scholarly journals Outcome of Allogeneic Haematopoietic Stem Cell Transplantation in Myeloproliferative Neoplasms-Unclassifiable: A Retrospective Study By the Chronic Malignancies Working Party of EBMT

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3335-3335
Author(s):  
Donal P. McLornan ◽  
Vittoria Malpassuti ◽  
Simona Iacobelli ◽  
Anne Lippinkhof-Kozijn ◽  
Linda Koster ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Median Time ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Working Party ◽  
Adult Patients ◽  
World Health ◽  
Haematopoietic Stem Cell ◽  
Abnormal Karyotype ◽  
The Impact

Introduction Myeloproliferative Neoplasm (MPN) unclassifiable (MPN-U), is a heterogeneous disease that presents with an MPN-type clinical/ histological phenotype yet fails to meet diagnostic criteria for other MPN entities. Incidence is <5% of all MPN when stringent World Health Organisation (WHO) 2016 classification is followed. No well-defined treatment algorithm exists and therapeutic approaches vary, ranging from observation alone, cytoreductive or experimental agents, high dose chemotherapy and in some instances allogeneic Haematopoietic Cell Transplantation (allo-HCT). Outcome analysis for this allo-HCT cohort is lacking.We hereby report on a retrospective, multicentre, EBMT-registry based study of adult patients with a confirmed diagnosis of MPN-U according to updated WHO 2016 criteria that received an allo-HCT. Methods This registry-based analysis was approved by the Chronic Malignancies Working Party of the EBMT. Patient selection was performed by identifying adult patients who underwent first allo-HCT for MPN-U between 2000-2015, using either Reduced Intensity Conditioning (RIC) or Myeloablative conditioning (MAC) as defined by standard EBMT criteria. Further data collection requests (MED-C) forms were sent to centres to improve data completeness. Statistical analyses were performed with SPSS 22 (SPSS Inc./IBM, Armonk, NY) and R. Overall Survival (OS) was calculated from the date of transplant until death or last observation alive. Cumulative incidence functions were used to estimate Non-Relapse Mortality (NRM) and Relapse Incidence (RI) within a competing risk setting. Results A total of 70 patients, 48 (69%) male and 22 (31%) female, with a confirmed diagnosis of MPN-U were analysed. Median age was 57 years (range (r), 22-70 years). Of these patients, 37 (53%) underwent allo-HCT in the period 2001-2010 and 33 (47%) between 2011-2015. MAC regimens were utilised in 31 (44%) patients while 39 (56%) received RIC. Patients were most frequently transplanted within the first two years from diagnosis, with a median time to allo-HCT of 13 months (r, 3-244 months). Diagnostic karyotype was normal in 36 (51%) and abnormal in 23 (33%) patients, with data missing for 11 (16%) patients. A total of 45 (64%) patients had received prior treatment, 23 (33%) patients were untreated and data was incomplete in 2 (3%) patients. Regarding donor type, 27 (39%) patients had a Matched Sibling Donor (MSD) and 43 (61%) an Unrelated Donor (URD). Most frequent conditioning regimens were TBI-based in the MAC cohort and Fludarabine-Busulphan in the RIC cohort. A trend towards higher rates of delayed/failed engraftment was noted in the RIC compared to MAC cohort (p=0.09). Where successful, median time to neutrophil engraftment in both cohorts was similar (18 days for MAC and 17 for RIC) and both platforms demonstrated similar platelet engraftment times (17.5 days). Incidence of grade II-IV aGVHD at 3 months was higher in the MAC (37%) compared to RIC cohort (16%; p=0.05) and the 12-month cumulative incidence of cGVHD for MAC was 52% (95%CI: 32.4, 71.6) and for RIC 32.1% (95%CI: 14.8, 49.4; p=0.117)). Median follow-up was 87 months (minimum and maximum of censored cases: 31 and 196 months). The median OS estimates at 1, 3 and 5-year were 77%, 55% and 42% (MAC) and 59%, 44% and 41% (RIC), respectively (p=0.33). No significant difference existed in OS rates between those who had pre-transplant therapy versus not. Relapse remained significant: cumulative incidences of relapse at 1,3 and 5-years were 10%, 23% and 27% (MAC) and 28%, 36% and 36% (RIC), respectively (p=0.28). NRM probabilities at 1, 3 and 5-years post allo-HCT were also considerable: 19%, 29%, and 34% (MAC) and 28%, 28% and 28% (RIC), respectively (p=0.84). Main causes of NRM were infection and GVHD. Univariate analysis associated use of an URD with a significantly worse OS and NRM compared with MSD. Moreover, the presence of abnormal karyotype at time of allo-HCT was associated with a trend towards a higher risk of relapse (p=0.06). Conclusions This study highlights the potentially curative role of allo-HCT in MPN-U and provides clinicians with robust engraftment, GVHD and outcome data. Both engraftment and OS rates appear acceptable yet NRM and CIR rates in both settings remain high and need to be addressed. The impact of abnormal karyotype at the time of allo-HCT and a trend towards higher risks of relapse requires further elucidation. Disclosures McLornan: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Robin:Novartis Neovii: Research Funding. Chalandon:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte Biosciences: Consultancy, Honoraria. Beelen:Medac GmbH Wedel Germany: Consultancy, Honoraria. Kröger:Sanofi-Aventis: Honoraria; Riemser: Research Funding; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Medac: Honoraria; JAZZ: Honoraria; DKMS: Research Funding; Celgene: Honoraria, Research Funding. Milojkovic:Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Hernandez Boluda:Incyte: Other: Travel expenses paid.

