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 .

The Disease Risk Index Predicts Outcomes Including Relapse and Survival in CD34-Selected Allogeneic HCT for Acute Leukemia and Myelodysplastic Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3498-3498
Author(s):  
Christina Cho ◽  
Patrick Hilden ◽  
Jonathan U. Peled ◽  
Scott T. Avecilla ◽  
Pere Barba ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Cumulative Incidence ◽  
Disease Risk ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Donor Type ◽  
Very High

Abstract INTRODUCTION: T-cell depleted allogeneic peripheral blood stem cell transplant (TCD PBSCT) using CD34 selection achieves relapse rates comparable to those of unmodified grafts (Pasquini et al., JCO 2012), but disease-related predictors of outcome have not been fully characterized in the TCD setting. We evaluated the prognostic utility of the refined Disease Risk Index (DRI; Armand et al., Blood 2014) in TCD PBSCT. METHODS: This was a retrospective analysis of patients who underwent first allogeneic HCT with TCD PBSCT for AML, ALL, or MDS at a single center between 1/2000 and 12/2015. Overall survival (OS), relapse-free survival (RFS), and chronic GVHD/relapse-free survival (CRFS) were estimated by the Kaplan-Meier method. Cumulative incidence of relapse, non-relapse mortality (NRM), acute GVHD (aGVHD), and chronic GVHD (cGVHD) were estimated using the cumulative incidence method for competing risks. The univariate association between variables of interest and OS/RFS/CRFS was evaluated using the log-rank test; Cox regression models assessed the adjusted effect of significant covariates on OS and RFS. Given only 1 patient with very high DRI, the high/very high DRI groups were combined. Similarly, given few patients with low DRI, the low/intermediate groups were combined in multivariate analysis. RESULTS: The analysis comprised a total of 519 patients. Median age was 55 years (range 18-73). There were 302 patients (58%) transplanted for AML, 144 (28%) for MDS, and 73 (14%) for ALL. Seventeen patients had low DRI scores (3%), 431 intermediate (83%), and 71 high/very high (14%). Median follow-up among survivors was 53.1 months (range 4.6-171.0). Two-year estimates for outcomes of interest were OS 62.8% (95% CI 58.5, 66.9), RFS 58.1% (95% CI 53.7, 62.3), and CRFS 54.0% (95% CI 49.5, 58.2). The cumulative incidence of relapse at 2 years was 17.3% (95% CI 14.2, 20.7). There were 0 relapse events in patients with low DRI, whereas intermediate and high/very high DRI scores were associated with a significantly increased incidence of relapse (p < 0.001), with 2 year estimates 14.7% (95% CI 11.5, 18.3) and 37.1% (95% CI 25.8, 48.4), respectively. The cumulative incidence of NRM was 24.6% (95% CI 20.9, 28.4) at 2 years. The cumulative incidence of aGVHD at 100 days was 12.5% (95% CI 9.8, 15.5) for grade 2-4 and 2.5% for grade 3-4 (95% CI 1.4, 4.1); with a cumulative incidence of cGVHD of 4.7% (95% CI 3.1, 6.7) at 1 year. NRM, aGVHD, and cGVHD did not vary with DRI. In univariate analysis, DRI was associated with significant differences in OS, RFS, and CRFS (Table 1; Figure). Additional factors associated with poorer OS in univariate analysis were HCT-CI score > 0, KPS < 90, donor type (matched unrelated or mismatched vs. matched related donor), and age > the median of 55.3 years; HCT-CI and KPS also correlated with significant differences in RFS. On multivariate analysis (Table 2), high/very high DRI corresponded to significantly greater risk of death (HR 1.72 for OS, [95% CI 1.24, 2.40]) and relapse or death (HR 1.86 for RFS [95% CI 1.35, 2.55]), compared with low/intermediate DRI. Multivariate analysis also showed that KPS < 90 was associated with worse OS and RFS, as did a higher HCT-CI score. Neither age nor donor type was significantly associated with OS in multivariate analysis. CONCLUSION: In a large cohort of patients undergoing first TCD PBSCT at a single center for acute leukemia or MDS, DRI score significantly correlated with relapse incidence as well as OS, RFS, and CRFS. We have previously shown that the HCT-CI score, which incorporates patients' baseline comorbidities, is also predictive of outcomes after TCD PBSCT. Combining these prognostic tools will serve to better select appropriate patients for TCD PBSCT, a transplant approach currently under investigation in a multicenter phase 3 trial (BMT CTN 1301). Disclosures Koehne: Atara Biotherapeutics: Consultancy.

