Post-transplant cyclophosphamide in matched and haploidentical transplant recipients receiving myeloablative timed sequential busulfan conditioning regimen: Results of a phase II study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7007-7007
Author(s):  
Uday R. Popat ◽  
Rohtesh S. Mehta ◽  
Roland Bassett ◽  
Amanda Leigh Olson ◽  
Amin Majid Alousi ◽  
...  
Keyword(s):  
Phase Ii ◽  
Disease Risk ◽  
Phase Ii Study ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Area Under The Curve ◽  
Pharmacokinetic Studies ◽  
Target Area ◽  
Post Transplant

7007 Background: Myeloablative stem cell transplants have a lower rate of relapse than reduced intensity regimens. Timed sequential busulfan (TSB) with fludarabine (Flu) is a promising myeloablative regimen for patients undergoing matched sibling (MSD) or unrelated (MUD) donor transplantation (HCT) with low non-relapse mortality (NRM) (Popat et al Lancet Haematology 2018), but was not tested in haploidentical (haplo). Also, whether this approach can be used with post-transplant cyclophosphamide (PTCy) in MSD, MUD and haplo HCT is unknown. To address these issues, we conducted a prospective phase II study. Methods: Patients with hematological malignancies with MSD, MUD or haplo donor were eligible. They received fixed doses of Busulfan(BU) 80mg/m2 either on day -13 and -12 (n=45) or on -20 and -13 (n=10). Then, Flu 40mg/m2 was given on day -6 to -2 followed by Bu dosed to achieve target area under the curve (AUC) of 20,000 umol/min for the whole course based on pharmacokinetic studies. Thiotepa 5mg/kg was given on day -7 to haplo group. GVHD prophylaxis was PTCy 50mg/kg on day 3 and 4 and tacrolimus. Haplo and later MUD recipients also received mycophenolate mofetil. Results: 55 patients with a median age of 47 (15-65) years were enrolled. 30 patients had AML or MDS, 9 CML or MPD, 5 lymphoma, 5 myeloma and 6 ALL. About half had haplo 26 (47%); others had MUD 18 (33%) or MSD 11(20%). Disease risk index was high in 18 (32%), intermediate in 32 (58%), and low in 5 (9%) patients. Comorbidity score was ≥3 in 22 (40%) patients. With a median follow up of 17 months (5-28), 1-year OS, PFS, NRM and relapse rates were 71% (60-84%), 63% (51-77%), 20% (9-31%), and 17% (7-27%), respectively [Table]. There were no graft failures. Day 100 grade II-IV and III-IV acute GVHD rates were 38% (25-51%) and 9% (95% CI 1-17%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 10% (2-28%) and 8% (0-15%), respectively. 1-year OS in MSD, MUD and haplo groups were 91% (75-100%), 72% (54-96%), and 62% (45-83%) respectively (P=0.11). Conclusions: Myeloablative TSB with PTCy is feasible in MSD, MUD and haplo HCT. It lowers the incidence of severe acute and chronic GVHD without apparent increase in relapse. Clinical trial information: NCT02861417. [Table: see text]

scholarly journals Timed Sequential Busulfan and Post-Transplantation Cyclophosphamide in Matched and Haploidentical Transplantation: Results of a Phase II Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3373-3373
Author(s):  
Uday Popat ◽  
Rohtesh S. Mehta ◽  
Roland L. Bassett ◽  
Amanda L. Olson ◽  
Julianne Chen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Fixed Dose ◽  
Pharmacokinetic Studies ◽  
Target Area ◽  
Haploidentical Transplantation