Allogeneic haematopoietic stem cell transplantation—clinical outcomes: impact of leg muscle strength

2021 ◽  
pp. bmjspcare-2021-003256
Author(s):  
Shin Kondo ◽  
Kumiko Kagawa ◽  
Takashi Saito ◽  
Masahiro Oura ◽  
Kimiko Sogabe ◽  
...  
Keyword(s):  
Stem Cell ◽  
Muscle Strength ◽  
Stem Cell Transplantation ◽  
Clinical Outcomes ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Haematopoietic Stem Cell Transplantation ◽  
Haematopoietic Stem Cell ◽  
Lower Extremity Muscle ◽  
The Impact

ObjectivesMuscle strength decline is reported to predict mortality in many cancers. However, there is little knowledge of the relation between muscle strength decline and clinical outcomes of allogeneic haematopoietic stem cell transplantation (allo-HSCT). This study aimed to determine the impact of pre-transplant lower extremity muscle strength (LEMS) on post-transplant overall survival (OS) and non-relapse mortality (NRM).MethodsIn this retrospective cohort study, 97 adult patients underwent allo-HSCT during 2012–2020. LEMS was defined as knee extension force divided by patient’s body weight. The patients were divided into low and high LEMS groups based on pre-transplant LEMS. OS was measured using the Kaplan-Meier method and the Cox proportional hazards model. The cumulative incidence of NRM was evaluated using the Fine and Gray method, with relapse considered as a competing risk event.ResultsProbability of OS was significantly lower in the low LEMS groups (HR 2.48, 95% CI 1.20 to 5.12, p=0.014) than in the high LEMS group on multivariate analysis. Five-year OS was 25.8% and 66.4% in the low and high LEMS groups, respectively. Risk of NRM was significantly higher in the low LEMS group (HR 4.49, 95% CI 1.28 to 15.68, p=0.019) than in the high LEMS group. The cumulative incidence of NRM was 41.4% and 11.1% in the low and high LEMS groups, respectively.ConclusionsPre-transplant LEMS was a significant factor in predicting OS and NRM.

scholarly journals Post-Transplant Cyclophosphamide in Acute Leukemia Patients Receiving More Than 5/10 HLA-Mismatched Allogeneic Stem Cell Transplantation: A Study on Behalf of the ALWP of the EBMT

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3890-3890
Author(s):  
Michele Wieczorek ◽  
Myriam Labopin ◽  
Luca Castagna ◽  
Eolia Brissot ◽  
Gerard Socié ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Median Time ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Advisory Committees ◽  
Free Survival

Abstract Background Post-transplant cyclophosphamide (PTCy) is a powerful strategy to prevent occurrence of graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Initially developed in the setting of haploidentical HSCT, PTCy has been increasingly used for fully HLA-matched transplants with favorable results. The purpose of this retrospective multi-center study is to evaluate PTCy-based GvHD prevention for patients with acute leukemia receiving a traditionally prohibitive highly mismatched HSCT and to describe their outcome. Methods This is a registry-based study employing the data set of the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT). We retrospectively assessed the outcome of adult patients with acute myeloid or lymphoblastic leukemia (AML/ALL), transplanted between 2010 and 2020 with grafts from HLA-mismatched donors with more than 5/10 mismatches using PTCy-based GvHD prophylaxis. Results The study cohort consisted of 59 patients, with a median time of follow up of 20 (95% CI, 14-39) months. The median age was 47 (range, 18-69) years. Forty-four patients had a diagnosis of AML, 14 of ALL and one case of mixed phenotype acute leukemia. At time of transplant, 39 (66%) were in first or second complete remission, 4 (7%) were in later remission and 16 (27%) had active, relapsed or refractory, disease. Conditioning regimens were myeloablative for 54% of cases and peripheral blood was the preferred source of stem cells (64%). All donors were related. Most patients (85%) received a 4/10 HLA-matched transplant, the most commonly mismatched loci were C and DQB1, often with a double mismatch involving the same locus. Two cases of fully mismatched donors were also recorded. PTCy was always associated with other immunosuppressive treatments, especially with the standard combination of calcineurin inhibitors and mycophenolate mofetil. In only 8 cases in vivo T-cell depletion was realized with anti-thymocyte globulin. A large proportion of patients (86%) attained engraftment with a median time of 19 (range, 11-37) days. Only 8 patients did not reach engraftment and all of them died of infection or disease relapse in the first one-hundred days (range, 6-99) after HSCT. Thirty-three patients (58%) did not present any sign of acute GvHD (aGvHD). Cumulative incidence of grade II-IV and grade III-IV aGvHD at day 180 were 30.3% and 14.3%, respectively. At 2 years, the cumulative incidence of chronic GvHD (cGvHD) was 21%, and 7% for extensive cGvHD. Twenty-four patients died during the study period, mostly because of leukemia progression (n=13, 54%), infectious complications (n=6, 25%) and interstitial pneumonia (n=2, 8%). Other causes of death were hemorrhage, GvHD, and another non HSCT-related that accounted for one case (4%) each. At 2 years, the overall survival (OS), leukemia-free survival (LFS), and a GVHD and relapse free survival (GRFS) were 56%, 54% and 47% respectively. Rates of relapse incidence and non-relapse mortality were 28% and 19%, respectively. Conclusion According to this preliminary data overview, transplantation in a highly mismatched framework is possible, without unfavorable OS, LFS and GVHD rates. Despite the important limitation of the retrospective non-controlled nature of this analysis, these findings suggest that PTCy-based strategies could help overcome the barrier of HLA-matching and configure a new setting of transplantation, encouraging more in-depth investigations. Figure 1 Figure 1. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Angelucci: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene BSM: Honoraria, Other: DMC; Blue Bird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini-Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: steering commitee, Speakers Bureau; Vertex Pharmaceuticals: Honoraria, Other: DMC; Crispr therapeutics: Honoraria, Other: DMC; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Mohty: Takeda: Honoraria; Jazz: Honoraria, Research Funding; Gilead: Honoraria; Adaptive Biotechnologies: Honoraria; Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Astellas: Honoraria.

