scholarly journals The Impact of Age in Allogeneic Stem Cell Transplantation with Thiotepa Busulfan and Fludarabine (TBF) for Myelofibrosis : A Retrospective Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4858-4858
Author(s):  
Federica SORA ◽  
Patrizia Chiusolo ◽  
Sabrina Giammarco ◽  
Idanna Innocenti ◽  
Francesco Autore ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Total Dose ◽  
Cell Transplantation ◽  
Older Patients ◽  
Research Funding ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Allogeneic hematopoietic stem-cell transplantation (HSCT) currently remains the only curative therapy for intermediate or high risk disease.myelofibrosis (MF). We are reporting 56 patients (pts) who underwent an allogeneic HSCT in our Centre between 2016 and 2020, and assessed factors predictive of outcome. The median age was 59 years (36-72). Most patients (72%) were JAK2+ and had int2-high DIPSS (92%). The conditioning regimen consisted of thiotepa, busulfan , fludarabine (TBF). All pts received thiotepa 10 mg/kg and fludarabine 150 mg/m^2. The dose of busulfan was adjusted considering the age and the comorbidity score. One pt received 3 days of busulfan (total dose 9.6 mg/kg); 47 received 2 days (total dose 6.4 mg/kg) and 8 received one day of busulfan iv (3.2 mg/kg). Donor was an identical sibling in 13 pt, haploidentical in 18, matched unrelated donor (UD) in 18 and a mismatchedUD in 7. Thus we had 31 HLA matched and 25 HLA mismatched grafts. Fortytwo patients received post-transplant cyclophosphamide (PTCy)-based GVHD (Graft versus host disease ) prophylaxis with cyclosporine and mycophenolate mofetil , and 14 patients received a standard GvHD prophylaxis (CSA+MTX+ATG). The 2 year survival (OS) was 73 % and disease free survival (DFS) was 66 % and the cumulative incidence (CI) of TRM was 23% and of relapse 11%. The incidence of acute GvHD grade II-IV was 22% in HLA matched and 50% in HLA mismatched pts (p=0.022), grade III-IV was 6% and 25% respectively (p=0.042) . The incidence of moderate-severe chronic GvHD was 25% in HLA matched and 36% in HLA mismatched grafts (p=0.36). HLA had a major impact on survival : 85% vs 49% survival for matched vs mismatched patients (p=0.01). Patients age >60 years had a major impact on outcome, with a 2 year survival of 51% vs 88% in patients over (n=24) or under 60 years of age (n=32) (p=0.007; the DFS was 46 % and 80% respectively and the CI of TRM was 42% vs 9% (p=0.003). As to the total dose of busulfan, we found 26% TRM in patients receiving busulfan for 2 days (total doe 6.4 mg/kg) (n=47) and 0% in older patients receiving 1 day only (total dose 3.2 mg/kg) (n=8) ; relapse rate was 10% and 20% respectively. In multivariate cox analysis including age, spleen size ,DIPSS score, number of transfusion received and donor type, only HLA matching influenced the incidence of acute GvHD; transfusion burden and age plays a role in NRM and OS; DIPSS predicts relapse . In conclusion: older patients with MF have a high NRM and need to be prepared with a milder conditioning regimen. Disclosures Laurenti: Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria; BeiGene: Honoraria. Sica: Pfizer: Honoraria.

scholarly journals Evaluation of Reversed Administration Order of Busulfan (BU) and Cyclophosphamide (CY) as Conditioning on Liver Toxicity in Allogenic Hematopoietic Stem Cell Transplantation (ALLHSCT)

2020 ◽  
Author(s):  
Mani Ramzi ◽  
Nasrin Namdari ◽  
Shirin Haghighat ◽  
Hourvash Haghighinejad
Keyword(s):  
Stem Cell ◽  
Mortality Rate ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Liver Toxicity ◽  
Conditioning Regimen ◽  
Liver Function Tests ◽  
Hematopoietic Stem ◽  
Transplantation Center

Background: Busulfan (BU) in combination with cyclophosphamide (CY) is used as an effective conditioning regimen in hematopoietic SCT. Busulfan, depletes glutathione level in liver and causes elevated levels of CY metabolites. Cyclophosphamide metabolites are highly toxic for sinusoidal endothelial cells and cause VOD/ SOS with high mortality rate. Materials and Methods: Between September 2013 and September 2015, all adult patients with acute leukemia who were candidates for myeloablative allogenic SCT and were admitted to Stem Cell Transplantation center were enrolled in this prospective randomized clinical trial. We tested the hypothesis that reverse administration from BU-CY (n=28) to CY-BU group (n=27) would reduce liver toxicity. Results: Liver function tests were significantly higher in the BU-CY group between day -1 and +4 (p<0.05), but VOD/SOS was not diagnosed in both groups. The incidence and severity of acute GVHD was higher in the BU-CY group, but not statistically significant. Engraftment and mortality rate were not different. Conclusion: These data support the concept that CY-BU is associated with less liver toxicity, suggesting CY-BU is superior to BU-CY as conditioning.

