLA-A, -B, -Cw (serological matching or intermediate resolution DNA typing), DRB1 and DQB1 (high resolution DNA typing). Three patients had unrelated donors with an allele mismatch in HLA DRB1 (2 with an additional mismatch in HLA Cw) and 7 patients were transplanted from unrelated donors with an antigen mismatch in HLA Cw. Thirty-six patients were transplanted in complete remission (CR) and 35 with untreated or refractory disease (non-CR). Median patient age was 51 years (range, 20–66). Sustained engraftment was attained in all evaluable patients. With a median follow-up of now 41.3 months (range, 20.4–70.4) in surviving patients, probabilities of overall survival for patients transplanted in CR and non-CR were 80% (95% CI, 66 to 94%) and 17% (95% CI, 5 – 29%) at 4 years, respectively. Relapse-free survival rates were 57% (95% CI, 39 – 75%) and 14% (95% CI, 2 – 26%). Of the 35 evaluable patients transplanted in CR, 10 patients suffered a relapse between days 68 and 868 after transplantation (cumulative incidence 29%). Five patients with late relapse (>1 year after transplantation) achieved a subsequent CR after conventional chemotherapy, blood stem cell boost and treatment with granulocyte-macrophage colony-stimulating factor, lasting 2000+, 1841+, 909+, 847+ and 480 days, respectively. Depending on donor type, relapse-free survival was similar in patients transplanted from unrelated or sibling donors. Overall survival in patients transplanted in complete remission from unrelated vs. sibling donors was 84% (95% CI, 73 – 95%) vs. 77% (95% CI, 68 – 86%). The cumulative incidence of non-relapse mortality (NRM) in CR patients was 11% at 4 years and beyond (3 patients deceased before day 100 and 1 patient 25 months after transplantation), but amounted to 37% at 4 years in non-CR patients. Nine of the 33 surviving patients (27%) have actually active chronic GvHD (5 limited and 4 extensive disease). This update confirms that allogeneic HSCT from related or unrelated donors with 8 Gy TBI/fludarabine conditioning is feasible with low NRM and preserved long-term antileukemic activity in AML patients in first or later CR.

Download Full-text

Similar Survival after Bone Marrow Versus Peripheral Blood Stem Cell Transplantation from Matched Unrelated Donors in Children with Hematologic Malignancies.

Blood ◽

10.1182/blood.v106.11.2066.2066 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2066-2066

Author(s):

Roland Meisel ◽

Hans-Juergen Laws ◽

Stephan Balzer ◽

Benedikt Bernbeck ◽

Christof Kramm ◽

...

Keyword(s):