scholarly journals Burden and Impact of Geriatric Syndromes Associated with Allogeneic Hematopoietic Cell Transplantation in Older Adults

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3370-3370
Author(s):  
Richard J Lin ◽  
Theresa A Elko ◽  
Patrick Hilden ◽  
Parastoo B. Dahi ◽  
Ann A. Jakubowski ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Older Patients ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Geriatric Syndromes ◽  
The Impact

Abstract While there has been significant increase in the number of older patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT), the prevalence and the impact of geriatric syndromes associated with allo-HCT remains unknown. Using an institutional database and the electronic medical record, we retrospectively examined the incidence, predictive factors, and the impact of common geriatric syndromes of delirium, urinary incontinence, pressure ulcer, and mechanical fall among 527 patients age 60 and above (range 60-78.7) who underwent first allo-HCT for hematological malignancies at our institution from 2001 to 2016. We hypothesize that allo-HCT-associated geriatric syndromes negatively impact non-relapse mortality and overall survival. We identified all relevant geriatric events from the start of the conditioning regimen to 100 days post stem cell infusion. Among common geriatric syndromes, we found that delirium had the highest 100-day cumulative incidence at 21% (95% CI 18-25), followed by falls at 7% (95% CI 5-9) (Figure 1). There were only 11 incidences of new urinary incontinence and 3 incidences of new pressure ulcers. With a median follow-up of 46 months for survivors, the 3-year probability of overall survival and progression-free survival is 47% (95% CI 42-51) and 40% (95% CI 36-44), respectively (Figure 1). The 2-year cumulative incidence of non-relapse mortality is 28% (95% CI 24-32). We assessed the association of standard, pre-transplant patient demographic, clinical, geriatric, and laboratory characteristics with the cumulative incidence of delirium and fall. We found that prior fall within last year, potentially inappropriate medications use prior to transplant admission (defined by 2015 American Geriatric Society updated Beers criteria), platelet count <50 k/µl, creatinine clearance <60 ml/min predicted delirium in the multivariate analysis. Age over 70 and impaired activities of daily living (ADL) predicted fall in the multivariate analysis with prior fall within last year close to be a significant variable (Table 1). We next investigated the impact of delirium and fall on transplant outcomes. Delirium, but not fall, is independently associated with significantly increased risk of death at 100 days adjusted for standard transplant variables (OR 6.3, 95% CI 3-13.4, p<0.001). In addition, patients who experienced delirium and fall during their initial transplant admission had significantly increased length of stay (11 and 15 days longer, respectively, both p<0.001). In a landmark analysis of 100-day post-transplant survivors, both delirium and fall are associated with significantly increased long-term non-relapse mortality, with hematopoietic cell transplantation comorbidity index (HCT-CI) as an additional significant predictor (Table 2). While limited by the retrospective design and likely under-reporting, our findings establish for the first time the baseline incidence and predictors of common geriatric syndromes associated with allo-HCT. Importantly, we have demonstrated significant negative impact of delirium and fall on the short- and long-term transplant-associated mortality and morbidities. The temporal pattern and impact of geriatric delirium and fall warrants preemptive, targeted, longitudinal, and multidisciplinary interventions to improve transplant outcomes and to expedite functional recovery after allo-HCT for older patients. Disclosures Perales: Takeda: Other: Personal fees; Novartis: Other: Personal fees; Abbvie: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy.

