Busulfan Dosing May Affect Survival Following Reduced Intensity Stem Cell Transplantation in Patients with Acute Myelogeneous Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4328-4328
Author(s):  
Karen K Ballen ◽  
Steven L McAfee ◽  
Bimalangshu R Dey ◽  
Christine Dube ◽  
Eyal C Attar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Complete Remission ◽  
Total Dose ◽  
Conditioning Regimen ◽  
Allogeneic Transplantation ◽  
Unrelated Donor ◽  
Gvhd Prophylaxis ◽  
Acute Myelogeneous Leukemia ◽  
Reduced Intensity

Abstract Abstract 4328 The prognosis for patients with acute myelogeneous leukemia over age 60 is poor, with a 5 year survival of less than 10%. Reduced intensity allogeneic transplantation has been employed in an attempt to improve survival. We report 23 patients who received reduced intensity allogeneic transplantation after a conditioning regimen of busulfan and fludarabine. Fifteen patients received a transplant from a matched sibling donor,1 patient from a 5/6 matched child and 7 patients from a fully matched (10/10) unrelated donor. We treated 10 patients with the reduced intensity conditioning regimen of busulfan IV 0.8 mg/kg daily Days -6, -5, -4, -3 (total dose 3.2 mg/kg) and fludarabine IV 30 mg/m2 Days -6,-5, -4, -3 (total dose 120mg/kg). After November, 2007, 10 patients were treated with twice daily busulfan IV 0.8mg/kg (total dose 6.4 mg/kg) with the same dose of fludarabine. Three patients were treated on a national protocol in which the same dose of busulfan (6. 4 mg/kg) was administered but given at 0.8 mg/kg four times daily for 2 days on Days -4 and -3 with fludarabine. GVHD prophylaxis was cyclosporine or tacrolimus with either cellcept or (after July, 2008) methotrexate. Seven recipients of unrelated donor or mismatched transplants also received rabbit antithymocyte globulin 1.5 mg/kg Days -3, -2, -1 (total dose 4.5 mg/kg) as part of their GVHD prophylaxis. Median age was 65 years (range 46-70 years). Fourteen patients were in 1st complete remission, 8 were in 2nd complete remission, and one patient had active disease at the time of transplant. Two patients had received a prior autologous stem cell transplant and 2 patients had received a prior allogeneic transplant. The median days to neutrophil (ANC >500) and platelet engraftment (plt >20K) were 15 and 14 respectively. The median length of stay was 25 days (range 13-40 days). Median follow-up was 12 months among the 10 patients still alive. The incidence of acute GVHD Grades II-IV and chronic GVHD were 44% and 35% respectively. Transplant related (non relapse) mortality at 100 days and at 6 months was 0. The overall non-relapse mortality was 4%. Relapse rate was 67% in the daily busulfan group and 46% in the higher dose busulfan group. The one-year overall and disease-free survivals for all patients were 44% and 25% respectively. Causes of death were relapse in 12 patients and in one patient sepsis six years after transplant. In multivariate analysis, disease status, age, and GVHD did not predict for survival, perhaps due to the small sample size. There was a trend to improved survival in the higher dose busulfan group but the follow up was shorter for these patients. In summary, 1) Reduced intensity transplantation is tolerated well in an older population with acute myelogeneous leukemia, with no transplant related mortality at Day 100 or at 6 months post transplant; 2) Relapse rermains the most common cause of death; 3) There was a trend to improved survival with a twice daily busulfan dosing. Future studies will address the outcomes of twice daily busulfan dosing in a larger cohort of older patients with AML in complete remission. Disclosures: Spitzer: Genzyme: Consultancy.

scholarly journals Efficacy of Reduced-Intensity Allogeneic Stem Cell Transplant after Brentuximab Vedotin in Patients with Hodgkin Lymphoma Relapsed after Autologous Transplant

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5943-5943
Author(s):  
Francesco Zallio ◽  
Alessandro Busca ◽  
Nicola Mordini ◽  
Maria jose Fornaro ◽  
Benedetto Bruno ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Complete Remission ◽  
Conditioning Regimen ◽  
Brentuximab Vedotin ◽  
The Other ◽  
Survival Outcomes ◽  
Allogeneic Transplant ◽  
Reduced Intensity