Stem Cell ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Status ◽

Event Free Survival ◽

Free Survival ◽

Stem Cell Source ◽

Detectable Difference ◽

Unrelated Donors ◽

Recipient Age

Abstract Peripheral blood stem cells (PBSC) are increasingly used instead of bone marrow (BM) for allogeneic haematopoietic stem cell transplantation (alloHSCT) in children. Prior studies in adults have suggested a comparable outcome with both stem cell sources in matched unrelated donor (MUD) transplantation. However, relative benefits of PBSC versus BM transplantation may substantially differ in children and adults due to a greater propensity to GvHD in older patients and a higher proliferation rate of blasts in childhood leukemia. Here we present the first comparison of the outcome following PBSC vs. BM transplantation from HLA-matched unrelated donors in an entirely pediatric cohort. Between 1992 and 2004, a total of 61 pediatric patients (pts) with haematologic malignancies underwent PBSC (n=38) or BM (n=23) transplantation from ≥ 5/6 HLA antigen-matched unrelated donors following myeloablative conditioning at our institution. PBSC and BM groups were comparable with regard to GvHD prophylaxis, disease category, disease status at transplant and recipient age, while differences were detected in recipients sex (more male pts in PBSC group, p=0.06), conditioning regimen (more busulfan-based conditioning in PBSC group, p=0.01) and median year of transplant (PBSC transplantations were more recent, p=0.001). Engraftment was achieved significantly faster after PBSC compared to BM transplantation (p=0.001). Median time to neutrophil engraftment was 18 (range: 9–28) and 24 (14–43) days for the PBSC and BM cohort, respectively. The rate of acute GvHD grade III/IV (PBSC vs. BM: 28.9% vs. 19.0%, p=0.54) and chronic GvHD (63.0% vs. 56.3%, p=0.75) was comparable between both groups. While there was a statistically non-significant trend towards increased risk of clinically extensive chronic GvHD following PBSC transplantation (48.1% vs. 25.0%, p=0.2), this did not translate into any detectable difference in treatment-related mortality (PBSC vs. BM: 28.9% vs. 26.1 %) or death of disease (21.7% vs. 21.1%) (p=1.0). With a median follow up of 3.4 years (PBSC) and 10.0 years (BM) overall survival (PBSC vs. BM: 47.5 ± 8.6 % vs. 51.8 ± 10.5 %; p = 0.88) and event-free survival (43.3 ± 8.3 % vs. 51.8 ± 10.5 %; p = 0.60) is without detectable difference between both groups. This result was confirmed in a multivariate analysis including stem cell source, recipient age, recipient sex, conditioning regimen, disease status at transplant and year of transplant as covariates, showing that advanced disease status at transplant is the only significant, independent risk factor for overall mortality (RR 2.4, 95%-CI 1.1–5.2, p=0.02). In conclusion, our data provide evidence that in pediatric recipients of MUD transplantation the use of PBSC instead of BM leads to a faster neutrophil engraftment and a trend towards higher incidence of extensive chronic GvHD. As overall survival and event-free survival is comparable when using PBSC and BM, PBSC is a valid alternate stem cell source for pediatric alloHSCT from MUDs. Supported by the Elterninitiative Kinderkrebsklinik e.V., Duesseldorf

Download Full-text

Bone Marrow Versus Mobilized Peripheral Blood Stem Cells for Non T Depleted Haploidentical Transplantations with Post Transplantation Cyclophosphamide in Acute Lymphoblastic Leukemia: On Behalf of the ALWP of the EBMT

Blood ◽

10.1182/blood-2019-121644 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 589-589

Author(s):

Arnon Nagler ◽

Myriam Labopin ◽

Emanuele Angelucci ◽

Yener Koc ◽

Mutlu Arat ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Lymphoblastic Leukemia ◽