Allogeneic Stem Cell Transplantation in Idiopathic Myelofibrosis: The Italian Experience.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3008-3008
Author(s):  
Francesca F. Patriarca ◽  
Alessandra A. Sperotto ◽  
Barbara B. Bruno ◽  
Andrea A. Bacigalupo ◽  
Alberto A. Bosi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
The Other ◽  
Haematopoietic Stem Cell ◽  
Idiopathic Myelofibrosis ◽  
Myeloablative Conditioning ◽  
Italian Experience ◽  
Potential Risk Factors ◽  
The Impact

Abstract Allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative treatment for idiopathic myelofibrosis (IM), but it is associated with a high transplantation-related (TRM) mortality rate, especially in advanced and elderly patients. Recently, reduced-intensity conditioning (RIC) regimens were reported to be feasible in these subgroups of patients. Herein, we reported a preliminary analysis of the data of the Gruppo Italiano Trapianto Midollo Osseo (G.I.T.M.O.) Registry regarding a total of 92 patients with IM, who underwent allogeneic HSCT in 25 different Italian Transplant Centres between 1986 and 2005. One Centre performed 26 transplants, 4 Institutions performed between 6 and 10 transplants and the other 20 Centres realized five or less procedures. Ten transplants (11 %) were performed before 1995, 26 (28%) between 1996 and 2000 and 56 (61%) between 2001 and 2005. Sixty patients (65%) were male and median age was 49 years ( range 21–68). Thirty-nine patients (42%) were older than 50 and 8 older than 60 years. Forty-four (48%) received myeloablative conditioning and 48 (52%) a RIC regimen. Myeloablative conditioning was based on cyclophosphamide plus thiotepa ( 42% of the patients) or busulfan (37%) or total body irradiation at the dose of 10–12 Gy (21%). RIC transplants consisted of a combination of fludarabine and 2 Gy TBI (44%) or cyclophosphamide (4%) or busulphan (4%) or an association of thiotepa and cyclophospamide (48%). GVHD prophylaxis included cyclosporin-A and short-course methotrexate, with the association of ATG in 11 patients. Stem cells came from matched sibling donors for 70 patients (76%), missmatched sibling donors for 10 patients (11%) and from matched unrelated donors for the remaining 12 patients (13%). Forty-nine patients (53%) received BM cells and the other 53 cases (47%) PBSC. Seventy-eight out 92 (85%) achieved full engrafment. One-year TRM was 35%. Causes of TRM were as following: GVHD (33% of the patients), infections (36%), bleeding (12%), veno-occlusive disease (3%), thrombotic thrombocytopenic purpura (6%). We observed a trend of higher TRM rate in patients transplanted before 2000 in comparison with those transplanted later (48% vs 33%). However, other potential risk factors for TRM, such as patient age > 50 years, conventional conditioning and unrelated or mismatched donors did not significantly increase TRM rate. There are 43 patients (47%) alive 12 to 156 months after transplantation ( median, 35 months). We conclude that, albeit TRM rate has been lowered in transplants performed in the last 5 years, it still involves one-third of the patients and remains a matter of concern. The ongoing analysis will focus on the impact of the clinical and biological factors at transplant on the outcome of the patient population.

Autologous Stem Cell Transplantation (ASCT) in HIV Associated Lymphoma (HIV-Ly) Patients: An Updated Analysis of the EBMT Lymphoma Working Party (EBMT-LWP) Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1887-1887 ◽  
Author(s):  
Pascual Balsalobre ◽  
Jose L. Diez-Martin ◽  
Alessandro Re ◽  
Maria G. Michieli ◽  
Josep-Maria Ribera ◽  
...  
Keyword(s):  
Median Time ◽  
Highly Active Antiretroviral Therapy ◽  
Cumulative Incidence ◽  
Bacterial Infections ◽  
Conditioning Regimen ◽  
Working Party ◽  
Previous Treatment ◽  
Median Number ◽  
Viral Loads ◽  
Highly Active