Abstract Background: Timed sequential busulfan (TSB) with fludarabine is a promising myeloablative conditioning regimen for patients undergoing matched donor transplantation. Whether this approach can be used for haploidentical transplantation using post-transplant cyclophosphamide (PTCy) GVH prophylaxis is not known. Furthermore, usefulness if any of PTCy GVH prophylaxis in matched donors receiving TSB is also not known. To address these issues, we conducted a prospective phase II study of TSB conditioning regimen with PTCy GvHD prophylxis. Methods: Patients with hematological malignancies and adequate organ function were eligible for this study if they had 8/8 matched related or matched unrelated or a haploidentical related donor. They received a fixed dose of busulfan 80mg/m2 on day -13 and -12. Fludarabine 40mg/m2 was given on day -6 to -2 followed by busulfan dosed to achieve target area under the curve (AUC) of 20,000 μmol-min for the whole course based on pharmacokinetic studies done on day -13 and -6. Thiotepa 5mg/kg was given on day -7 to recipients of haploidentical donor. Graft-versus-host disease (GVHD) prophylaxis included cyclophosphamide 50mg/kg given on day 3 and 4 and tacrolimus. Haploidentical donor recipients and later MUD recipients received mycophenolate mofetil, in addition. Results: Forty five patients with a median age of 48 (15-65) years were enrolled. Twenty four patients had AML or MDS, 9 CML or MPD, 5 Lymphoma, 4 Myeloma and 3 ALL. Donors were matched sibling 11, matched unrelated 18, and haploidentical 16. Disease risk index was high in 13, intermediate in 27, and low in 5 patients. Sixteen patients had comorbidity score of 3 or higher. With a median follow up of 12 months (1-22), 1 year OS, PFS, NRM and relapse rates were 73% (60-88%), 68% (54-84%), 17% (5-29%), and 17% (5-29%) (Table), respectively. There were no graft failures. The median time to neutrophil engraftment was 16 days (13-39), and that of platelets (≥ 20K/µL) was 26 days (11-167). Day 100 grade II-IV and III-IV acute GVHD rates were 42% (27-57%) and 7% (95% CI 0-15%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 11% (1-21%) and 8% (0-17%), respectively. One year OS in recipients of matched sib, matched unrelated and haploidentical donor were 89% (71-100%), 66% (45-95%), and 69% (49-96%) respectively and were not significantly different (P=0.31). Conclusion: Timed sequential busulfan with PTCy results in lower incidence of severe acute and chronic gvhd and promising overall survival irrespective of donor source. Disclosures Oran: Celgene: Consultancy, Research Funding; ASTEX: Research Funding; AROG pharmaceuticals: Research Funding. Rezvani:Affirmed GmbH: Research Funding. Shpall:Affirmed GmbH: Research Funding. Champlin:Sanofi: Research Funding; Otsuka: Research Funding.

scholarly journals Comparison of Peripheral Blood Stem Cells (PBSC) to Bone Marrow (BM) for T-Replete HLA-Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 683-683 ◽  
Author(s):  
Asad Bashey ◽  
MeiJie Zhang ◽  
Shannon R. McCurdy ◽  
Stefan O. Ciurea ◽  
Andrew St. Martin ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Disease Risk ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Advisory Committees ◽  
Mortality Risks ◽  
Post Transplant

Abstract T cell-replete haploidentical donor transplants (HAPLO-HCT) using post-transplant cyclophosphamide for control of alloreactivity is now being increasingly utilized. HAPLO-HCTs were originally performed using BM grafts. However, recently, a few single center studies have reported good outcomes using G-CSF mobilized PBSC grafts for HAPLO-HCT. No prospective randomized comparisons of BM to PBSC grafts for HAPLO-HCT have been performed. Therefore, we analyzed outcomes for 687 adults (496 BM, 191 PBSC) who received HAPLO-HCT for hematologic malignancies using post-transplant cyclophosphamide + mycophenolate + calcineurin inhibitor for GVHD prophylaxis between 2009 and 2014 in the United States. The primary outcome was overall survival. The characteristics of recipients of BM and PBSC were similar except BM recipients were older, more likely to have a performance score ≥90, HCT-CI index ≤2, be CMV seronegative, have a lymphoid malignancy and receive reduced-intensity conditioning. Most PBSC transplants occurred between 2012 and 2014. The median follow-up was 35 and 20 months for recipients of BM and PBSC grafts, respectively. Cox regression models were built to study the effect of graft type adjusted for other significant factors on overall mortality, non-relapse mortality, relapse and graft-versus-host disease (GVHD) and outcomes censored at 2-years to accommodate differential follow-up between treatment groups (Table 1). After adjusting for age, CMV serostatus, disease risk index (disease type/disease status for myeloid and lymphoid malignancy and cytogenetic risk for acute leukemia and myelodysplastic syndrome) and transplant conditioning regimen there were no significant differences in risks for overall mortality (HR 1.00, p= 0.98; 2-year overall survival: 54% and 57%) or non-relapse mortality (HR 0.92, p=0.74; 2-year non-relapse mortality: 17% and 16%) after transplantation of BM compared to PBSC, respectively. However, relapse risks were higher after transplantation of BM compared to PBSC (HR 1.49, p=0.009; 2-year relapse: 45% and 28%). Subset analyses explored the effect of graft type separately for myeloablative and reduced intensity conditioning regimen adjusting for age, CMV serostatus and disease risk index. Consistent with the main analysis there were no differences in overall or non-relapse mortality risks and relapse risks were higher with BM compared to PBSC with myeloablative regimens (Table 1). Although this may in part be explained by lower chronic GVHD risks with transplantation of BM grafts, chronic GVHD was not significantly predictive of relapse risk when modeled as a time-dependent covariate (HR= 0.73, p=0.49). Grade II-IV acute GVHD risks (HR 0.45, p<0.001; 22% and 37%), adjusted for conditioning regimen were lower after transplantation of BM compared to PBSC. Chronic GVHD risks adjusted for age and performance score were also lower after transplantation of BM compared to PBSC (HR 0.35, p<0.001; 20% and 41%) but rates of moderate and severe chronic GVHD were not significantly different (28% and 32%). There were no differences in incidence of hematopoietic recovery by graft type. In conclusion, compared to BM grafts HAPLO-HCT with PBSC are associated with similar overall survival and non-relapse mortality risks but lower relapse risks with myeloablative conditioning regimens. Longer follow up is needed to ascertain whether survival differences may occur later. The observed adverse effect of BM grafts on relapse with myeloablative regimens must be studied further in the setting of carefully controlled trials. Table 1. Table 1. Disclosures Ciurea: Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board. Hamadani:Takeda: Research Funding. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees. Wingard:Ansun: Consultancy; Gilead: Consultancy; Astellas: Consultancy; Fate Therapeutics: Consultancy; Merck: Consultancy.