Advisory Board ◽

Post Transplantation ◽

Peripheral Blood Stem Cells ◽

Free Survival ◽

Stem Cell Source ◽

Cell Source ◽

Blood Stem Cells

Background: The number of non T depleted haploidentical stem cell transplantations (haplo SCT) with post transplantation cyclophosphamide (PTCy) in adult patients (pts) with acute lymphoblastic leukemia (ALL) is increasing (Shemtov N et al, Leukemia 2019). Although the original haplo SCT with PTCy were performed with bone marrow (BM) grafts, the use of peripheral blood stem cells (PBSC) as the stem cell source may provide some advantages in engraftment and anti-leukemic effect which may be of special importance in ALL. Aim: The goal of this study was to compare BM to PBSC as stem cell source for non-T-cell-depleted haplo SCT with PTCy in adult pts with ALL in first or second complete remission (CR). Methods: The study was based on the haplo SCT with PTCy in adult pts with ALL that met the study inclusion criteria and that were reported to the European Society for Blood and Marrow Transplantation (EBMT) registry from 2010 to 2018. Multivariate analyses (MVA) were performed using the Cox proportional hazard model. Results: A total of 314 pts were reported, 157 of whom received BM and 157 received PBSC as the stem cell source. The median age at transplantation was 37 years (range, 18-68 years) and 36 years (range, 18-73 years), 66% and 62% were males, respectively. Diagnosis was Ph negative B-ALL in 39% and 41% of the pts, Ph positive in 32% and 34 % and T ALL in 29% and 25%, respectively.61% and 65% were in CR1, while 39% and 35% were in CR2. Pts and donor characteristics did not differ between the groups. More pts in the BM group received myeloablative conditioning (MAC), 87% vs 71% in the PBSC group, p<0.0001. The cumulative incidence of engraftment at d60 was higher in the PBSC group compared to BM: 98% vs 93%, respectively p=0.0005. The incidence of 100 days acute(a) and 2y chronic(c) graft vs host disease (GVHD) were not significantly different between the BM and the PBSC graft source; Grade (Gr) II-IV 26% and 36%, III-IV 14% and 14%, total chronic 31% and 36% and extensive 12% in both, respectively. GVHD was the cause of death in 18% of pts receiving PBSC graft in comparison to 13% of those that received BM grafts. In MVA there was a trend for higher incidence of aGVHD II-IV HR 1.52 (0.973-2.38), p=0.065 and cGVHD HR 1.58 (0.995-2.51), p=0.053 in pts receiving PBSC vs BM grafts, respectively. Similarly, there was a trend for higher non relapse mortality (NRM) in the PB vs BM group HR 1.66 (0.99-2.8), p=0.056. There was no difference in relapse incidence (RI) HR 1.23 (0.76-2.0), p=0.416.While, leukemia free survival (LFS), overall survival (OS) and GVHD rel free survival (GRFS) were significantly better in pts receiving BM in comparison to PBSC graft HR 1.43 (1.0-2.03), p=0.047, HR 1.59 (1.08-2.34), p=0.018 and HR 1.42 (1.03-1.95), p=0.03, respectively. Conclusion: In pts with ALL in remission receiving haplo SCT with PTCy, the use of BM versus PBSC grafts resulted in better LFS, OS and GRFS. Disclosures Angelucci: Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorporated, and CRISPR Therapeutics: Other: Partecipation in DMC; BlueBirdBio: Other: Local advisory board; Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Partecipation in DMC. Socie:Alexion: Consultancy. Blaise:Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Download Full-text

Transplantation of Peripheral Blood Stem Cells from Unrelated Donors Is Not Associated with Inferior Survival Compared to Bone Marrow Transplantation in Children with Hematologic Malignancies - A Registry Analysis from the German/Austrian Pediatric Registry for Stem Cell Transplantation (PRST).

Blood ◽

10.1182/blood.v108.11.3109.3109 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3109-3109

Author(s):