Improved Immune Reconstitution Following Pre-Emptive CD8-Depleted Donor Lymphocyte Infusions (DLIs) after Haploidentical Stem Cell Transplantation (SCT) Using a Reduced-Intensity Conditioning (RIC) Regimen.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2908-2908
Author(s):  
Paolo Corradini ◽  
Anna Raganato ◽  
Matteo Carrabba ◽  
Lorenza Gandola ◽  
Claudia Lombardo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Total Dose ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Immune Recovery ◽  
Grade Ii ◽  
The Impact

Abstract Allogeneic stem cell transplantation (SCT) from an haploidentical family donor has been reported as a viable option in acute leukemias when matched donors are unavailable. However, the extensive T-cell depletion (TCD), required to prevent graft-versus-host disease (GVHD), is associated to delayed immune recovery and high transplant-related mortality. In an ongoing phase I–II trial for patients (pts) with advanced hematological malignancies, we combined a RIC regimen, including thiotepa (10 mg/kg), fludarabine (120 mg/ms), cyclophosphamide (60 mg/kg) and TBI (2 Gy), with pre-emptive administration of CD8-depleted DLIs (starting from 1x104 up to 1x105 cells/kg). Ex-vivo and in-vivo TCD were carried out by CD34+ cell selection using the CliniMACS device and alemtuzumab (30 mg day −2), respectively. The aim of the study was to investigate in a dose finding study the safety and the impact on immune-reconstitution of CD8-depleted DLIs. Six-teen pts with hematological malignancies (n=14 NHL/HD, n=1 ALL, n=1 AML) were included, median age was 35 years (range, 15–65), 10 (63%) were chemorefractory, and 68% and 75% had failed a previous auto or at least 3 CT lines, respectively. Pts received a median of 10.6 x106/Kg CD34+ and 1x104/kg CD3+. All pts engrafted with full donor chimerism from day +30. At a median follow-up of 9 months, 12 pts were alive and 4 died (n=1 infection, n=3 disease). The estimated OS at 2 years was 58%; 7 of 16 (44%) relapsed at median time of 100 days after SCT. CD8-depletion of 14 donor lymphocyte aphereses was performed with a new depletion protocol (Clinimacs CD8-Microbeads) that reduces the content of CD8+ cells by at least 3 logs. The median CD3+, CD4+, CD56+/CD3+, CD20+ cell recovery were 62% (range, 35–91%), 88% (63–128%), 51% (8–78%), 76% (33–128%), respectively. Before DLIs, only 1 of 16 pts (6%) developed de novo acute GVHD (grade II). A total of 22 CD8-depleted DLIs were administered to 9 of 16 pts without any engraftment problem. The first cohort of pts (n=5) received a total dose of 3–6x104/kg CD8depleted DLIs starting at day +45 divided in 3 monthly infusions: none of them developed aGVHD. Given no toxicity, we escalated doses and the second cohort (n=4) received a total dose of 10–25x104/kg CD8-depleted DLIs divided in 3 monthly infusions: 3 pts had acute GVHD (grade II). Overall, the incidence of acute GVHD was higher (75% vs 0%, P&lt;0.04) in pts receving larger numbers of donor cells. Interestingly, the median values of CD4+/ul and CD8+/ul were 98 (range, 8–612) and 150 (range, 15–988) at 4 months; 247 (range, 55–333) and 235 (range, 3–1000) at 5 months after SCT. The median value of CD19+/ul cells were 134 (range, 0–292) and 160 (range, 0–256) at 4 and 5 months, respectively. NK cells remained between the value of 394/ul and 569/ul in the first 6 months after SCT. Our results suggest that: (1) haploidentical SCT with RIC regimen is feasible with a high rate of engraftment and a low acute GVHD incidence; (2) pre-emptive CD8-depleted DLIs are feasible without GVHD until the total dose of 6 x104/kg; 3) higher doses can induce acute GVHD, but no grade III–IV was observed; 4) despite the limited number of pts, we observed a faster immune recovery and a relatively low mortality rate for infections.