Abstract Purpose: The prognosis of patients with Hodgkin lymphoma (HL) who relapse following autologous stem cell transplantation (ASCT) is generally poor, because salvage chemo-radiotherapy is able to produce only short-lasting remissions. In a previous study on a large patients' population (Sarina B et al, Blood 2010) was clearly demonstrated that the availability of a donor could significantly improve survival outcomes after allogeneic transplant, in particular for the subset of patients who reach a status of pre-transplant complete remission; however the application of this procedure is actually limited by a difficulty to obtain an objective response before alloSCT. It was recently shown that Brentuximab vedotin, a new generation antibody-drug conjugate, is able to induce nearly 30% of complete remission in HL patients relapsing after autologous transplant; therefore this agent could effectively work in relapses after ASCT as a platform to allow a better disease control in order to improve the outcome of the allografting procedure. Aims: Aim of this study was to retrospectively investigate if brentuximab vedotin administered as a salvage therapy in HL patients relapsing after ASCT could improve the efficacy of a subsequent reduced-intensity allogeneic transplant. Methods: Between August 2011 and September 2013, 11 patients underwent to allo-SCT at four hematologic Divisions of Northern Italy for HL relapse after ASCT, after brentuximab vedotin administered as a bridge to the allografting procedure. Median age was 32 years (range 21-61) and median number of prior regimens was 5, including ASCT. Patients received a median of 6 cycles (range 4-7) of brentuximab vedotin administered every 3 weeks as a 30-minute outpatient IV infusion; median time between the last dose of brentuximab vedotin and the allo-SCT was 1 month (range 1-5 months). No patient experienced progression during treatment with brentuximab vedotin (4 complete remissions and 7 partial remission/stable disease). All but one patients did not have a HLA identical sibling, so they required a matched unrelated (6 patients), haploidentical donor (3 patients) or cord blood (1 patient); peripheral stem cells were the source in patients with HLA identical sibling or unrelated, whereas bone marrow was used in the haplo setting. Reduced-intensity was the conditioning regimen performed in all patients. Post transplant cyclophosphamide plus mycophenolate mofetil/tacrolimus was the graft-versus-host disease (GVHD) prophylaxis of the haplo setting, while Metotrexate/cyclosporine was administered in the other patients. Patients were monitored for engraftment and infectious complications per institutional standards; survival outcomes were defined according to the European Blood and Marrow Transplantation (EBMT) criteria for survival analysis. Results: One patient had primary graft failure with autologous reconstitution; she was a patient with a high body-mass index, in whom the drug's doses of the conditioning regimen were underestimated in order to avoid excessive toxicity. All the other patients engrafted; median time to neutrophil recovery was 20 days (range 15-26). At a median follow-up of 12 months, the 2-year progression free survival was 51%, 2-year Overall Survival was 61%. There were 2 toxic deaths, one for EBV reactivation and one for leuko-encefalopathy disease, resulting in a 2-year non-relapse mortality of 18%. Conclusions: These data suggest that brentuximab vedotin represents a promising salvage therapy in HL patients relapsed after ASCT. Despite the bias concerning the differences in source of stem cells and pre-transplant conditioning regimens, we showed that brentuximab could be administered in patients who are candidates to a RIC allo-SCT, with encouraging survival outcomes. Further clinical trials with larger number of patients and longer follow-up are recommended to confirm the promising role of brentuximab as a bridge to alloSCT. Disclosures No relevant conflicts of interest to declare.

The Addition of ONE-Day Rest Between LAST ATG Infusion and STEM CELL Infusion DID NOT Affect Gvhd Occurrence After Allogeneic TRANSPLANTATION with Fludarabine-Busulfan-ATG Conditioning.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3029-3029
Author(s):  
Roberto Crocchiolo ◽  
Sabine Fuerst ◽  
Jean El-Cheikh ◽  
Angela Granata ◽  
Claire Oudin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Allogeneic Transplantation ◽  
Unrelated Donor ◽  
Progression Rate ◽  
Gvhd Prophylaxis