scholarly journals Use of the Dana-Farber/CIBMTR Disease Risk Index (DRI) to Compare Outcomes of T-Replete HLA-Haploidentical Transplants Using Post-Transplant Cyclophosphamide to Matched Sibling and Matched Unrelated Donor Transplants : A Multivariate Analysis of 498 Contemporaneous Allogeneic Transplants from a Single Center

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1203-1203
Author(s):  
Asad Bashey ◽  
Xu Zhang ◽  
Stacey Brown ◽  
Katelin Connor ◽  
Lawrence E. Morris ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Term Survival ◽  
Post Transplant

Abstract Introduction: Many patients, especially those from of ethnic minorities or mixed race, lack timely access to an HLA-identical sibling or 8 of 8 matched unrelated donor for allografting. HLA-haploidentical related donors (HID) are almost universally and rapidly available, and may be a valid alternative donor option for these patients. The approach developed in Baltimore that uses T-replete grafts from HID and post-transplant cyclophosphamide (ptCy) to control alloreactivity, (HIDT-ptCy), has demonstrated promising outcomes. No randomized comparisons of HIDT-ptCy to HLA-identical sibling transplants (MRDT) and matched unrelated donor transplants (MUDT) have been reported. We previously reported equivalent outcomes for HIDT-ptCy, MRDT and MUDT in a retrospective analysis (Bashey et al J. Clin Oncol 2013 vol 31:1310). In the current study we have used the recently developed and validated Dana-Farber/CIBMTR Disease Risk Index (DRI) (Armand et al Blood 2014 vol 123: 3664) as a measure of patient disease risk together with other patient, disease and transplant parameters in a multivariate analysis to compare outcomes of HIDT-ptCy to MRDT and MUDT in 498 consecutive patients who underwent a first allogeneic transplant for hematologic malignancy [MRDT (n=186), MUDT (n=196) and HIDT-ptCy (n=116)] at our center between 2/2005 and 2/2014. Methods Ex-vivo T-depleted transplants and cord blood transplants were excluded. Supportive care measures were identical between the three groups. Cumulative incidences of acute and chronic GVHD were estimated with death being treated as the competing risk. Cox proportional hazards models, stratified on the three transplant groups, were developed using overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM), relapse as endpoints and other parameters as covariates. Adjusted survival and incidence of a transplant were calculated as the average survival and incidence of the given transplant, weighted by proportion of each patient prognostic factor in the pooled samples. GVHD was prospectively documented by a single dedicated nurse using established criteria including NIH consensus criteria for chronic GVHD. Results: Characteristics of the HIDT-ptCy patients were as follows: median age 51 (20-74); male 54%; regimen- myeloablative (40%) non-myeloablative (60%); graft- PBSC (80%) bone marrow (20%) ; Diagnoses- AML 41%, ALL 17%, CLL 11%, MDS/MPD 11%, NHL 10%, HL 9%, CML 9%, MM 2%; DRI- low (20%), intermediate (41%), high (34%), very high (5%); Sorror HCT-comorbidity index - 0 (29%), 1-3 (55%), >4 (16%); 14% had prior autografts. Median HLA mismatches were 5/10 (range 2/10 to 5/10). When compared to MRDT and MUDT, HIDT-ptCy patients had similar characteristics but were less likely to have myeloablative conditioning (p<0.001) and were more likely to have a BM graft (p<0.001). Median follow-up of surviving patients following MRDT, MUDT and HIDT-ptCy were 49m, 31m and 32 m. On multivariate analysis covariates found to have a significant effect upon the chosen endpoints were - OS: DRI, regimen intensity, age, HCT-CMI; DFS: DRI, regimen intensity, year of transplant, age &HCT-CMI; NRM: regimen intensity, diagnosis, age; Relapse: DRI, year of BMT, age. Adjusted estimates for OS, DFS, NRM and relapse are shown in Fig 1. For MRDT, MUDT and HIDT-ptCy respectively, adjusted estimates are as follows: NRM at 1year 10%, 10% and 9% and 2yrs 15%, 16%, 15%, Relapse at 1year – 21%, 29%, 30% and 2 yrs -27%, 35%, 32%; OS at 1 yr 80%, 78%, 75% and 2 yrs – 69%, 61% , 62%. DFS at 1 yr – 67%, 63%, 62% and 2 yrs – 57%, 50%, 54% (p=NS for all endpoints). The cumulative incidences of acute GVHD at 180 days were: grade 2-4 – 28%, 48% and 41% (p=0.055 MUDT vs HIDT and p=0.003 MRD vs HIDT); grade 3-4 – 9%, 19% and 17% (p=NS MUD vs HIDT, p=0.022 MRD vs HIDT) and chronic GVHD at 3 yrs were: extensive- 54%, 57%, 41% (p=0.004 MUD vs HIDT, p=0.014 MRD vs HIDT); NIH severe – 16%, 16%, 8% (p=0.035 MUD vs HIDT, p=0.044 MRD vs HIDT). Conclusions: These data demonstrate that HIDT-ptCy produce similar long-term survival, DFS, NRM and relapse to MRDT and MUDT. Rates of extensive and severe chronic GVHD are lower following HIDT-ptCy than MRDT and MUDT. HIDT-PtCy should be considered a standard-of-care option for patients who may benefit from allografting but lack a conventional donor. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