The Impact of Allogeneic Hematopoietic Stem Cell Transplantation in Children and Adolescents with Recurring Hodgkin’s Lymphoma: An EBMT Study on 151 Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3061-3061 ◽  
Author(s):  
Alexander Claviez ◽  
Carmen Canals ◽  
Marc Boogaerts ◽  
Jerry Stein ◽  
Stephen Mackinnon ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Performance Status ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
The Impact ◽  
Time Point

Abstract Background: Allogeneic hematopoietic stem cell transplantation (HSCT) has become a therapeutic option for patients with recurring Hodgkin’s lymphoma (HL). Standardized inclusion criteria, the optimal time point and the type of conditioning regimen have, however, not been clarified yet. Moreover, high treatment related mortality (TRM) has hampered the widespread use of this procedure. Only few data are available on the impact of allogeneic HSCT in pediatric and adolescent patients. Patients and Methods: We analyzed patients registered in the EBMT Lymphoma Database (age < 21 years at transplantation) who received an allogeneic HSCT for relapsed or refractory HL between 1987 and 2005. Results: A total of 151 patients (56% male) were included. Median age at diagnosis and HSCT was 15 and 18 years, respectively. 57% of patients had received three or more lines of treatment prior to allogeneic HSCT including autologous HSCT in 77 patients with a median interval of 18 months between autologous and allogeneic HSCT. The majority of donors were matched related (63%), followed by matched unrelated (25%) and mismatched donors. A full myeloablative conditioning regimen was given to 40% of patients and 60% received a regimen of reduced intensity. Disease status at HSCT was sensitive (complete or partial remission) in 59% and refractory (no change or progression) in 41%. 23% of the patients developed grade 2–4 acute graft versus host disease (GvHD). Of 35 patients with evaluable chronic GvHD, limited and extensive GvHD were balanced. With a median follow-up of 25 months (maximum 154), 75 patients (50%) are alive and 59 of them disease-free. 56 patients (37%) relapsed after a median time of 5 months (<1 to 36 months) and only 16 were alive at last contact. The probability for progression-free survival (PFS) at 2 and 5 years were 39% and 29% respectively. The cumulative incidences (CI) for relapse at 1, 2 and 5 years were 29%, 37% and 44%, respectively, whereas the CI for TRM at 1, 2 and 5 years were 20%, 24% and 27%, respectively. In multivariate analysis, HLA disparity (p=.002), HSCT before 2001 (p=.01) and female sex (p=.02) were associated with a higher TRM, while poor performance status (p=.005) and refractory disease (p=.04) resulted in an inferior PFS. Reduced treatment intensity had no impact on relapse rate within one year after HSCT but was associated with a higher incidence of relapse (p=.02) beyond 12 months. The PFS and TRM of patients without adverse prognostic factors (HSCT >2001, matched donors and good performance status at HSCT) at 1, 2 and 5 years was 67%, 50% and 43%, and 11%, 17% and 17%, respectively. Conclusion: This study of young patients with HL receiving allogeneic HSCT indicates a comparable outcome to adult patients. Transplantation was beneficial especially for patients with a good performance status, HSCT in recent years and available matched donors. Allogeneic HSCT should be carefully selected at an early time point in children failing standardized primary and salvage treatment.

Allogeneic Stem Cell Transplantation in Patients ≥70 Years Old

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2309-2309
Author(s):  
Christopher C Walling ◽  
Pamela A Shaw ◽  
Noelle V Frey ◽  
Saar I Gill ◽  
Elizabeth O. Hexner ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Older Patients ◽  
Research Funding ◽  
Age Groups ◽  
Hematopoietic Stem ◽  
Younger Patients ◽  
Allogeneic Hsct