Abstract Abstract 3029 Introduction: Antithymocyte globulin (ATG) is part of many conditioning regimens for allogeneic stem cell transplantation (AlloSCT) with the aim of reducing graft-versus-host disease (GvHD), due to in vivo T-cell depletion. ATG administration may be accompanied by fever, chills, headache or other side effects that affect patient's management and can cause a delay in stem cell infusion. In order to improve ATG tolerance, since November 2010 we modified our fludarabine-busulfan-ATG (FBA) conditioning for RIC transplants with the addition of 1-day rest between the last ATG administration and stem cell infusion. No modification of drugs or GvHD prophylaxis occurred: five days of fludarabine, two days of i.v. busulfan and two days of ATG Thymoglobuline (10 mg/kg total dose) were administered during conditioning, and ciclosporine for GvHD prophylaxis together with MMF only in the presence of a mismatched unrelated donor (MMUD). Aim: To analyse whether the addition of 1-day rest between ATG administration and stem cell infusion impacted on outcome of adult patients receiving AlloSCT after FBA conditioning with respect to previous no-rest modality, in particular acute grade 2–4 or grade 3–4 GvHD. Methods: The 1-day rest cohort (ATG-rest) was compared with a previous consecutive cohort of patients (no rest) transplanted at our center. Analysis of acute GvHD among the two groups was performed as well as of chronic GvHD, OS, PFS, NRM, relapse/progression. Results: A total of 64 and 63 patients were included in ATG-rest and no-rest cohorts respectively. First patient in the no-rest cohort received AlloSCT on November 2008. Follow-up was thus longer in this cohort: median 27 months (21–37) vs. 15 (11–20), p<0.0001. No significant differences of patients' age, diagnosis and disease status at AlloSCT between the two groups were observed; matched unrelated donors (MUDs) were higher in the ATG-rest group whereas the number of MMUDs was similar in both groups (see Table 1). Rate of acute and chronic GvHD and NRM, probabilities of OS and PFS did not differ between the two groups (Table 1). Unexpectedly, relapse/progression rate was lower in the ATG-rest groups (p=0.002), although disease status at AlloSCT was not significantly different between the two cohorts. Median day of relapse or progression from AlloSCT in the no-rest group was +165 (35–476) vs. +57 (8–215) in ATG-rest one, p=0.004. No difference in relapse/progression was observed according to donor (HLA-identical sibling vs. MUD vs. MMUD) and a lower relapse risk in 1-day rest group is confirmed after adjustment for type of donor: HR = 0.29 (0.12–0.72), p=0.01. Conclusion: The addition of 1-day rest between last ATG administration and stem cell infusion did not impacted on GvHD occurrence after AlloSCT after FBA conditioning. The finding of a reduced rate of relapse/progression in the ATG-rest group deserves to be investigated and requires longer follow-up. Disclosures: No relevant conflicts of interest to declare.

Reduced-Intensity Allogeneic Transplantation after Failure of Autologous Transplantation: A Prospective Multi-Center CALGB Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3122-3122
Author(s):  
Asad Bashey ◽  
Kouros Owzar ◽  
Jeffrey L. Johnson ◽  
Steven M. Devine ◽  
Richard K. Shadduck ◽  
...  
Keyword(s):  
T Cell ◽  
Autologous Transplantation ◽  
Allogeneic Transplantation ◽  
High Dose ◽  
Unrelated Donor ◽  
Group Setting ◽  
Donor Chimerism ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity

Abstract Relapse of malignancy (RM) remains the most important cause of treatment failure following high-dose chemotherapy and autologous hematopoietic transplantation (AHCT). Allogeneic transplantation (allo-HCT) can salvage some patients who relapse or develop MDS following AHCT. However, myeloablative allo-HCT has been associated with a prohibitive transplant-related mortality (TRM) in such patients. CALGB study 100002 prospectively assessed the safety of reduced-intensity allo-HCT (RICT) in patients who failed prior AHCT. Eligibility required the development of RM or MDS > 6 months following AHCT for a hematologic malignancy and an available HLA-identical sibling (MSD) or 9/10 locus matched related donor, or a 10/10 matched unrelated donor. Between Dec 02 and Mar 06, 82 patients were registered from 11 CALGB centers. Patient characteristics: median age = 51 (17–70); male-63%; diagnoses - NHL 30%, HD 26%, MM 18%, MDS 16%, AML 8%, CLL 2%; donor - MSD 43%, MUD 55%, 9/10 MRD 2%. Median time between AHCT and RICT was 2.6 yrs (0.6–5.7 yrs). Preparative regimen for patients with MSD was fludarabine 30 mg/m2/d x 5 d, busulfan (i.v.) 3.2 mg/kg/d x 2 d. For patients without MSD rabbit ATG (Thymoglobulin ®) 2.5mg/kg/d x 4 d was added. PBSC 2–8 x 106 CD34+ cells/kg was used as the graft. GVHD prophylaxis consisted of tacrolimus tapering at d +90 and methotrexate 5 mg/m2 x 3 doses for MSD patients. For non-MSD patients, tacrolimus was tapered starting d +180, a fourth dose of methotrexate and MMF (d 0 to d +60) were added. Primary endpoint was TRM at 6 months. For 56 patients with > 6 months post-RICT follow-up (median follow-up 1.3 yrs), 6 month TRM was 8.7% (MSD patients 4.2%, non-MSD patients 9.3%). Total cumulative TRM was 14.3% (MSD 16.7%, non-MSD 12.5%). Reported cumulative rates of II–IV and III–IV acute GVHD are 28.2% and 11.8% respectively. Chimerism studies were performed centrally on peripheral blood (PB) specimens. The percentage of patients from MSD patients who achieved full (> 90%) donor T-cell (CD3) chimerism in PB on day 30, 60, 90 and 180 post transplant are 15, 40, 47, 57 and 60% respectively. In contrast, for non-MSD patients the corresponding rates are 78, 68, 86 and 91 % respectively. Both MSD and non-MSD patients achieved full (>90%) donor chimerism in myeloid cells by d 30 in > 80% of patients. This study observed a <10% 6-month TRM for RICT following AHCT failure in the multi-center, co-operative group setting. Also, the use of a more potent GVHD prophylaxis regimen seems to enable TRM rates for non-MSD patients to approximate those seen for MSD patients. MSD patients achieve slower onset of full-donor chimerism in T-cells with this regimen. A successor study will assess means of increasing early T-cell chimerism in the MSD patients.