A Prospective Phase II Study on Tandem Autografting-Nonmyeloablative Allografting for Newly Diagnosed Myeloma: Final Results of the Gruppo Italiano Trapianto Midollo Osseo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3026-3026
Author(s):  
B. Bruno ◽  
M. Rotta ◽  
F. Patriarca ◽  
D. Mattei ◽  
B. Allione ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Chronic Gvhd ◽  
New Drugs ◽  
Newly Diagnosed ◽  
Disease Response ◽  
Post Transplant ◽  
Primary Endpoints ◽  
Prospective Phase

Abstract The development of nonmyeloablative conditionings has recently reduced the transplant-related mortality (TRM) and extended the eligible age for transplantation up to 65–70 years. From January 2000 to June 2005, 106 newly diagnosed patients younger than 65 years were enrolled in a prospective phase II study at 15 Italian Centers. Fifty-eight were also previously described in a comparison of autografting with allografting based on a genetic randomisation (Bruno et al. N Engl J Med 2007). Here we report on a larger GITMO experience with a longer follow-up. Induction chemotherapy consisted of VAD-based regimens, followed by a cytoreductive autograft with melphalan 200 mg/m2, and by a non-myeloablative 2 Gy TBI-based allograft from an HLA-identical sibling. Graft-vs-host disease (GVHD) prophylaxis included cyclosporin and mycophenolate mofetil. Primary endpoints were overall (OS) and event-free (EFS) survivals. Secondary endpoint was TRM. One-hundred-two (96%) patients, median age 54 (30–65), completed the tandem program whereas 4 withdrew their consent. After a median follow-up of 54 (21–94) months, OS was not reached and median EFS was 35 (31–56) months post-transplant. Incidences of acute grade II-IV GHVD and extensive chronic GVHD were 40% and 50% respectively. Fourteen (13%) patients died from TRM, 14 (13%) from disease progression, 2 from lung cancer (2%) and 1 from lymphoma (1%). Overall response, defined as complete (CR) and partial remission, was 91% (93/102), with 53 patients achieving CR. Overall 39/102 patients relapsed, however only 8/53 of those who reached CR post-transplant. By multivariate-analysis disease response prior to allografting was significantly associated with longer OS (HR 0.27, CI 0.09–0.80, p<0.018) and longer EFS (HR 0.23, CI 0.11–0.49, p<0.001). Interestingly, chronic GVHD was not correlated with either the achievement of post-transplant CR (HR 0.87, CI 0.45–1.65, p<0.66) or its duration (HR 0.79, CI 0.45–1.40, p<0.42). Presence of del(13) was evaluated only in a subset of 39 patients: 13 carried del(13) and 26 did not. OS was not reached in the patients without del(13) and was 52 months in patients with del(13) (p=0.32), however EFS was not reached in the patients without del(13) whereas was 27 months for patients with del(13) (p=0.04). Given the encouraging results, the design of prospective studies that incorporate new drugs to cytoreduce the disease pre-transplant and enhance graft-vs.-myeloma are warranted to lower relapse rates and improve clinical outcomes.