Roland Meisel ◽

Caroline Spohr ◽

Thomas Klingebiel ◽

Dagmar Dilloo

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Disease Status ◽

Hematologic Malignancies ◽

Stem Cell Source ◽

Cell Source ◽

Unrelated Donors

Abstract The optimum stem cell source for allogeneic hematopoietic stem cell transplantation (HSCT) remains highly controversial. A recent study in older children and adolescents receiving HSCT from HLA-identical sibling donors has revealed higher mortality after peripheral blood stem cell (PBSC) compared to bone marrow (BM) transplantation (Eapen et al, JCO, 2004). However, despite the increasing use of PBSC in pediatric HSCT from matched unrelated donors (MUD), comparative studies on the relative risks and benefits of both stem cell sources are lacking. We therefore analysed the outcome of unrelated PBSC (n=118) and BM (n=102) transplants reported to the German/Austrian Pediatric Registry for Stem Cell Transplantation (PRST) between 1998 and 2003. Patients with hematologic malignancies (ALL, AML, CML, or MDS), who had received unmanipulated HSCT from ≥ 5/6 HLA antigen-matched unrelated donors following myeloablative conditioning were included into the analysis. PBSC and BM groups were comparable with regard to sex, age, CMV serostatus, GvHD prophylaxis, disease status at transplant, prophylactic growth factor use and degree of HLA-matching, while differences were detected in disease category (more MDS patients in PBSC group, p=0.02), transplanted cell dose (higher CD34-cell graft content in PBSC group, p=0.001) and median year of transplant (PBSC transplantations were more recent, p=0.01). Engraftment was achieved significantly faster after PBSC compared to BM transplantation: 15 vs. 19 days for neutrophil engraftment (p=0.001) and 21 vs. 25 days for platelet engraftment (p<0.01). The rate of acute GvHD grade II–IV (PBSC vs. BM: 44% vs. 39%, p=0.48) and severe acute GvHD Grade III/IV (29% vs. 21%, p=0.17) did not significantly differ between both groups. Moreover, the incidence of chronic GvHD (PBSC vs BM: 35% vs 33%, p=0.9) and extensive chronic GvHD (18% vs 18%, p=0.85) was identical at 3 years post transplant. In the PBSC group there was a statistically non-significant trend towards a higher risk for treatment-related mortality (PBSC vs BM: 34% vs 25%, p=0.14) and a lower risk for death of disease (PBSC vs. BM: 14% vs. 23%, p=0.16). However, this did no translate into a survival difference. With a median follow up of 2.9 years (PBSC) and 3.1 years (BM) overall survival (PBSC vs. BM: 50±5% vs. 46±6%; p=0.63) and event-free survival (45±5% vs. 44±6%; p=0.59) is comparable between both groups. This clinically most relevant result was confirmed in a multivariate analysis showing that advanced disease status at transplant (RR 2.4, 95%-CI 1.5–3.8, p=0.001) is a significant, independent risk factor for treatment failure, while the stem cell source (PBSC vs BM) has no effect (RR 1.1, 95%-CI 0.7–1.6, p=0.8). In summary, our data provide first evidence from a large, registry based analysis, that in pediatric recipients of MUD transplantation the use of PBSC instead of BM is not associated with inferior survival. Therefore, PBSC is a valid alternate stem cell source for pediatric HSCT from MUDs.

Download Full-text

The influence of stem cell source on transplant outcomes for pediatric patients with acute myeloid leukemia

Blood Advances ◽

10.1182/bloodadvances.2018025908 ◽

2019 ◽

Vol 3 (7) ◽

pp. 1118-1128 ◽

Cited By ~ 12

Author(s):

Amy K. Keating ◽

Jurgen Langenhorst ◽

John E. Wagner ◽

Kristin M. Page ◽

Paul Veys ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Confidence Interval ◽

Myeloid Leukemia ◽

Pediatric Patients ◽

Free Survival ◽

Stem Cell Source ◽

Cell Source ◽

Matched Sibling ◽

Acute Myeloid

Abstract When hematopoietic stem cell transplant (HSCT) is necessary for children with acute myeloid leukemia (AML), there remains debate about the best stem cell source. Post-HSCT relapse is a common cause of mortality, and complications such as chronic graft versus host disease (cGVHD) are debilitating and life-threatening. To compare post-HSCT outcomes of different donor sources, we retrospectively analyzed consecutive transplants performed in several international centers from 2005 to 2015. A total of 317 patients were studied: 19% matched sibling donor (MSD), 23% matched unrelated donor (MUD), 39% umbilical cord blood (UCB), and 19% double UCB (dUCB) recipients. The median age at transplant was 10 years (range, 0.42-21 years), and median follow-up was 4.74 years (range, 4.02-5.39 years). Comparisons were made while controlling for patient, transplant, and disease characteristics. There were no differences in relapse, leukemia-free survival, or nonrelapse mortality. dUCB recipients had inferior survival compared with matched sibling recipients, but all other comparisons showed similar overall survival. Despite the majority of UCB transplants being HLA mismatched, the rates of cGVHD were low, especially compared with the well-matched MUD recipients (hazard ratio, 0.3; 95% confidence interval, 0.14-0.67; P = .02). The composite measure of cGVHD and leukemia-free survival (cGVHD-LFS), which represents both the quality of life and risk for mortality, was significantly better in the UCB compared with the MUD recipients (HR, 0.56; 95% confidence interval, 0.34-1; P = .03). In summary, the use of UCB is an excellent donor choice for pediatric patients with AML when a matched sibling cannot be identified.