Abstract Background: While reduced intensity conditioning has allowed older patients to undergo allogeneic hematopoietic stem cell transplantation (HSCT) for a variety of hematologic malignancies, age is still viewed as a relative contraindication. In particular, only limited and conflicting data are available on outcomes of patients ≥ 70 years old. Methods: To determine outcomes and utility or futility of transplant for "older" patients, we conducted a retrospective study of all patients 65 and older who underwent allogeneic SCT at our institution between March 2002 and March 2015. 33 patients age 70-75 (median 71 years) were compared to 95 concurrent allogeneic HSCT recipients age 65-69 (median 67). Results: The two groups (70-75 and 65-69) were similar in terms of donor type (70% URD 30% MRD vs. 67% URD 27% MRD 3% cord blood, p=0.86), conditioning regimen (75% flu/bu vs. 65% flu/bu, p =0.26), HCT-CI scores (mean 2.7 vs 2.9, p=0.29), disease phase (9% vs. 15% with primary refractory/active disease, p=0.651) and disease distribution (AML/MDS in 76% and 80%, p=0.7). The OS for all patients was 51% at 1 year and 38% at 2 years, with a median follow up of 13.1 mo and no differences between age groups (fig 1, p=0.70). The median survival was 12.5 months in the 70-75 group vs. 13.7 months in the 65-69 group. As seen in Table 1, transplant was well tolerated and outcomes similar between both age groups with minimal 30 day mortality. Comparing patients age 70-75 to those 65-69, there was no difference in OS at 100d, 1 year or 2 years. There was no difference in grade II-IV acute GVHD (p=0.50). The cause of death was similar in both groups; of the patients who died, death was treatment-related in 45% and 40% of 70+ versus younger patients respectively, largely due to GVHD and infection. Relapse accounted for death in 55% and 57% of older versus younger patients who died. Conclusions: These data suggest that at least selected patients ≥70 years old can tolerate allogeneic HSCT similar to patients ages 65-69. Outcomes in both age groups remain limited by a high risk of relapse highlighting that better methods for tumor control are needed such as post-transplant maintenance or novel disease-specific strategies that minimize GVHD but allow for enhanced GVL induction. However age ≥70 should not be an absolute contraindication for transplant. Figure 1 Figure 1. Disclosures Shaw: Vitality Institute: Research Funding; Novartis: Research Funding. Frey:Servier: Consultancy; Amgen: Consultancy; Novartis: Research Funding. Gill:Novartis: Patents & Royalties, Research Funding. Luger:Astellas: Honoraria; Dava Oncology: Honoraria; Pfizer: Consultancy; Onconova: Other: Clinical Trial --Institutional PI; Seattle Genetics: Other: Clinical Trial--Institutional PI; Ariad: Other: Clinical Trial--Institutional PI; Celgene: Other: Clinical Trial--Institutional PI; Cyclacel: Other: Clinical Trial, Institutional PI. . Mangan:Novartis: Research Funding; Incyte: Other: Advisory Board. Stadtmauer:Celgene: Consultancy; Takeda: Consultancy; Teva: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Amgen: Consultancy. Porter:Genentech: Other: Spouse Employment; Novartis: Patents & Royalties, Research Funding.

Peripheral Blood Stem Cell Transplantation in Fanconi Aplastic Anemia: Report of Ten Cases.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5310-5310
Author(s):  
O. Alphan Kupesiz ◽  
Gulsun Tezcan ◽  
Volkan Hazar ◽  
M.Akif Yesilipek
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Aplastic Anemia ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematological Parameters ◽  
Conditioning Regimen ◽  
Antifungal Prophylaxis ◽  
Unrelated Donor ◽  
Hematopoietic Stem

Abstract Allogeneic hematopoietic stem cell transplantation (SCT) from healthy donors is the only treatment modality for the correction of hematological abnormalities in Fanconi aplastic anemia (FAA) patients. We have performed SCT by using two different non total body irradiation conditioning regimens. While anti-thymocyte globulin (ATG, 10–30mg/kg/day, 3 days), cyclophosphamide (5mg/kg/day, 4 days) and thoraco-abdominal radiation (total 5Gy) were used for six patients (regimen A), fludarabine (120–150mg/m2 totally), cyclophosphamide (10mg/kg/day, 4 days), ATG (30mg/kg/day, 3 days) were given to four patients (regimen B). Six of the patients received regimen A and 4 regimen B. Donors were HLA-matched sibling in 5, HLA-matched parent in 2, partly HLA-matched parent in 2 and HLA-matched unrelated donor in one. All patients and donors were screened by diepoxybutane (DEB) test. Seven of the patients were DEB positive. All donors were DEB negative. Median age of the patients was 10 years. All patients received antimicrobial, antifungal prophylaxis and intravenous immunoglobulin (IVIG, 500 mg/kg weekly) from day −7 to day +180. Cyclosporin A (CsA) was used for graft-versus-host disease (GVHD) prophylaxis in eight patients and CsA plus mycophenolate mofetil in one matched unrelated patient. Neutrophil and platelet engraftment occurred in all patients on day 10 (median) and day 21 (median), respectively. Grade II-IV acute GVHD occurred in two patients who received regimen A. Conditioning-related toxicity was milder in regimen B than that in regimen A. Three patients succumbed from complications of grade IV acute GVHD, post-transplant acute myeloid leukemia and fungal pulmonary infection in regimen A group. All of the regimen B group were alive with normal hematological parameters. Totally, seven patients are alive with sustained engraftment and transfusion independent with median follow-up 19 months (range 2–50). We conclude that fludarabine based conditioning regimen is well tolerated and ideally suited to reduce regimen-related toxicities while achieving sustained engraftment in FAA patients SCT using sibling, related and unrelated donor.