Abstract ASCT has been reported as a feasible, safe and effective treatment in HIV-Ly patients (pts) receiving Highly Active Antiretroviral Therapy (HAART). We hereby present an updated analysis of the EBMT experience on HIV-Ly pts treated with an ASCT since 1999. Sixty eight pts from 20 institutions [56 (82%) males, median age of 41 (29–62) years] were included. Twenty-two pts met AIDS criteria (other than lymphoma) at the time of HIV-Ly diagnosis. Forty-nine pts were diagnosed of NHL (31 DLBCL; 8 Burkitt/Burkitt-like; 4 plasmablastic; 3 anaplastic, 3 PTCL), 80% of them presenting with stage &gt;II and 18 pts of HL, 61% of them presenting with stage &gt;II. Median (range) lines of therapy before ASCT was 2 (1–5). Thirty-five pts were autografted in CR (16 in CR1), 25 in chemosensitive disease and 8 in chemoresistant disease. Sixty-five pts received the BEAM protocol as a conditioning regimen and the remaining three received TBI-based protocols. Two pts received more than 1 ASCT (censored at time of 2nd ASCT). At the time of ASCT the median number of CD4+ cells was 162 (8–1159)/mcl and 34 pts had undetectable HIV viral loads. HAART was given in 55/57 pts during conditioning but withdrawn in 25% of them. The median number of CD34+ cells infused was 4.5 (1.6–21.2) ×106/kg and G-CSF was used until engraftment in 60/67 pts for a median of 8 (2–21) days. All pts but one who died on day +15 reached neutrophils&gt;500/ml at a median time of 11 (8–36) days. Platelet count &gt;20.000/ml was reached in 61 pts at a median time of 14 (6–455) days. Twenty three pts (34%) died: disease-progression (n=15), acute ASCT-related complications (n=6) [bacterial infections (n=4), multi-organ failure (n=1), other complications (n=1)] and 2 pts died from HIV-related complications. Cumulative incidence of NRM was 4.4% (95%CI 1.5–13.3) and 7.6% (95%CI 3.3–17.6) at 3 and 12 months, respectively. Age &gt; 50 years at ASCT [RR 4.37 (95%CI 1.01–18.89), p = 0.05] was the only independent adverse prognostic factor for NRM. Relapse occurred in 19 (28%) pts giving a cumulative incidence of 23.6% (15.2–36.9) and 29.6% (20.0–43.8) at 12 and 24 months, respectively. Median time to progression was 4.5 (0.5–32) months. Histology (NHL other than DLBCL) [RR 3.2 (95%CI 1.0–9.6), p = 0.04], the use of &gt;2 previous treatment lines [RR 2.7 (95%CI 1.0–7.2), p = 0.05] and not being in CR at ASCT [RR 3.5 (95%CI 1.2–9.7), p = 0.02] were significantly associated with a higher risk of relapse post-ASCT. With a median follow up time of 32 (2–81) months, PFS and OS were 56% (CI95% 43–70) and 61% (CI95% 48–74) at 3 years, respectively. Pts with refractory disease showed a poorer OS [RR 5.1 (95%CI 1.8–14.6), p = 0.002] and PFS [RR 5.3 (95%CI 2.0–13.7), p = 0.001]. One pt developed an in-situ epithelioma and myelodisplastic syndrome (+4y) and another one a kidney adenocarcinoma (+3y). The results of the largest experience on ASCT for HIV-Ly indicate that this approach is a useful treatment in terms of NRM, long-term OS, and PFS, with significantly better results in patients autografted with chemosensitive disease.

TGFB1 Functional Polymorphisms: Impact on Outcome in Allogeneic Unrelated Donor Haematopoietic Stem Cell Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3011-3011
Author(s):  
Mariano Berro ◽  
Louise Cooke ◽  
Neema P Mayor ◽  
Gustavo Kusminsky ◽  
Steven G.E. Marsh ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Myeloid Leukaemia ◽  
Cell Transplantation ◽  
Haematopoietic Stem Cell Transplantation ◽  
Haematopoietic Stem Cell ◽  
Wild Type ◽  
Functional Polymorphisms ◽  
The Impact ◽  
Donor Genotype

Abstract Allogeneic haematopoietic stem cell transplantation (HSCT) using volunteer unrelated donors (UD) is a life-saving intervention for patients with haematological malignancies. It is recognised that numerous genetic factors in both patient and donor play a role in outcome. TGF beta 1 is a member of a highly pleiotrophic family of growth factors involved in the regulation of numerous immunomodulatory processes and may play a role in carcinogenesis. Several functional polymorphisms have been identified, such as a single nucleotide polymorphism (SNP) at codon 10 (c.29T&gt;C, p.L10P) of exon 1. Conflicting data has been published regarding the impact of the SNP on plasma levels and its role in sibling HSCT. To date there are no published data in UD HSCT. We hypothesised that this polymorphism may influence the outcome of UD HSCT by modulating the immune response. We genotyped, for the presence of a SNP at codon 10, a large group of patient/donor pairs (314) who underwent an UD HSCT using a donor provided by the Anthony Nolan Trust, in a UK transplant centre. The transplant took place between 1997 and 2006 and the median follow up time was 5.8 years (0.8–10.18 years). The diagnoses were chronic myeloid leukaemia 69 (21%), acute lymphoid leukaemia 76 (24%), acute myeloid leukaemia 76 (24%), myelodysplasic syndrome 25 (8%), lymphoproliferatives disorders 37 (11.8%) and others 31 (9.9%). Myeloablative conditioning regimens were used in 69.9% of transplants; T-cell depletion was included in 86.9% of conditioning protocols. Sixty eight percent of the transplants were full matched (10/10), and 12.7% were 12/12. The patients’ observed SNP frequencies were TC 55.7%, TT 32% and CC 12.1%, and for the donor were 51%, 34.7% and 14.3% respectively. There were no significant effects of the presence of a SNP in either the patient or donor groups alone. However, when we analysed the impact of the total number of SNPs present in the pair, we found that multiple SNPs (3–4 SNPs vs 2 or less) were associated with a significantly decreased overall survival (OS) (5 years: 30% vs 42%, log-rank p=0.04), disease free survival (DFS) (5 years: 17% vs 25%, log-rank p=0.02) and a higher treatment related mortality (1 and 3 years: 42% and 45% vs 25% and 30%, respectively, log-rank p=0.03). In multivariate analysis there was a trend to improved OS in the pairs with fewer SNPs (HR: 0.7; 95% CI 0.4,1.0; p=0.07). We speculated that the impact of the donor genotype might differ depending on the patient genotype. In patients with a wild type genotype, the donor genotype did not impact significantly on outcome. Conversely, the patients with a SNP at codon 10 (TC or CC), had significantly better DFS when using a donor with a wild type genotype compared to those with a SNP present (5 years: 34% vs 21%; log-rank p= 0.04). In conclusion, we have shown for the first time in a large number of UD HSCT pairs that increased numbers of SNPs in the TGFB1 gene at codon 10 in patients and donors are associated with a worse outcome following UD HSCT. While an exact functional mechanism remains unclear, these data emphasise the importance of pursuing functional analyses of TGF beta in this setting. In addition, identification of these SNPs pre-transplant will allow for transplant conditioning and immunosuppression regimens to be tailored to the individual patient, as well as assisting in the most appropriate choice of donor.