Download Full-text

Improved graft-versus-host disease-free, relapse-free survival associated with bone marrow as the stem cell source in adults

Haematologica ◽

10.3324/haematol.2015.138990 ◽

2016 ◽

Vol 101 (6) ◽

pp. 764-772 ◽

Cited By ~ 14

Author(s):

R. S. Mehta ◽

R. P. de Latour ◽

T. E. DeFor ◽

M. Robin ◽

A. Lazaryan ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Graft Versus Host Disease ◽

Relapse Free Survival ◽

Free Survival ◽

Host Disease ◽

Graft Versus Host ◽

Stem Cell Source ◽

Cell Source ◽

Disease Free

Download Full-text

Post-Transplant Cyclophosphamide Versus Antithymocyte Globulin in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation from HLA-Identical Sibling Donors: A Retrospective Analysis from the Acute Leukemia Working Party of the EBMT

Blood ◽

10.1182/blood-2019-123269 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 148-148

Author(s):

Giorgia Battipaglia ◽

Myriam Labopin ◽

Rose-Marie Hamladji ◽

Didier Blaise ◽

Patrice Chevallier ◽

...

Keyword(s):

Stem Cell ◽

Cyclosporine A ◽

Myeloid Leukemia ◽

Acute Gvhd ◽

Chronic Gvhd ◽

The Other ◽

Free Survival ◽

Stem Cell Source ◽

Gvhd Prophylaxis ◽

Cell Source

Introduction. In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an HLA-identical matched sibling donor (MSD), use of cyclosporine A in association with methotrexate has been the main graft-versus-host disease (GVHD) prophylaxis strategy. Addition of antithymocyte globulin (ATG), especially when using peripheral blood stem cells (PBSC) as source, has also been shown to favor lower rates of chronic GVHD. More recently, use of post-transplant cyclophosphamide (PTCY) in the haploidentical setting resulted in low incidences of both acute and chronic GVHD. Its use has therefore been subsequently reported in other donor settings, including MSD. The aim of our study was to compare GVHD prophylaxis containing either PTCY or ATG in patients diagnosed with acute myeloid leukemia and undergoing allo-HSCT from a MSD. Methods. This was a retrospective study from the EBMT registry. Included were adult patients undergoing their first allo-HSCT during the period 2008-2018 and who were in complete remission at time of allo-HSCT. Results. Globally, 197 and 1,913 patients receiving either PTCY or ATG, respectively, were identified who fulfilled inclusion criteria. Patients in the PTCY group were younger (median age 47 versus 54 years, p<0.01) and had undergone allo-HSCT more recently (median year of allo-HSCT: 2015 versus 2014, p<0.01). Peripheral blood was the more frequently used stem cell source, this being significantly more frequent in the ATG group (95% versus 70%) than in the PTCY group (p<0.01). The conditioning regimen was more frequently myeloablative in the PTCY group (59% versus 48% in the ATG group, p<0.01). Cyclosporine-A alone was the most used systemic immunosuppressive agent associated with either PTCY (22%) or ATG (28%), while 34% and 29% of patients in the ATG group and 7% and 12% in the PTCY group also received either methotrexate or mycophenolate mofetil along with cyclosporine A. No statistical differences were observed for incidence of grade II-IV acute GVHD at 100 days after allo-HSCT, this being 19% versus 17% in the PTCY and ATG groups, respectively (p=0.81). On the other hand, a significantly higher incidence of chronic GVHD at 2 years was observed with the use of PTCY (37% versus 30%, p<0.02) and for extensive chronic GVHD (16% versus 12%, p<0.01) as compared to ATG. There was no impact of conditioning intensity on GVHD incidence. No statistical differences were observed on univariate analysis for all other transplant outcomes, with a leukemia-free survival (LFS) of 55% versus 58%(p=0.75), overall survival (OS) of 64% versus 65% (p=0.61), GVHD-free, relapse-free survival (GRFS) of 44% versus 49% (p=0.19), relapse incidence (RI) of 36% versus 32% (p=0.56) and non-relapse mortality (NRM) of 8% versus 10% (p=0.78). Of note, the cumulative incidences of death due to GVHD were 4.4% and 4% in the PTCY and ATG groups, respectively (p=0.53). Also, there were no differences between the 2 groups for death due to infections: 6% in the PTCY group and 6.3% in the ATG group, respectively (p=0.49). On multivariate analysis, these results were confirmed, with a higher risk of chronic GVHD of any grade (HR=1.41, 95%CI 1.03-1.92; p<0.01) and extensive chronic GVHD (HR=1.68, 95%CI, 1.07-2.62; p<0.01) with PTCY, and no differences with respect to the other outcomes. We also observed that, regardless of the use of PTCY or ATG, use of PBSC was associated with lower RI (HR=0.64, 95% CI 0.46-0.89; p<0.01), higher LFS (HR=0.71, 95% CI 0.53-0.95; p<0.03), and OS (HR=0.72, 95% CI 0.52-0.99; p<0.05). On the other hand, we found no statistical differences in terms of both acute GVHD (HR=0.73, 95%CI, 0.48-1.12; p=0.15) and chronic GVHD (HR=0.83, 95% CI 0.56-1.21; p=0.33) according to stem cell source. These results were also confirmed in a matched-pair analysis. Conclusion. In conclusion, our results highlight that in the HLA-identical sibling setting, the use of ATG provides similar outcomes to those seen with PTCY except for chronic GVHD for which a protective effect of ATG is confirmed as previously reported by different other studies. Disclosures Blaise: Sanofi: Honoraria; Molmed: Consultancy, Honoraria; Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria. Chevallier:Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria. Socie:Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Download Full-text