scholarly journals Risk Factors for Adverse Outcomes Following Haploidentical Hematopoietic Cell Transplantation with Posttransplant Cyclophosphamide: A Two-Center Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4889-4889
Author(s):  
Viviane De Jesus Torres Lima ◽  
Anderson Felipe Felipe Da Silva ◽  
Andreza Alice Feitosa Ribeiro ◽  
Mariana Nassif Kerbauy ◽  
Lucila Kerbauy ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Disease Risk ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Adverse Outcomes ◽  
Very High

Abstract Introduction Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for several malignant hematologic diseases. As only 30% of patients will have a matched related donor, alternative donors play a significant role in HCT. Luznik et al pioneered the use of posttransplant cyclophosphamide (PTCy) based GVHD prophylaxis in haploidentical transplantation (haplo-HCT), which greatly expanded the pool of donors and nearly revolutionized the field. Despite the increasing use of haplo-HCT with PTCy, some questions remain, namely the selection of the best donor, graft source and conditioning regimen, and risk factors for adverse outcomes. Methods Retrospective study conducted at two Brazilian centers. All patients with hematologic malignancies who underwent first HCT between 2010 and 2021, haploidentical with posttransplant cyclophosphamide, were included. The objective was to identify risk factors for adverse outcomes following haploidentical HCT with PTCy. Independent variables are detailed in table 1. Acute GVHD was graded according to the MAGIC criteria and chronic GVHD was diagnosed according to the NIH consensus criteria. Survival and cumulative incidence curves were built with the Kaplan-Meier and Gray methods, and compared with the logrank and Gray tests, respectively. Multivariate analyses were carried out with Cox models. GVHD, as an independent variable, was included as a time-dependent covariate. Results A total of 103 patients were included (table 1). In brief, median age was 39 y/o and most patients were male (58%); 71 patients had low or intermediate disease risk index, while 29 had high or very high-risk disease. Bone marrow was the preferred stem-cell (72%, followed by peripheral blood stem-cells - 28%) and reduced-intensity, the most frequent conditioning regimen (43%). Median follow-up for the whole cohort was 2.6 years. Overall survival at 2 years was 51.7% (95CI 42.4-63.0%, figure 1). Multivariable analyses are in table 2. Risk factors for death were age at transplant (HR = 1.03 for each year; 95CI 1.01-1.05; p = 0.002), high or very high disease risk index (HR = 2.73; 95CI 1.52-4.90; p = 0.0008), and compared with low or intermediate, and mother as the donor (HR = 3.50; 95CI 1.44-8.47; p = 0.006). Progression-free survival at 2 years was 45.8% (95CI 36.6-57.2%). In multivariate analysis (table 2), progression-free survival was significantly poorer for older patients (HR = 1.02; 95CI 1.01-1.04; p = 0.009), high or very high disease risk index (HR = 2.29; 95CI 1.30-4.04; p = 0.004), compared with low or intermediate, and mother as a donor (HR = 3.15; 95CI 1.37-7.22; p = 0.007; figure 2). Two-year relapse rate was 22.2% (95CI 15.2-32.5%). Risk factors for relapse (table 2) were high or very high disease risk index (HR = 3.55; 95CI 1.44-8.74; p = 0.006), compared with low or intermediate, and mother as the donor (HR = 2.85; 95CI 1.12-7.25; p = 0.007). Two-year non-relapse mortality was 32.0% (23.9-42.9%). The only risk factor we found was age at transplantation (HR = 1.03 for each year; 95CI 1.01-1.05; p = 0.02; table 2). We found no effect of GVHD, acute or chronic, on relapse, nor on non-relapse mortality. Rates of grades II-IV and III-IV acute GVHD and 2y-chronic GVHD were 30.4% (95CI 22.7-40.8%), 6.9% (95CI 3.4-14.1%) and 19.8% (95CI 13.2-29.7%), respectively. The only risk factor (table 2) identified for grades II-IV acute GVHD was tacrolimus (HR = 0.36; 95CI 0.14-0.95; p = 0.04) compared with cyclosporine. We have not carried out multivariate analysis for grades III-IV acute GVHD due to the low number of events (only 7). In multivariable analysis (table 2), peripheral blood graft was a risk factor for chronic GVHD (HR = 3.72; 95CI 1.53-9.01; p = 0.004; figure 3), compared with bone marrow, while tacrolimus was protective (HR = 0.27; 95CI 0.11-0.68; p = 0.005), compared with cyclosporine. Conclusion Our results show that mother as the donor was an important risk factor for poorer OS, PFS and relapse, and mothers might not the best choice of donor. Tacrolimus was protective for both grades II-IV aGVHD and for cGVHD, suggesting that tacrolimus may be more effective than cyclosporine in preventing GVHD. PBSC was a risk factor for cGVHD without any impact on relapse, and this result does not support the systematic use of PBSC in detriment of BM. As expected, age at transplant negatively impacted OS, PFS and NRM as well as high/very high DRI led to poorer OS, PFS and relapse. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals High Peripheral Blood Stem Cell (PBSC) CD34+ Cell Dose Increases the Risk of Chronic Gvhd after Human Leukocyte Antigen (HLA) Matched Sibling Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5877-5877 ◽  
Author(s):  
Ezzideen Barjes Alrawi ◽  
Erica D. Warlick ◽  
Qing Cao ◽  
Mukta Arora ◽  
Shernan G. Holtan ◽  
...  
Keyword(s):  
Disease Risk ◽  
Conflicts Of Interest ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Blood Type ◽  
Platelet Recovery ◽  
Cell Dose ◽  
Matched Sibling