scholarly journals Impact of Age on Hospitalization and Readmission on Post Allogeneic Stem Cell Transplantation Outcome, Single Center Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4122-4122
Author(s):  
Eshrak Al-Shaibani ◽  
Shiyi Chen ◽  
Wilson Lam ◽  
Arjun Law ◽  
Ivan Pasic ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hospitalization Period

Abstract Background: Recent advances and improvement of supportive care allowed allogeneic stem cell transplantation (HCT) to be offered to selected older patients. However, data regarding outcome and factors affecting the outcomes are limited. Method: We retrospective analyzed the outcome in 332 patients, median age 65 years (60-76), who underwent HLA-matched related (n=85), matched unrelated (n=205) and haploidentical donor (n=42) HCT, between January 2014 to December 2019. Of these 60% were male. Diagnosis was leukemia: 193, MDS: 76, MF: 46 and others: 17. Graft source was PBSC in 98%. Reduce-intensity conditioning regimen was used in 95%, and in vivo T-cell depleted in 89% of patients. We categorized them to 3 age-groups (G): G1 60-65y, (n=175), G2 &gt;65-70y (n=127), and G3 &gt;70y (n=30).Cox models were used to compare the rates of overall survival (OS), non-relapse mortality( NRM), event free-survival (EFS), length of hospitalization for HCT, GVHD and reasons of re-hospitalization during the first year post HCT. Results: The median follow up was 14 months (range: 1-123 months). Median days of hospitalization during HCT period were 30-days (range: 20-132 days), with trend towards significance when stratified by age group (p=0.049). HCT-CI scores were 0-1 (n=143), 2-3 (n=107) and &gt;3 (n=70). The cumulative incidences of grade II-IV acute-GVHD was 38.3% and 16.3% for grades III-IV. Moderate-severe chronic-GVHD was 23.7%. Increasing age was not associated with increases in acute GVHD (p=0.86) or chronic-GVHD (p= 0.6). Overall, 188 (56%) patients were re-hospitalized within the first 6-month of HCT, and 61 (18%) in the second 6-month period. The 2-year OS rate (Fig 1) were 56% in G1, 53% in G2 and 34% in G3 (p=0.05). The 2-year EFS rate (Fig 2) were 54% for G1, 49% for G2, and 31% for G3 (P=0.04). Cumulative incidence of NRM at 2-year (Fig 3) were 25% in G1, 36% in G2 and 52% in G3 (p=0.008). Further results are illustrated in Table 1. Risk factors such as age, KPS, HCT-CI, donor-type, readmission and GVHD were analyzed for their associations with outcomes using univariate analyses, those with significant results entered in multivariate-analysis Table 2. Patients aged 60-≤65 had significantly better EFS (p=0.04) and associated with a border line significant trend for lower NRM (p=0.05) than those aged &gt;70. Re-admission in the first 6-month post HCT had a significant impact on the OS, EFS and NRM. HCT-CI &gt;3 had significant impact on NRM. Conclusion: Age had a significant impact on hospitalization period during HCT. Age &gt;70 had significant impact on EFS and trend toward higher NRM. HCT-CI, acute and chronic-GVHD and readmission in first 6-month post-HCT were significant risk factors. Readmission in the first 6 months correlated with lower OS, EFS and higher NRM. Acute GVHD III-IV or moderate-severe chronic GVHD associated with poor outcomes. Selecting patients based on HCT-CI, and good management of GVHD and post-HCT complication may improve the clinical outcome. Figure 1 Figure 1. Disclosures Law: Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Kim: Bristol-Meier Squibb: Research Funding; Pfizer: Honoraria; Paladin: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding.

scholarly journals Contemporary Conditioning Regimen before Allogeneic Stem Cell Transplantation for Children with Non-Malignant Diseases