Permissive HLA-DPB1 Mismatch and Survival after Unrelated Donor Allogeneic Stem Cell Transplantation for Hematological Malignancies: A Comparative Analysis of Different Immunogenetic Models on 422 Patients from GITMO and IBMDR

Blood ◽

10.1182/blood-2018-99-115216 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 482-482

Author(s):

Francesca Lorentino ◽

Nicoletta Sacchi ◽

Elena Oldani ◽

Valeria Miotti ◽

Alessandra Picardi ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Research Funding ◽

Disease Status ◽

Hla Matching ◽

Graft Versus Host ◽

Stem Cell Source ◽

Functional Distance ◽

Cell Source ◽

Advisory Role

Abstract Introduction: Hematopoietic Stem Cell Transplantation (HSCT) from unrelated donors (UD) is a curative therapy for many hematologic malignancies. HLA matching plays a major role in determining HSCT outcome but the relative role of incompatibilities at the different HLA loci is still debated. In particular, over 80% of UD-HSCT are performed across HLA-DPB1 mismatches (mm): a number of previous studies have devised immunogenetic models to elucidate the impact of HLA-DPB1 mm on HSCT outcome, but a comparative analysis of these models in a recent and well-characterized cohort is lacking. Methods: We selected 422 adult patients (pts) who received an 8/8 (HLA-A, B, -C and -DRB1) allele level-matched UD-HSCT from 2012 to 2015: of them, 382 (90%) had a mm at one or both HLA-DPB1 alleles. We classified functional HLA-DPB1 matching by four models, on the basis of: I) differential immunogenicity of alleles belonging to 3 groups of T-cell epitopes (TCE), as defined by functional studies (Zino, Blood, 2004) and refined by in silico prediction (Crivello, BBMT 2015); II) a similar model subdividing allelles in 4 TCE groups (TCE4, Crocchiolo, Blood 2009); III) differences in "delta functional distance" scores between the alleles of donor and pt, based on 12 polymorphic AA in HLA-DPB1 exon 2 (Crivello, Blood 2016); IV) mismatches in the rs9277534 single-nucleotide polymorphism in the HLA-DPB1 3′ UTR region, predicted on the basis of the DPB1 genotype (Schöne, Hum Immunol 2018), and previously shown to be associated to the expression levels of HLA-DPB1 molecules (HLAexp, Petersdorf, NEJM 2015). Indication for HSCT was acute leukemia (55%), lymphoma and multiple myeloma (29%), myelodysplastic and myeloproliferative syndromes (16%). According to EBMT score definition, 45% of pts were in early, 26% in intermediate, and 29% in advanced disease status. Conditioning regimens were myeloablative (64%) or reduced intensity (36%). Peripheral blood was the preferred stem cell source (81%). Graft-versus-host disease (GvHD) prophylaxis was based on anti-thymocyte globulin (ATG) in 91% of pts, mostly associated with cyclosporine and methotrexate (81%). Median follow-up was 3.2 