Abstract CD34+ cell dose is a critical determinant of outcomes after allogeneic PBSC transplantation, with a CD34 dose ≥2.0 x 10e6/kg shown to positively impact hematopoietic engraftment and survival. However, it is unknown whether additional benefits are observed with even higher CD34 cell doses. Therefore, we further explored the effect of intermediate, high and very high CD34 cell doses on the incidence of engraftment, acute and chronic graft-versus-host disease (GVHD) and transplant related mortality (TRM) and on probability of survival and GVHD-Relapse-free survival (GRFS). Three hundred and five consecutive patients transplanted with GCSF-mobilized PBSC from HLA-matched sibling donors (MSD) were evaluated. Patients were ≥16 years of age, had a hematological malignancy and received a myeloablative or a nonmyeloablative conditioning regimen between 2002 and 2012. The median recipient age was 52 years (r, 19-74 years) with most being male (n=194, 63.8%) diagnosed with leukemia (72%) or lymphoma (22%), and intermediate disease risk index (DRI, n=204, 67%). The median age for the donor were 49 years (r,17-76 years). In 159 patients (52%) the donor and recipient were sex matched with 89 male patients having a female door (29%). The ABO blood type was matched in 195 patients (64%), 153(50%) received a myeloablative (MA) conditioning regimen, and 37 (12%) received a reduce intensity conditioning regimen containing ATG. The median follow up of surviving patients was 793 days (r, 14-4562 days). Patients were divided in four CD34 dose quartiles: first quartile (QT1), ≤4.8 x10e6/kg, QT2 4.8-6.0 x10e6/kg, QT3 6.0-7.5 x10e6/kg, and QT4 ≥ 7.6 x 10e6/kg. Notably, the CD3 doses were similar for all quartiles: QT1 was 3.4 x 10e8/kg (r, 0.3-10.0), QT2 was 2.7 x 10e8/kg (r, 1.1-7.6), QT3 was 2.8 x 10e8/kg (r, 0.8-7.2) and QT4 was 2.8 x 10e8/kg (r, 1.4-7.7); there was no correlation between CD34 and CD3 cell doses. Patient and donor characteristics were similar in the four groups except for shorter median follow-up (P <0.01) in QT1, more sex mismatched grafts (P <0.01) in QT3, and lower median number of cell collections (P <0.01) and more female donor: male recipient pairs (P< 0.01) in QT4. Multivariate analysis results are summarized on the table. Higher CD34+ cell dose was associated with improved platelet recovery with trends toward lower TRM and improved overall survival. Chronic GVHD however was also higher. In summary, additional studies are needed to establish a survival benefit in recipients of higher cell doses >4.8 x 10e6 CD34 cells/kg. Unless survival is positively impacted, the higher risk of chronic GVHD would argue for assigning an upper CD34 cell dose limit to reduce this risk that can significantly impair quality of life. Table Table. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Phase II Trial of Melphalan Based Reduced-Intensity Conditioning for Transplantation of T-Replete HLA-Haploidentical Peripheral Blood Stem Cells with Posttransplant Cyclophosphamide in Patients with Hematologic Malignancies