Unrelated Cord Blood Transplantation: Comparison After Single Unit Cord Blood Intrabone Injection and Double Unit Cord Blood Transplantation In Patients with Hematological Malignant Disorders. A Eurocord-EBMT Analysis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 223-223 ◽  
Author(s):  
Vanderson Rocha ◽  
Myriam Labopin ◽  
Annalisa Ruggeri ◽  
Marina Podestà ◽  
Dolores Caballero ◽  
...  
Keyword(s):  
Cord Blood ◽  
Median Time ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Adult Patients ◽  
Myeloablative Conditioning ◽  
Blood Transplantation ◽  
Gvhd Prophylaxis ◽  
The Impact

Abstract Abstract 223 The use of single cord blood unit for transplantation in adult patients is limited due to the high risk of graft failure and delayed neutrophil and platelet recoveries. The limited hematopoietic progenitors in UCB grafts and their homing after IV injection, have prompted investigators to study the design of delivering CB grafts directly into the bone marrow (BM) space (IBCBT) or to use double cord blood transplantation (dUCBT) to improve engraftment. To evaluate the impact of IBCBT, we made a retrospective based registry comparison with dUCBT performed in the same time period (2006-2010) and reported to Eurocord-EBMT. We included 87 and 149 patients who received either IBCBT or dUCBT, respectively, after a myeloablative conditioning regimen for malignant disorders. IBCBT was performed in 8 EBMT centers whereas dUCBT was performed in 56 EBMT centers. Majority of patients in both groups had acute leukemia. IBCBT patients were older (p<0.001), more frequently received an autologous graft (p<0.001) and had positive CMV serology (p<0.001), and importantly had more advanced disease at transplantation (p=0.04). Median number of infused (after thawing) nucleated cells injected intrabone was 2.5×107/kg and it was 3.9×107/kg in dUCBT (p<0.001). In 72% of both groups, CB grafts were HLA 4/6 (the highest HLA disparity was taken into consideration in dUCBT). Other differences were regarding GVHD prophylaxis that was based on CSA+MMF in 100% of IBCBT and in 62% of dUCBT cases; ATG was used in all IBCBT and 40% of dUCBT. Median follow-up time was 18 months in IBCBT and 17 months in dUCBT. At day 30, cumulative incidence (CI) of neutrophil recovery (ANC >500) was 83% after IBCBT and 63% after dUCBT, and at day 60, it was 90% in both groups; the median time to reach ANC>500 was 23 and 28 days after IBCBT and after dUCBT (p=0.001) respectively. At Day-180 CI of platelets recovery was 81% after IBCBT and 65% after dUCBT (p<0.001) with a median time of 36 days and 49 respectively (p=0.002). At day 100, CI of acute GVHD (II-IV) was 19% and 47% (p<0.001) and chronic GVHD 34% and 37% respectively (p=NS) respectively. Unadjusted 2 years-CI of NRM and RI were 31% and 23% after IBCBT and 35% and 28% after dUCBT, respectively (p=NS). Unadjusted 2 y-DFS estimation was 47% after IBCBT and 37% after dUCBT (p=NS). In multivariate analysis adjusting for statistical differences between 2 groups (such as status of the disease at transplant, age, CMV, previous transplants, GVHD prophylaxis), recipients of IBCBT had improved DFS (HR: 1.64, p=0.035), faster platelet recovery (HR:2.13, p<0.001) and decreased acute GVHD (HR:0.31; p<0.001) compared to dUCBT recipients. We did not find a cut-off value of number of nucleated cells after IBCBT or dUCBT that could be associated with outcomes after both approaches. In conclusion, both strategies have extended the use of CB transplants to adults in need of cord blood transplantation. Therefore, IBCBT is an option to transplant adult patients with single CB units after myeloablative conditioning regimen and may impact the total costs of cord blood transplantation. Based on these results, intra-bone technique may disclose new transplant potentialities also with other HSC sources. Disclosures: No relevant conflicts of interest to declare.