y. Results: Among the four models adopted to classify functional HLA-DPB1 matching, the TCE4 provided the best results in predicting mm that were permissive (P) or non permissive (NP) for HSCT outcomes. By this model, P mismatched pairs (N=135) had a significantly superior 3-y overall survival (OS) and Graft-versus host disease and Relapse-Free Survival (GRFS) compared to NP pairs (N=247) (60±8% vs 49±7%, p .05; and 36±8% vs 29±5%, p .04). This was associated with a higher transplant-related mortality (TRM), 30±6% in NP mm and 21±6% in P mm, p .09 and a higher 3-y CI of extensive cGvHD in NP mm (12±4%) compared to P (4±2%), p .01 (Figure 1). No effect was found for relapse incidence. Cox multivariate analysis (adjusted for pt age, donor/host gender and CMV, disease status, Sorror score, conditioning intensity, stem cell source, ATG use, HLA matching on 5 loci, center effect), showed that a NP mm compared to P mm was associated with higher hazards for OS (HR 1.6, p .01), GRFS (HR 1.4, p .02), TRM (HR 1.9, p .01), cGvHD (HR 1.6, p .03) and extensive cGvHD (HR 3.6, p <.01). No interaction was found between HLA matching on 5 loci and HLA-DPB1 permissivity predicted by TCE4. Directionality of NP mm did not impact on clinical risk stratification. Of the 382 transplants with HLA-DPB1 mismatches, 229 had unidirectional mismatches in GvH direction and thus could be classified by the HLAexp model. The predicted expression level of the mismatched allele in the patient was associated with 100-d CI of grade≥2 aGvHD: 32±10% in high expression (N=76) versus 16±6% in low expression (N=153) mismatched alleles, p <.01. This was also confirmed in adjusted Cox multivariate analysis for grade≥2 aGvHD (HR 2.2, p <.01). However, this did not have a significant impact on severe aGvHD, TRM and OS. No significant associations with clinical outcomes were found for the "delta functional distance" or the TCE3 model, respectively. Conclusions: Our study provides further proof that functional HLA-DPB1 matching is crucially associated to UD-HSCT outcome also in recent transplants, and suggest that, at least in the cohort under analysis, mainly composed of Italian pts transplanted using an ATG-based prophylaxis, the TCE4 model appears superior to other models in stratifying risk groups and predicting survival. Figure. Figure. Disclosures Patriarca: Medac: Other: Travel, accommodations, expenses; Jazz: Other: Travel, accommodations, expenses; Celgene: Other: Advisory Role; Travel, accommodations, expenses; Janssen: Other: Advisory role; MSD Italy: Other: Advisory Role. Rambaldi:Italfarmaco: Consultancy; Roche: Consultancy; Omeros: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Amgen Inc.: Consultancy. Fleischhauer:GENDX: Research Funding. Vago:GENDX: Research Funding; Moderna TX: Research Funding.

Download Full-text