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Melhem M. Solh ◽  
Gabriel Hinojosa ◽  
Justin Laporte ◽  
Scott R. Solomon ◽  
Lawrence E. Morris ◽  
...  
Keyword(s):  
Phase Ii ◽  
Peripheral Blood ◽  
Cumulative Incidence ◽  
Phase Ii Trial ◽  
Disease Risk ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Myeloablative Conditioning ◽  
Peripheral Blood Stem Cells ◽  
Very High

T-replete haploidentical donor transplants using posttransplant cyclophosphamide (haplo) have greatly expanded donor availability and are increasingly utilized. Haplo were originally performed using truly nonmyeloablative conditioning and a bone marrow graft. We have also developed myeloablative conditioning and peripheral blood stem cell (PBSC) grafts for use with haplo. However, some patients may not tolerate myeloablative conditioning but may still benefit from a more dose-intensified preparative regimen to control malignancy and diminish graft rejection. To this end, we enrolled 25 patients on a prospective phase II trial utilizing a regimen of fludarabine 30 mg/m2/day × 5 days and Melphalan 140 mg/m2 on day -1 (flu/Mel) followed by infusion of unmanipulated PBSC graft from a haploidentical donor. GVHD prophylaxis included cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil on day 35, and tacrolimus on day 180. Median age was 57 years (range from 35 to 68). Transplantation diagnosis included AML (n = 11), ALL (n = 4), MDS/MPD (n = 6), NHL/CLL (n = 3), and MM (n = 1). Using the refined Disease Risk Index (DRI), patients were low (n = 1), intermediate (n = 13), and high/very high (n = 11). 22 out of 25 patients engrafted with a median time to neutrophil and platelet engraftment of 18 days and 36 days, respectively. All engrafting patients achieved full peripheral blood T-lymphocyte and myeloid donor chimerism at day 30. The 180-day cumulative incidence for acute GVHD grades II–IV and III-IV was seen in 20% (95% CI 8%–37%) and 8% (95% CI 2%–22%), respectively. The 2-year cumulative incidence of chronic GVHD was 16% (95% CI 5%–33%) (moderate-severe 12% (95% CI 3%–27%)). After a median follow-up of 28.3 months, the estimated 2-year OS, DFS, NRM, and relapse were 56% (95%CI 33–74%), 44% (95%CI 23%–64%), 20% (95% CI 8%–37%), and 36% (95% CI 17%–55%), respectively. Among patients with high/very high risk DRI, 2-year OS was 53% compared to 69% for low/intermediate DRI. When compared with a contemporaneous cohort of patients at our center receiving haploidentical transplant with nonablative fludarabine, Cytoxan, and total body irradiation flu/Cy/TBI regimen, the outcomes were statistically similar to the 2-year OS at 56% vs. 63% p = 0.75 and DFS at 44% vs. 46% p = 0.65 .

Chronic GVHD Is Not Increased with the Use of PBSC Instead of Bone Marrow for T-Replete HLA-Haploidentical Transplanation Using Post-Transplant Cyclophosphamide : A Multivartiate Analysis of 116 Consecutive Transplants from a Single Center

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3922-3922
Author(s):  
Asad Bashey ◽  
Xu Zhang ◽  
Stacey Brown ◽  
Katelin Connor ◽  
Lawrence E. Morris ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multivariate Analysis ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Cox Model ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Increased Risk