Mismatches in Low Expression HLA Class II Loci and MIC-A in Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3050-3050
Author(s):  
Poliana Patah ◽  
Marcelo Fernandez-Vina ◽  
Peter Stastny ◽  
Ping Liu ◽  
Pedro Cano ◽  
...  
Keyword(s):  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Low Expression ◽  
Reduced Intensity ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Little is known of the possible additive effects of mismatches in low expression class II HLA loci (DQB1, DPB1 and DRB3,4,5), and mismatches in MHC class I chain related (MIC-A) on the outcomes of unrelated donor HSCT. We investigated such hypothesis in a group of 139 consecutive patients (pts) with myeloid leukemias transplanted from 01/02 to 02/06 in our institution. All pts received a 8/8 matched graft (HLA-A, -B, -C, -DRB1). Preparative regimens were ablative [IV Busulfan-based (n=93) or Cy/TBI (n=1)], and reduced intensity [(Fludarabine (Flu)/Bu 130 mg/m2/2 doses plus Gleevec (n=7), and Flu/Melphalan 140 mg/m2 (n=38)]. Stem cell (SC) source was bone marrow (n=107) or peripheral blood (n=32). ATG was given in 134 cases. GVHD prophylaxis was tacrolimus and mini-methotrexate in all cases, with additional pentostatin in 38 pts. High-resolution typing was sequence-based for HLA-A, B, DRB1; SSP was used for DRB3/4/5, DQB1 and DPB1, SBT/SSOP for HLA-C and nucleotide-sequencing for MIC-A. A Cox proportional hazards regression model was used to study aGVHD-free and relapse-free survival (RFS). Variables with a p-value < 0.25 by univariate analysis were included in the multiple regression analysis (MV). Variables were age, gender, weight, conditioning regimen, GVHD prophylaxis, diagnosis, cytogenetics, SC source, ABO group, infused CD34 and CD3 cell dose, and HLA matching. aGVHD-free survival was calculated from transplant date to date of development of grade II-IV aGVHD or completion of 100 days of follow-up. Results: Median age was 50 yrs (range, 14–75). Diagnoses were MDS (n=19), AML (n=95), CML (n=18) and other MPD diseases (n=6). 61 patients (44%) were in 1st or 2nd CR at transplant; all CML pts were in >1st chronic phase (CP). 133 (96%) patients engrafted neutrophils at a median of 13 days. 49 (35%) and 13 (09%) pts developed grade II-IV and III-IV aGVHD, respectively. Chronic GVHD incidence was 33%. With a median follow-up of 16 months (range, 2–64), 78 pts are alive. Median survival has not been reached. Reduced-intensity conditioning regimen was the only covariate which influenced aGVHD-free survival by MV analysis [p= 0.05; HR 0.53 (95%CI 0.28–1.0)]. Treatment-related mortality was higher among patients who had more than 3 mismatches in the low-expression loci and/or in MIC-A [p=0.01; HR 3.87 (95%CI 1.33–11.26)]. Among the 82 pts who were in CR at transplantation, 10/10 matching status reduced the incidence of grade II-IV aGVHD [p= 0.04; HR 0.35 (95%CI 1.18–0.72)], while the presence of a MIC-A mismatch determined a higher grade II-IV aGVHD incidence [p=0.02; HR 2.7 (95%CI 1.15–6.31)]. Conclusion: Multiple mismatches in low expression loci and in MIC-A increase treatment-related mortality in HLA 8/8 matched donor-recipient pairs in a cumulative manner.

Comparison Of Unrelated Cord Blood (CB) and Peripheral Blood Stem Cell (PB) Transplantation In Adults With Myelodysplastic Syndrome (MDS) After Reduced Intensity Conditioning Regimen (RIC): A Collaborative Study From Eurocord and Chronic Malignancies Working Party (CMWP-EBMT)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3334-3334
Author(s):  
Marie Robin ◽  
Annalisa Ruggeri ◽  
Myriam Labopin ◽  
Dietger Niederwieser ◽  
Reza Tabrizzi ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
Myelodysplastic Syndrome ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Unrelated Cord Blood ◽  
Reduced Intensity