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3398-3398
Author(s):  
Christina Peters ◽  
Mary Slatter ◽  
Paul Veys ◽  
Franco Locatelli ◽  
Adriana Balduzzi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Research Funding ◽  
Bone Marrow Failure ◽  
Conditioning Regimen ◽  
Common Disease ◽  
Malignant Diseases ◽  
Hematopoietic Stem ◽  
Significant Difference

Abstract Non-malignant diseases (NMD) include a wide spectrum of either congenital or acquired disorders occurring in early and later childhood. The primary goal of conditioning in NMD is either the replacement of missing cells as in severe aplastic anaemia (SAA) or severe combined immunodeficiencies (SCID) or the exchange of a deficient blood cell compartment as in hemoglobinopathies, hemophagocytic syndromes or metabolic disorders. The right choice of a conditioning regimen before allogeneic hematopoietic stem cell transplantation (HSCT) is crucial for the outcome of patients with NMD, many of whom are often critically ill due to infections, organ dysfunctions, vascular complications or metabolic problems. As a consequence of a highly activated immune-system and no pre-treatment with chemotherapy, graft rejection is a known severe complication in these patients. To get up-to-date information on the most commonly used conditioning regimen for children with NMD, we performed an EBMT- registry-based analysis: 2187 patients from 39 countries with a congenital or acquired NMD below the age of 18 years who underwent first allogeneic HSCT between January 2010 and December 2014 registered in the EBMT database were included. 51% of children were transplanted before 4 years of age, 489 patients were less than 12 months old, and 61.5% were male. Majority of patients (32,2%) underwent HSCT for hemoglobinopathies (463 thalassemia major, 127 sickle cell disease), the second most common disease type was SCID with 17.4%, followed by other primary immunodeficiencies, chronic granulomatous disease and bone marrow failure syndromes (excluding Fanconi anaemia): 13.2%, 11% and 10.4%, respectively. The given conditioning regimen was under discretion of the treating physician. The most common conditioning regimen consisted of a combination of busulfan (bu)/fludarabine (flu) in 1063 patients, of treosulfan (treo)/flu in 422 patients; 473 patients received a combination of treo/flu/thiotepa (tt) and 229 patients received bu/flu/tt. The median total dose of the respective conditioning drugs was comparable (treo: 41 g/m2 or 42g/m2; bu: 160 mg/m2; tt: 201 and 205 mg/m2). In univariate analysis, overall survival (OS) was significantly different between the conditioning groups (p = 0.0032): 2y-OS 87.7% [84.3%-91.2%] for treo/flu/tt vs. 82.4% [78.5%-86.5%], 81.8% [77.8%-86.0%] for treo/flu, 80.8% [78.1%-83.5%] and 78.2% [75.2%-81.3%] for bu/flu and 81.3% [75.9%-87.0%] and 80.4% [74.9%-86.4%] for bu/flu/tt, respectively. Transplant-related mortality (TRM) was significantly different between the conditioning groups (p = 0.0015): day-100 TRM was lowest after treo/flu/tt: 4.8% [2.8%-6.7%] compared to 9.2% [6.3%-12.0%] after treo/flu, 7.9% [6.2%-9.5%] after bu/flu and 9.9% [5.9%-13.8%] after bu/flu/tt. TRM at 1 year post-transplant: 8.3% [5.5%-11.0%] for treo/flu/tt, 16.2% [12.2%-20.0%] after treo/flu, 16.9% [14.2%-19.4%] after bu/flu and 14.9% [9.7%-19.8%] after blu/flu/tt, respectively. In multivariate analysis, the HR was adjusted on age groups at HSCT, underlying disease, year of HSCT, stem cell source and donor types. 1-y OS was significantly better after treo/flu/tt (89.5 [86.5 - 92.6], CI 95%, p 0.0032) than with treo/flu, bu/flu or bu/flu, respectively. Day 100- and 1-year TRM was lower after treo/flu/tt compared to the other three conditioning combinations. A pairwise testing of the different treatment groups revealed no statistical significant difference in OS, TRM, disease-free survival (DFS) for bu/flu vs. treo/flu, bu/flu vs. bu/flu/tt and bu/flu/tt vs. treo/flu; a significant better OS, DFS and less TRM for treo/flu/tt vs. bu/flu, treo/flu/tt vs. treo/flu and a better DFS for treo/flu/tt vs. bu/flu/tt with a trend for better OS and less TRM for treo/flu/tt vs. bu/flu/tt. No statistically significant differences were found among the 4 conditioning regimens for acute or chronic GVHD. Conclusion: For children with NMD, a variety of conditioning regimen are in use to facilitate engraftment, prevent rejection, and enable sufficient cell function. Beside treo and bu, flu and tt are established drugs to eradicate lymphocytes. In this analysis, the combination of treo/flu/tt shows promising outcome results and should be further evaluated in diseases specific prospective trials. Disclosures Peters: Pfizer: Consultancy; Amgen: Consultancy; Jazz: Speakers Bureau; Novartis: Consultancy; Medac: Consultancy. Slatter:Medac: Other: Travel grants. Bader:Medac: Consultancy, Research Funding; Riemser: Research Funding; Neovii Biotech: Research Funding; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation in Older Patients with Acute Myeloid Leukemia: Analysis of the Francophone Society for Stem Cell Transplantation and Cell Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3447-3447
Author(s):  
Regis Peffault De Latour ◽  
Matthieu Resche-Rigon ◽  
Didier Blaise ◽  
Johan Maertens ◽  
Patrice Ceballos ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Sibling Donor