Prognostic Impact of Pretransplant Transfusion Amount on Outcome After Allogeneic Stem Cell Transplantation In Adult Patients with Severe Aplastic Anemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3503-3503
Author(s):  
Sung-Eun Lee ◽  
Jong-Wook Lee ◽  
Seung-Ah Yahng ◽  
Byung-Sik Cho ◽  
Ki-Seong Eom ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Aplastic Anemia ◽  
Cell Transplantation ◽  
Adult Patients ◽  
Prognostic Impact ◽  
Increased Risk ◽  
History Of ◽  
The Impact ◽  
Transfusion History

Abstract Abstract 3503 Background: Aplastic anemia (AA) is a life-threatening bone marrow failure disorder. Therefore, many patients with AA require blood transfusions as supportive management. Regular transfusions of packed red cell (PRC) lead to the development of iron overload, which is known to increase the risk of complications after stem cell transplantation (SCT). However, the prognostic impact of pretransplant transfusion history of PRC on outcome in AA has not been completely analyzed. We investigated the impact of pretransplant transfusion amount of PRC on outcome after allogeneic SCT in severe AA (SAA). Methods: 221 adult patients with SAA who underwent allogeneic SCT between January 1995 and August 2007 who had not received optimal iron chelating therapy were selected for retrospective analysis. Results: 221 patients were divided into two groups according to the mean amount of pretransplant transfusion (32 PRC units): receiving less than 32 PRC units (n=164), >32 PRC units (n=57) before SCT. The median follow-up duration of survivors after SCT was 47.9 (39.5-56.2) months in ≤32 PRC units of transfusion group and 42.8 (39.7-45.9) months in >32 PRC units of transfusion group. Primary engraftment was achieved in all, but 13 patients (9/164 patient, 5.5% in the ≤32 PRC units of transfusion group, 4/57 patients, 7% in the >32 PRC units of transfusion group, P=0.745) developed secondary graft failure. Acute GVHD (grade II-IV) developed in 27.4% in ≤32 PRC units of transfusion group and 42.1% in >32 PRC units of transfusion group (P=0.04), and extensive type of chronic GVHD occurred in 20.7% and 26.3% among evaluable patients, respectively. In the comparison between two groups, higher pretransplant transfusion group has significantly increased risk of transplant-related mortality (TRM) (<32 PRC units of transfusion: 8.2% vs >32 PRC units of transfusion: 25.2%, P=<0.000), and lower overall survival (OS) (91.8% vs 75.2%, P=0.001) than those with lesser transfusion history. Multivariate analysis revealed that higher pretransplant PRC amount [HR (95% CI) 3.09 (1.44-6.63), P=0.004] and donor type (related vs unrelated) [HR 2.41 (95% CI) (1.10-5.27), P=0.028] were independent prognostic factor for affecting OS. Conclusion: These results indicate that higher pre-transplant transfusion history of PRC was associated with increased TRM and decreased OS, and it has shown to have a negative impact on outcome after SCT in SAA. Disclosures: No relevant conflicts of interest to declare.

Maximally Tolerated Busulfan Area Under the Concentration-Time Curve (AUC) In Combination with Fludarabine as Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3499-3499
Author(s):  
Janelle Perkins ◽  
Teresa Field ◽  
Jongphil Kim ◽  
Hugo F. Fernandez ◽  
Lia Perez ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Systemic Exposure ◽  
Hematopoietic Cell ◽  
Time Curve ◽  
Concentration Time ◽  
Gvhd Prophylaxis ◽  
Dose Limiting Toxicity

Abstract Abstract 3499 Intravenous busulfan (IV Bu) dosing in hematopoietic cell transplantation (HCT) conditioning regimens has been based largely on bioequivalence studies done with the oral dosage form. As systemic exposure to Bu has been correlated to both efficacy and toxicity, we used area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to IV Bu when given daily in combination with fludarabine as HCT conditioning. Three AUC levels were planned: 6000, 7500, and 9000 micromole*min/L, in cohorts of 20 patients (pts) each, with an additional 10 pts to be enrolled at the maximally tolerated AUC. To be included, pts had be 16–65 years old and have a hematologic malignancy, an HLA A, B, C, DRB1 8/8 or 7/8 matched related or unrelated donor, Karnofsky performance status 70–100%, and adequate organ function. The initial dose of IV Bu for the first AUC level was 170mg/m2/day on day -6 and day -5 then, on day -4 and day -3 doses were adjusted based on pharmacokinetic modeling after the first dose to achieve an average daily AUC of 6000. First doses for the subsequent cohorts were based on the linear correlation between AUC and dose in the previous cohort: 180mg/m2/day for AUC 7500 and 220mg/m2/day for AUC 9000, with dose adjustment on days -4 and -3 as described. Pharmacokinetic analysis was done after the day -3 dose to verify the accuracy of the dose adjustments. The first 20 pts in the AUC 6000 cohort (DL1) were coenrolled onto a randomized trial of GVHD prophylaxis (tacrolimus and methotrexate vs tacrolimus and mycophenolate mofetil) and were analyzed separately from a second cohort of 20 pts receiving an AUC 6000 (DL1A) and GVHD prophylaxis with tacrolimus and methotrexate. 20 pts were then enrolled onto AUC 7500 (DL2), followed by 3 pts on AUC 9000 (DL3). All DL3 pts had dose limiting toxicity so accrual to that level was stopped. An additional 9 pts have been treated to date on DL2 (5 of these are <100 days posttransplant and are not evaluable for toxicity or GVHD). The median (and range) average daily AUC for each of the cohorts were: DL1 5955 (5375-6557); DL1A 6145 (4846-7018); DL2 7555 (5920-8682); DL3 8899 (8784-8955). There were no primary engraftment failures and median times to neutrophil engraftment were: DL1 15 days, DL1A 16 days, DL2 14 days, and DL3 12 days (p=0.01). The dose-limiting toxicity seen at DL3 was hepatic venoocclusive disease (VOD) which developed in all 3 pts; two of these pts died. There were no seizures attributable to IV Bu seen at any dose level. NCI CTCAE toxicities (observed in the first 100 days unrelated to infection or GVHD) that were significantly different between the dose level groups were dermatitis and VOD with more severe toxicity seen in DL2 and DL3. Diarrhea and the use of total parenteral nutrition appeared to be more common on DL2 and DL3 but not significantly so. The cumulative incidence of acute GVHD was similar across the cohorts (p=0.11). There was no difference between the dose levels in cumulative incidence of relapse (p=0.54) or event-free survival (p=0.4). Nonrelapse mortality at 6 months was significantly different: DL1 20%, DL1A 0%, DL2 17.5% and DL3 67% (p=0.008) as was overall survival at 6 months: DL1 75%, DL1A 90%, DL2 80%, DL3 33% (p=0.04). We conclude that in the pts studied, 7500 micromole*min/L is the maximally tolerated AUC based on protocol-defined criteria but exceeding an AUC of 6000 may not provide any survival benefit. Disclosures: Perkins: PDL BioPharma: Research Funding. Off Label Use: IV busulfan was used in combination with fludarabine as conditioning prior to allogeneic hematopoietic cell transplantation in patients with a variety of hematologic malignancies. Field:PDL BioPharma: Research Funding.