Abstract HLA-haploidentical related donors (HID) are a potential option for patients who need an allogeneic haploidentical transplant but lack an optimally matched conventional donor (HLA-identical sibling or 8 of 8 HLA-A, B, C, DRB1 matched unrelated donor) (MRD and MUD respectively). The Baltimore approach to HID transplantation that uses T-replete grafts and post-transplant cyclophosphamide to control alloreactivity (HIDT-ptCy) has demonstrated promising outcomes and appears to be safe and effective. Bone marrow (BM) grafts have almost exclusively been used for HIDT-ptCy in Baltimore. Early studies from other centers have demonstrated that G-CSF mobilized PBSC may be safely used for HIDT-ptCy (Castagna et al BBMT 2014, Raj et al BBMT 2014). HIDT-ptCy using BM grafts has been associated with relatively low rates and severity of chronic GVHD. However, it is unclear whether the use of PBSC for HIDT-ptCy will be associated with higher rates of chronic GVHD than with BM grafts as has been demonstrated for MRD and MUD transplants. We analyzed 116 consecutive HIDT-ptCy first transplants (BM=64, PBSC=52) performed for hematologic malignancies at our center. Identical supportive care measures were utilized for BM and PBSC patients. GVHD was prospectively documented using established criteria by a single dedicated nurse. NIH consensus criteria were used for chronic GVHD. Gray's test was used to compare the cumulative incidences of GVHD. A Cox model was used in multivariate analysis of GVHD outcomes. Characteristics of the patients are demonstrated in Table 1. Patients undergoing HIDT-ptCy using PBSC were significantly more likely to receive myeloablative conditioning, were younger, were less likely to have been transplanted prior to 2007. Although the frequency of diagnoses differed, the Dana-Farber/CIBMTR Disease Risk Index (DRI) was not significantly different between the two groups. Median follow-up for BM and PBSC patients was 44 m and 25 m. Six month cumulative incidences of acute GVHD grades 2-4 were 39% and 42% and grades 3-4 were 14% and 21% for BM and PBSC grafts respectively. The two year cumulative incidences of extensive chronic GVHD were 38% and 45% and for severe chronic GVHD were 8% and 6% respectively (p=NS for all BM vs PBSC comparisons). In a multivariate analysis assessing effects of patient, disease and transplant variables on GVHD outcomes, graft type i.e. PBSC vs BM was not a significant predictive factor for acute or chronic GVHD. These data demonstrate that unlike the case following MRDT and MUDT, G-CSF mobilized PBSC grafts are not associated with an increased risk of chronic GVHD than BM grafts following HIDT-ptCy. Severe chronic GVHD is very uncommon with both types of graft following HIDT-ptCy and is an indication of the effectiveness of ptCy in controlling alloreactivity in this setting. Disclosures No relevant conflicts of interest to declare.

Topotecan Is Active Against Wilms’ Tumor: Results of a Multi-Institutional Phase II Study

2007 ◽  
Vol 25 (21) ◽  
pp. 3130-3136 ◽  
Author(s):  
Monika L. Metzger ◽  
Clinton F. Stewart ◽  
Burgess B. Freeman ◽  
Catherine A. Billups ◽  
Fredric A. Hoffer ◽  
...  
Keyword(s):  
Phase Ii ◽  
Median Duration ◽  
Progressive Disease ◽  
Phase Ii Study ◽  
Wilms Tumor ◽  
Area Under The Curve ◽  
Salvage Chemotherapy ◽  
Target Area ◽  
Favorable Histology ◽  
Grade 3

Purpose A phase II study was conducted to evaluate the activity and safety of topotecan in pediatric patients with recurrent Wilms' tumor. Patients and Methods Patients with favorable histology Wilms' tumor (FHWT) and recurrence after at least one salvage chemotherapy regimen or with anaplastic histology Wilms' tumor (AHWT) in first or subsequent recurrence were eligible. Patients were stratified according to histology, with statistical considerations based on the FHWT stratum. Topotecan was administered intravenously over 30 minutes for 5 days on 2 consecutive weeks. Treatment dosages were adjusted to achieve a target area under the curve (AUC) of 80 ± 10 ng/mL*h. Tumor responses were measured after two cycles of treatment. Results Thirty-seven patients (26 patients with FHWT) were enrolled and received a total of 94 cycles of topotecan (range, one to six cycles). The median topotecan dosage required to achieve the target AUC was 1.8 mg/m2 (range, 0.7 to 3.2 mg/m2). Of 25 assessable patients with FHWT, 12 had partial response (PR), six had stable disease (SD), and seven had progressive disease (PD), for an overall response rate of 48% (95% CI, 27.8% to 68.7%). Of 11 assessable patients with AHWT, two had PR, one had SD, and eight had PD. The main toxicities were grade 3 and 4 neutropenia (median duration, 13 days) and thrombocytopenia (median duration, 7.5 days). Conclusion Topotecan administered on a protracted schedule is active against recurrent FHWT. Inclusion of topotecan in front-line clinical trials for patients with recurrent Wilms' tumor should be considered.

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