Abstract Background: Nowadays acute myeloid leukemia (AML) patients above the age of 60 years are often candidates for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT). However, little is known about the outcomes of HSCT in this particular population, due to the low number of HSCT with robust follow-up, the heterogeneity between centers, as well as reports usually mixing AML and other diseases such as myelodysplastic syndrome. We used the database of the Francophone society for stem cell transplantation and cellular therapy to address this question in a large cohort of patients in a recent time period. Patients and methods: 1167 consecutive patients aged ≥60 years with AML in complete remission (CR), transplanted between January 1st 2006 and January 1st 2016, reported to ProMISe (Project Manager Internet Server), an internet-based system shared by 36 Francophone transplantation centers, were reviewed. Classical post-HSCT endpoints were studied such as engraftment, acute and chronic graft-versus-host disease (GvHD), non-relapse mortality (NRM), relapse rate, leukemia free survival (LFS) as well as overall survival (OS). Cytogenetic risk was assessed according to the European Leukemia Network 2017 for patients in first complete remission. Data were analyzed using proportional hazards models and proportional sub-distribution hazards models in presence of competing risks. Results: Patients' Characteristics are detailed in Table 1. The median age at HSCT was 62.9 years (Interquartile range -IQR 61.9-66.1). Patients aged ≥60 years but less of 65 represented 63.8% of the population with 68.2% of patients transplanted in the recent period (2011-2016). Most patient had de novo AML (91.6%), in first CR (76.9%) with intermediate risk (83.8%) according to ELN-2017 classification. A matched unrelated donor (MUD) was used in 45 % of transplants and the majority of patients received peripheral blood stem cells (83.7%). Half of the patients received fludarabine and 2 days busulfan as conditioning regimen. The majority of patients (70.9%) received anti-thymocyte globuline (ATG). Engraftment occurred in 1089 patients (93.3%; 95%CI, 91.9-94.8). Day 100 cumulative incidence of grade II-IV acute GVHD was 24.6% (15.7% grade II; 5.8% grade III; 3% grade IV). At last follow up, 378 patients had developed chronic GVHD (severe in 37.2% of them; 95%CI, 34.0-40.3). With a median follow-up of 3.5 years (95%CI, 3.1-3.7 years), overall survival (OS) and LFS probabilities at 3 years were 50.7% (95%CI, 47.7-54.0) and 44.8% (95%CI, 41.8-48.1), respectively. In multivariable analysis, the only factor associated with worse OS was the use of a mismatched unrelated donor compare to MUD [Hazard Ratio (HR): 1.35 (95% CI, 1.01 to 1.80), p=0.04]. At 3 years, relapse incidence was 34.4% (95% CI, 31.5-37.4). The use of a sibling donor compared to MUD [Sub-distribution Hazard Ratio (SHR): : 1.49 (95% CI, 1.19 to 1.87), p<0.001], poor risk AML in CR1 according to ELN classification [SHR: 1.49 (95% CI, 1.10 to 2.02), p=0.01], as well as the use of ATG in the conditioning regimen [SHR: 1.57 (95% CI, 1.21 to 2.05), p<0.001] were associated with a higher risk of relapse. During the study, 534 patients died (main causes of death was relapse, 53%); leading to a CI of NRM of 20.7% at 3 years (95%CI, 18.2-23.2). A karnofsky score above 90% [SHR: 0.74 (95% CI, 0.56 to 0.98), p=0.04] and the use of a sibling donor compare to MUD [SHR : 0.43(95% CI, 0.30 to 0.63), p<0.001] were associated with reduced NRM. Conclusion: With more than 3 years follow-up, which is long enough for our results to be considered to be robust, the use of a mismatched unrelated donor was the only factor associated with worse overall survival in this population of AML patients aged of 60 years or more. Relapse appeared as the first cause of death, independently related to AML ELN poor risk classification, but also to the use of a sibling donor and of ATG in the conditioning regimen. This study highlights the major role of alloreactivity in this particular population, where modulation of T-cell alloreactivity as well as donor choice should be urgently addressed in well-designed prospective trials. Disclosures Peffault De Latour: Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