Fludarabine and Targeted Busulfan Is Safe and Effective Conditioning Before Hematopoietic Stem Cell Transplantation in Adult Patients with Acute Lymphoblastic Leukemia in First Remission

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 891-891
Author(s):  
Ghada M Kunter ◽  
Janelle Perkins ◽  
Lia Perez ◽  
Joseph Pidala ◽  
Teresa Field ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Older Patients ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Unrelated Donor ◽  
Risk Of Relapse

Abstract Abstract 891 Background: Chemotherapy for adult patients with acute lymphoblastic leukemia (ALL) is associated with high risk of relapse and an overall 2-year survival of 40 to 50%. Allogenic hematopoietic cell transplantation (HCT) in first complete remission (CR1) decreases the risk of relapse and improves outcome over chemotherapy for adult ALL pts, but non-relapse mortality (NRM) is a drawback especially in older patients. In the MRC UKALL XII/ECOG E2993 trial, the 2 year NRM of patient with an allogenic donor was 19% in standard risk patients and 36% in patients over 35 years or those with high risk leukemia. We tested safety and efficacy of a non-irradiation regimen consisting of fludarabine (FLU) and pharmacokinetically-targeted busulfan (BU) for adults with ALL in CR1. Methods: We report the outcomes of 42 consecutive patients with ALL in CR1, 21 positive for the Philadelphia chromosome (Ph+). All patients were in complete morphologic remission before HCT. The median age was 33 (range: 19–62) years, 19 were females and 23 males. Median time from diagnosis to HCT was 6 (range: 3–45) months. Thirty patients were treated to achieve an average daily BU area under the curve (AUC) of 5300 microM-min for 4 days, and 12 patients were treated on a clinical trial to achieve an average daily BU AUC of 6000 to 7500 microM-min for 4 days. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus in all patients, in combination with either methotrexate (88%) or sirolimus (12%). Twenty (48%) patients received grafts from matched related donor, 16 (38%) from matched unrelated donor and 6 (14%) from a mismatched unrelated donor. The median follow-up of surviving patients is 2 (median 1.2–4.3) years. Results: Overall survival at 2 years was 66% (95% CI 52%–81%) for all patients, 70% (95% CI 51%–88%) for Ph- and 63% (95% CI 41%–85%) for Ph+ patients (p=0.59). Overall survival did not differ by age, above or below 35 years (p=0.39). Disease-free survival at 2 years was 59% (95% CI 44%–74%) for all patients, 65% (95% CI 45%–84%) for Ph- and 52% (95% CI 28%–74%) for Ph+ pts (p=0.49). The cumulative incidence of relapse at 2-year was 27% (95% CI 16%–45%). The cumulative incidence of acute GVHD grades II–IV was 64% (95% CI 51%–81%) and grades III–IV GVHD was 25% (95% CI 13%–47%). The cumulative incidence of non-relapse mortality (NRM) was 5% (95% CI 1%–18%) at 100 days and 14% (95% CI 7%–30%) at 2 years. Conclusions: These data show that FLU with myeloablative doses of PK targeted BU is an effective alternative to total body irradiation and etoposide or cyclophosphamide for conditioning patients with ALL without an increased risk of relapse after HCT. The low NRM allows to safely delivering myeloablative chemotherapy and allogenic HCT to older patients. This HCT regimen should be prospectively compared to chemotherapy for adult patients with ALL. Disclosures: No relevant conflicts of interest to declare.

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