Abstract Background Outcome of patients with intermediate or high risk IPSS myelodysplastic syndrome (MDS) is poor in the absence of hematopoietic stem cell transplantation (HSCT). Choice of the best stem cell source is debated in this poor risk population. Unrelated cord blood transplantation (UCBT) has been used for patients lacking an HLA identical donor. This is the first study comparing well matched unrelated adult peripheral blood (PB) stem cell transplant to mismatched UCBT for patients with MDS. Method Patients with MDS transplanted from 2005 to 2011 with either unrelated CB or PB receiving a reduced intensity conditioning (RIC) were included. All PB donors were Human Leucocyte Antigens (HLA)-allele matched (10/10) or one allele mismatched (9/10) (-A, -B, -C, DRB1, -DQB1). Overall survival (OS) and disease-free survival (DFS) were estimated by Kaplan-Meier. Relapse incidence (RI), non-relapse mortality (NRM), engraftment, acute and chronic graft-versus-host disease (GVHD) were calculated using cumulative incidence (CInc) methods. Risk factors for outcomes were analyzed by Cox and Fine & Gray models. Results 502 patients transplanted with PB or 129 with CB (80 with double units) were compared. Among the PB recipients, 363 (72%) were 10/10 matched and 123 (25%) 9/10 matched. Most CB (98%) recipients had at least one HLA mismatch on 6 antigens tested (-A, -B antigen level and DRB1 allelic level), 32% had one mismatch and 66% had 2 mismatches. Median follow-up was 12 months for PB and 24 months for CB. MDS was transformed into AML in 416 patients. MDS WHO classification was: RA in 37, RCMD in 31, RAEB1 in 50 and RAEB2 in 87 and unclassified in 10 patients. Considering only patients with MDS, cytogenetic according to IPSS was: good in 96, intermediate in 57 and poor in 65 patients. PB and CB groups were different for age, gender, incidence of secondary AML (CB: 71% vs PB: 64%) and conditioning regimen. CInc of engraftment was lower in CB patients, 78 vs 96% (p<0.0001). Grade II to IV acute GVHD was 29% and 31% for PB and CB. Chronic GVHD was more frequent after PB (42% vs 23%, p=0.001). The unadjusted 2-year OS and DFS were better in patients transplanted with PB (46% vs 30% and 43% vs 28%, p=0.0001). There was no statistical difference for OS and DFS between single and double UCBT. RI was not significantly different (25 vs 30%, p=0.09) whereas NRM was higher in patients transplanted with CB (42 vs 33%, p=0.02). In multivariate analysis, OS (Hazard ratio (HR): 0.59, 95% confidence interval (CI): 0.44-0.80) and DFS (HR: 0.57, 1.89, 0.79) were higher in patients transplanted with PB compared to CB. Furthermore, after adjustment, CB was also a risk factor for higher NRM ((PB, HR: 0.55, 95%CI: 0.37-0.80) and RI ((PB, HR: 0.62, 95%CI: 0.39-0.97). The analyses were performed using 3 groups of patients according to donor HLA type: PB 10/10, PB 9/10 and CB. The unadjusted 2-year OS and DFS were better with PB 10/10 than with PB 9/10 or CB: 49%, 37% and 30% (p=0.0001) and 45%, 36%, 28% (p<0.0001), respectively. NRM was not significantly different between CB and PB 9/10: 42% vs 36%. RI was similar after CB and PB 9/10: 28% vs 30%. Chronic GVHD was significantly lower after CB (PB 9/10: 37% vs CB 23%, p=0.004). The multivariate analysis showed an advantage of OS for PB 10/10 compared to PB 9/10 (HR: 1.45, 95%CI: 1.06-1.97, p=0.02) whereas there was no significant difference between PB 9/10 and CB (HR: 1.24, 95%CI: 0.84-1.83, p=0.29). Likewise, DFS was better after PB 10/10 (HR: 0.57, 95%CI: 0.43-0.77, p=0.05) and it was similar after PB 9/10 or CB (HR: 1.34, 95%CI: 0.92-1.97, p=0.13). In the 9/10 PB no differences in the results were observed according to the specific mismatched locus (A, B, DRB1, vs C, DQB1) Conclusion Despite the limitation of a retrospective registry based study and the short term follow up, our study shows that transplants with PB from matched unrelated donor gives the best outcomes. In the absence of a 10/10 unrelated matched PB donor, a 9/10 PB donor or mismatched CB give similar results. Therefore, for MDS patients without a HLA 10/10 unrelated donor a 9/10 regardless of the specificity of the locus where the mismatch occurs mismatched HLA locus or a HLA mismatched CB are both alternative options for transplantation. Disclosures: Gluckman: Cord use: Honoraria; gamida: Honoraria.

scholarly journals Outcome of Hematopoietic Stem Cell Transplantation in Children with Primary Hemophagocytic Lymphohistiocytosis: A Single Institution Experience Using Reduced Intensity Conditioning

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Mohammed Essa ◽  
Enas Basher ◽  
Rodaina Abujoub ◽  
Abdulrahman Alsultan
Keyword(s):  
Stem Cell ◽  
Graft Failure ◽  
Conditioning Regimen ◽  
High Rate ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Donor Chimerism ◽  
Gvhd Prophylaxis

Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for primary hemophagocytic lymphohistiocytosis (HLH). Conventional myeloablative conditioning regimen using busulfan, cyclophosphamide with or without etoposide was associated with high rate of transplant-related mortality (Horne et al. BJH 2005). Reduced intensity conditioning (RIC) is used in HLH to minimize transplant-related toxicities. The use of alemtuzumab, fludarabine, and melphalan in HLH was associated with low mortality; however, mixed donor chimerism and graft failure were frequent (Allen et al. Blood 2018). A recent report in 25 HLH patients who underwent HSCT from HLA matched donors using targeted busulfan (45-65 mg/L X h), fludarabine, and serotherapy resulted in adequate stable donor chimerism, no graft rejection, and no mortality (Felber et al. Blood Adv. 2020). In this study, we reviewed the outcome of 16 HLH patients who underwent HSCT from HLA matched donors using RIC. All patients were initially treated using HLH-2004 protocol. They subsequently underwent HSCT from 10/10 HLA matched related or unrelated donor using RIC regimens. We initially used AFM conditioning regimen that included alemtuzumab (1 mg/kg), fludarabine (150 mg/m2), and melphalan (140 mg/m2) with or without thiotepa (10 mg/kg). GVHD prophylaxis included cyclosporine (CSA) and steroids. Given the high rate of low donor chimerism with AFM regimen, we subsequently used BF conditioning regimen that included busulfan (weight-based dosing for total of 16 doses) and fludarabine (160 mg/m2). Therapeutic drug monitoring of busulfan was performed. Thymoglobulin (10 mg/kg) was added in matched unrelated donor (MUD). GVHD prophylaxis included CSA and steroids in matched related donors (MRD) and CSA and methotrexate in MUD. Bone marrow was the stem cell source in all patients except one who underwent second transplant using peripheral blood stem cells. Supportive care was consistent among all patients. Defibrotide prophylaxis was administered to prevent sinusoidal obstruction syndrome (SOS). Donor chimerism &lt;5% from whole blood or &lt;20% in T-cell, graft failure, and death from any cause were considered as events. A total of 16 HSCT transplants were performed, 5 received AFM regimen and 11 received BF regimen. Patient and transplant characteristics are shown in Table. All patients had successful neutrophil and platelet engraftments. Among the five patients who underwent AFM conditioning, one patient with SH2D1A mutation is 8 years post transplant with stable full donor chimerism and another patient with PRF1 mutation who received AFM with thiotepa has stable sufficient donor chimerism 3 years post transplant. Both patients did not require donor leukocyte infusions (DLI). The remaining 3 patients had declining donor chimerism beyond the first year of transplant despite the frequent use of DLI, one of them had disease reactivation and underwent second HSCT using BF regimen. Event free survival (EFS) at 3 years was 60% and overall survival (OS) was 100%. Among the 11 patients who underwent BF regimen, 7 were transplanted using MRD and 4 MUD. The median cumulative area under the curve of busulfan was 64 mg/L X h (range, 56-73). Median donor myeloid chimerism was 97% (range, 83-100) and median T-cell chimerism was 78% (range, 40-93). One patient who underwent MUD had grade III acute GVHD and none had chronic GVHD. Two patients had mild SOS. There were no events among BF group with median follow up duration of 393 days (151-2080). The use of BF regimen in HLH was associated with excellent outcome and stable donor chimerism with no graft failure in comparison to AFM regimen. Longer follow up is needed to confirm our findings. Disclosures No relevant conflicts of interest to declare.

scholarly journals Outcome of Severe Aplastic Anemia Post Allogenic Stem Cell Transplant with Mycophenolate and Calcineurin Inhibitor for Graft Versus Host Disease Prophylaxis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4879-4879
Author(s):  
Omar Albanyan ◽  
Hyejeong Jang ◽  
Seongho Kim ◽  
Andrew Kin ◽  
Asif Alavi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Matched Donor