Cytomegalovirus and Effect on Early Chimerism in Patients with Myeloid Disorders Undergoing Stem Cell Transplantation Using Reduced Toxicity Ablative Conditioning Regimen

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5446-5446
Author(s):  
Shatha Y. Farhan ◽  
George Divine ◽  
Klodiana Neme ◽  
Danielle Pelland ◽  
Susan Wautelet ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Disease Risk ◽  
Conditioning Regimen ◽  
High Risk Patient ◽  
Hematopoietic Stem ◽  
The Mean ◽  
Reduced Toxicity ◽  
The Impact

Abstract Cytomegalovirus (CMV) remains a significant cause of morbidity after allogeneic hematopoietic stem cell transplantation (SCT). The influence of CMV on the chimerism in reduced toxicity ablative conditioning SCT in myeloid disorders is ill defined. A recent report published in Blood by Sellar et al showed that in patients who received alemtuzumab-based regimen, the group of patients who were recipient positive (R+)/ Donor negative (D-) had CMV-specific T cells that are exclusively of recipient origin and significantly influenced the chimerism status toward recipients. To explore the impact of seropositivity and seronegativity of CMV in recipients and donors on early chimerism, we undertook a retrospective analysis of patients with myeloid disorders who received four days of fludarabine and busulfan with or without anti-thymocyte globulin (ATG) at our center in the last 10 years. Methods: Chimerism assay was performed using a quantitative fluorescence-based short tandem repeat-polymerase chain reaction (STR-PCR) with capillary electrophoresis for PCR product resolution. Results: 42 patients were identified and included in the study. All patients received fludarabine (40 mg/m2/day x 4 doses), busulfan (3.2mg/kg/dose IV x 4 doses). Of these 42 patients, 25 had anti-thymocyte globulin. There were 28 male and 14 female patients with a median age of 62 years (range 48-74yrs). Median time to follow up was 8 months (0.8-54 months). Disease risk was considered advanced in 21 patients, intermediate in 4 and early in 17. Median blast number at time of SCT was 5%. Stem cell source included peripheral blood in all patients. There were no primary graft failures. Total recipient cell chimerism showed increase or persistence of recipient chimerism in 5/11 (45%) of R+D- vs 2/6 (33.3%) of R-D- in the group of patients who received ATG, p=1.0, with a mean of recipient chimerism at day 100 of 20.4% in the R+D- group compared to a mean of 17% in the R-D- group. In the group who did not get ATG, recipient chimerism persistence or increase was not that different between the R+D- patients 3/4 (75%) compared to 4/4 (100%) in patients who were seronegative for CMV (R-), p=1.0. The mean of recipient chimerism at day 100 in the R+D- no ATG group was 23.25% with a median of 12% while the mean and median at day 100 in the R- no ATG group were 35.25% and 19.5% respectively (p=0.573).When looking at the persistence or increase in recipient chimerism in the group of patients who were R+D-, in those who got ATG it was 45% increase vs 75% increase in those who did not get ATG (p=0.569) with a median of 12% vs 0% respectively (p=0.49). Also increase or persistence of recipient chimerism was 33.3 % in patients who were R- and got ATG vs 100% in R- no ATG patients (p=0.076)with median at day 100 of 0 vs 19.5% (p=0.098). Conclusion: In this small cohort from a single center, we found that in patients with myeloid disorders who received reduced toxicity ablative conditioning regimen, the group of patients who received ATG, there was no statistically significant increase in recipient chimersim in the R+D- group compared to R-D- group. This is different from what Sellar et al found in a small group of patients who received alemtuzumab. These results may indicate a difference between ATG and alemtuzumab in the effect of CMV seropositivity and negativity on the recipient chimerism, which need to be studied further in a larger retrospective or prospective study. This is especially important in myeloid disorders since persistent or increase in recipient chimerism may identify high-risk patient cohorts who may benefit from additional therapeutic interventions. Disclosures No relevant conflicts of interest to declare.

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