Abstract Introduction: Severe aplastic anemia (SAA) is a rare hematopoietic stem cell disorder characterized by hypocellular marrow and pancytopenia. Multiple factors play an important role in treatment approach include age, comorbidities, degree of pancytopenia and availability of stem cell donor to either immunosuppression irrespective (IST) or allogenic hematopoietic stem cell transplant (alloSCT). The use of nonmyeloablative conditioning regimen has improved the outcomes, however the choice for post-transplant GVHD prophylaxis remain a topic of debate. The use of mycophenolate mofetil (MMF) has been used as an alternative for methotrexate (MTX) as has shown to be associated with lower incidence of mucositis and shorter time to engraftment. Methods: We retrospectively evaluated consecutive adult patients with SAA who underwent alloSCT at Karmanoc Cancer Institute. All patients received fludarabine, cyclophosphamide and antithymocyte globulin for conditioning regimen with calcineurin inhibitors (CNI) and MMF for GVHD prophylaxis. MMF was started at day -3 at 15 mg/kg three times daily and stopped at day +30 in the absence of active GVHD. The primary objectives were to estimate cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD) and overall survival (OS). Secondary objectives were to evaluate time to engraftment, days of hospitalization and incidence of mucositis. Results: From January 2005 and May 2019, 33 patients with SAA underwent alloSCT. Patient characteristics are detailed in Table 1. Median age was 36 years (range, 18-71). Twenty-seven patients received bone marrow stem cells (82%) and six patients received peripheral blood stem cells (18%). Thirty patients (91%) received 8/8 HLA matched donor and three patients (9%) received 7/8 HLA matched donor. Sixteen patients (48%) received stem cells from sibling donor and 17 patients (52%) received stem cells from unrelated donor. Thirteen patients (39%) had received IST prior to alloSCT, and 20 patients (61%) received upfront alloSCT. For GVHD prophylaxis all patients received MMF and CNI (tacrolimus=32, and cyclosporine=1). Median time from diagnosis to transplant was 15.8 months for patients who received IST prior to alloSCT and 2 months for patients who received upfront alloSCT. Median time to platelet engraftment was 13.5 days and neutrophil engraftment was 12 days, while one patient experienced graft failure. The median number of days for hospital stay were 25 days. Four patients (11%) developed grade I-II mucositis, no grade III-IV mucositis was observed in the first 30 days and 6 patients had CMV reactivation. The 100-day cumulative incidence rate of grade II-IV aGVHD was 21.2% (95% CI, 9.2 - 36.5), grade III-IV aGVHD was 9.1% (2.3-21.9) and 1-year CIR of cGVHD was 21.2% (95% CI, 9.2-36.5). Comparing patients who received IST prior to alloSCT versus upfront alloSCT, the 100-day CIR of grade II-IV aGVHD was 30.8% (95% CI, 8.2 - 56.5) and 15% (95% CI, 3.6 - 34.0), respectively, (Gray p=0.26) and the 3-year CIR of cGVHD was 39.6% (95% CI, 13.1 - 65.5) and 27.8% (95% CI, 9.2 - 50.3), respectively, (Gray p=0.37). Comparing patients who received alloSCT from related versus unrelated donor, 100-day CIR of II-IV aGVHD was 12.5% (95% CI, 1.9 - 33.6) and 29.4% (95% CI, 10.2 - 51.9), respectively, (Gray p=0.26), and the 3-year CIR of cGVHD was 34.2% (95% CI, 11.4 - 58.9) and 29.4% (95% CI, 10.1 - 52.0), respectively (Gray p=0.90). Median follow up of surviving patient was 5 years (95% CI, 3.1-6.8). Three-year OS was 87% (95% CI, 75.7- 99.9) and median OS was not reached. Six patients died by the time of the analysis, one patient died from graft failure (86 days after transplant from 8/8 HLA MUD), two patients died due infectious complications (808 days and 1637 days after transplant), three patients died due to multiorgan failure (215, 297 and 1097 days after transplant). Conclusion: Our data with use of CNI and MMF for GVHD prophylaxis for SAA following alloSCT with nonmyeloablative conditioning regimen showed that the rate of mucositis was low, engraftment time was rapid, and hospitalization was short, while OS, rates of acute and chronic GVDH were comparable to previously published rates with CNI and MTX-based GVHD prophylaxis. Figure 1 Figure 1. Disclosures Modi: Genentech: Research Funding; Seagen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees. Deol: Kite, a Gilead Company: Consultancy.

Allogeneic Stem Cell Transplantation Using a Reduced Intensity Conditioning (RIC) Regimen Has the Capacity To Produce Durable Remissions and Long Term Disease-Free Survival in Patients with High Risk Acute Myeloid Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1141-1141
Author(s):  
S. Tauro ◽  
S. Mackinnon ◽  
K. Peggs ◽  
G. Begum ◽  
P. Mahendra ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Disease Free Survival ◽  
Allogeneic Transplantation ◽  
Disease Relapse ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Disease Free ◽  
Reduced Intensity

Abstract The toxicity of allogeneic stem cell transplantation (SCT) can be substantially reduced by the use of a reduced intensity conditioning (RIC) regimen and this has increased the proportion of patients with myeloid malignancies eligible for allogeneic transplantation. However, the capacity of RIC allografts to produce durable remissions in patients with AML and MDS has not yet been defined and consequently their role in the management of these diseases remains conjectural. Seventy-six patients with high risk AML or MDS were allografted using a fludarabine/melphalan RIC regimen incorporating alemtuzumab. The median age of the cohort was 52 years (range 18–71 years). There were 46 males and 30 females; 41 patients received an allograft from an unrelated donor and 35 from a matched sibling donor. The 100 day transplant related mortality was 9% and no patient developed greater than Grade 2 graft-versus-host disease (GVHD). With a median follow-up of 36 months (range 13–70 months) 27 patients were alive and in remission with a 3y actuarial overall survival (OS) and disease-free survival (DFS) rate of 41% and 37% respectively. The 3y OS and DFS of patients with AML in complete remission (CR) at the time of transplantation was 48% and 42% respectively. In a multivariate setting, Cox regression analysis demonstrated prognostic significance of disease stage at the time of transplant with improved DFS in patients with AML in CR at the time of transplantation (HR=2.03, 95% CI=1.02–4.07). Disease relapse was the commonest cause of treatment failure occurring at a median time of 6 months post-transplant. Fourteen out of 27 (52%) patients relapsed within 6 months and 23/27 (85%) within twelve months defining a relatively narrow window for therapeutic intervention to prevent disease recurrence. The extended follow-up in this series identifies a high risk of early disease relapse but provides evidence that RIC allografts are capable of producing sustained disease free survival in a significant number of patients with AML who would be ineligible for allogeneic transplantation using a myeloablative conditioning regimen.

Outcomes of 40 Adult Patients after Double Cord Blood Transplantation Using a Reduced Intensity Chemotherapy Conditioning Regimen.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 605-605
Author(s):  
Karen K. Ballen ◽  
Corey Cutler ◽  
Thomas R. Spitzer ◽  
Beow Yeap ◽  
Steve McAfee ◽  
...  
Keyword(s):  
Cord Blood ◽  
Total Dose ◽  
Aplastic Anemia ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cord Blood Unit ◽  
Reduced Intensity ◽  
Related Mortality

Abstract Umbilical cord blood is an alternative stem cell source for patients without matched related or unrelated donors. However, single cord blood unit transplantation in adults is associated with high transplant related mortality, mostly due to infection. In this study, we used a reduced intensity conditioning regimen followed by infusion of two partially matched cord blood units. The conditioning regimen was fludarabine 30mg/m2/day Days -8,-7,-6,-5,-4,-3 (total dose 180mg/m2), melphalan 100mg/m2/day Day -2, and rabbit antithymocyte globulin (thymoglobulin) 1.5 mg/kg/day Days -7,-5,-3,-1 (total dose 6.0 mg/kg). Cord blood units were a 4/6 or better HLA A, B, DR match with each other and with the patient, and contained a minimum combined pre-freeze cell dose of 3.7 x 107NC/kg. GVHD prophylaxis was cyclosporine and mycophenolate mofetil, for the first 21 patients, and tacrolimus and sirolimus for the second cohort of 19 patients. Forty patients, 22 males (55%) and 18 females (45%) with a median age of 48 years (range 19–64 years) were treated. The diagnoses were AML (n=14), ALL (n=1), NHL (n=10), CLL (n=2), MDS (n=5), Hodgkins Disease (n=5), aplastic anemia (n=2), and chronic myelogeneous leukemia (n=1). Thirty-five patients have greater than 100 days of follow-up and are included in this analysis. The cell doses infused were a median of 4.0 x 10 7NC/kg (range 3.0–6.7 x 107) and 1.9 x 10 5 CD34+ cells/kg (range 0.5–10.0 x 105). Two patients (both with MDS complicating aplastic anemia) experienced primary graft failure, and received second cord blood transplants using a different conditioning regimen. Among the remaining patients, the median time to an absolute neutrophil count &gt;500 was 21 days (range 14–70 days). There were two late graft failures. The median time to a platelet count &gt;20,000 unsupported was 43 days (range 21–125 days). The incidence of acute GVHD Grades II–IV was 40% for the patients receiving cyclosporine/MMF and 29% for patients receiving tacrolimus and sirolimus. There were no deaths from acute GVHD in the cyclosporine/MMF group and one death from acute GVHD in the tacrolimus/sirolimus group. Seven patients (20%) developed chronic GVHD. The 100-day transplant related mortality was 14%. Two deaths were related to Epstein Barr virus related lymphoproliferative disorder, and the other deaths were due to a CNS bleed, staphylococcal sepsis, and respiratory failure due to aspergillus infection. Two patients have relapsed and one has progressive disease. With a median follow up of 14 months (range 3–31 months) the overall survival is 74% and the disease-free survival is 67%. Chimerism analysis showed predominance of one cord by Day +100. In 71% of patients, the first cord blood unit infused predominated. In conclusion, engraftment of adult patients appears to be acceptable using double cord blood products and reduced intensity, non TBI conditioning regimen; the risk of serious acute and chronic GVHD is low, survival is excellent in a selected group of patients and relapse rate is low, suggesting preservation of graft versus leukemia effect despite the low T cell dose.

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