scholarly journals Myeloablative Conditioning with PBSC Grafts for T Cell-Replete Haploidentical Donor Transplantation Using Posttransplant Cyclophosphamide

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Scott R. Solomon ◽  
Melhem Solh ◽  
Lawrence E. Morris ◽  
H. Kent Holland ◽  
Asad Bashey
Keyword(s):  
Disease Risk ◽  
Risk Index ◽  
Hemorrhagic Cystitis ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Bk Virus ◽  
Peripheral Blood Stem Cells ◽  
Stem Cell Source ◽  
Impact On Survival ◽  
Blood Stem Cells

Relapse is the main cause of treatment failure after nonmyeloablative haploidentical transplant (haplo-HSCT). In an attempt to reduce relapse, we have developed a myeloablative (MA) haplo-HSCT approach utilizing posttransplant cyclophosphamide (PT/Cy) and peripheral blood stem cells as the stem cell source. We summarize the results of two consecutive clinical trials, using a busulfan-based (n=20) and a TBI-based MA preparative regimen (n=30), and analyze a larger cohort of 64 patients receiving MA haplo-HSCT. All patients have engrafted with full donor chimerism and no late graft failures. Grade III-IV acute GVHD and moderate-severe chronic GVHD occurred in 23% and 30%, respectively. One-year NRM was 10%. Predicted three-year overall survival, disease-free survival, and relapse were 53%, 53%, and 26%, respectively, in all patients and 79%, 74%, and 9%, respectively, in patients with a low/intermediate disease risk index (DRI). In multivariate analysis, DRI was the most significant predictor of survival and relapse. Use of TBI (versus busulfan) had no significant impact on survival but was associated with significantly less BK virus-associated hemorrhagic cystitis. We contrast our results with other published reports of MA haplo-HSCT PT/Cy in the literature and attempt to define the comparative utility of MA haplo-HSCT to other methods of transplantation.

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 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 Comparable Outcomes Among Adult Patients Allotransplanted for Myelodysplastic Syndrome Using Haploidentical, Matched Unrelated or Matched Sibling Donors: A Single-Center Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4914-4914
Author(s):  
Alice Garnier ◽  
Maxime Jullien ◽  
Thierry Guillaume ◽  
Pierre Peterlin ◽  
Amandine Le Bourgeois ◽  
...  
Keyword(s):  
Stem Cells ◽  
Myelodysplastic Syndrome ◽  
Peripheral Blood ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Peripheral Blood Stem Cells ◽  
Blood Stem Cells ◽  
Matched Sibling

Abstract Introduction: Allogeneic stem cell transplantation (allo-SCT) remains the only curative option for patients with myelodysplastic syndrome (MDS). If recent data have shown encouraging results with haploidentical (haplo) donors in this context, no comparison with allo-SCT using other source of graft (matched sibling [MSD] or unrelated [MUD] donors) has been reported so far. Methods: We retrospectively considered 102 consecutive adults transplanted for MDS between March 2010 and August 2020 in our Department, comparing outcomes between those receiving a graft from a MSD, a MUD or a haplo-donor. Results : Thirty-three, 48 and 21 patients respectively received a graft from a MSD, MUD or haplo donor. Peripheral blood stem cells (PBSC) were the source of graft for all patients. The median age of the whole cohort was 63 years old (range: 20-74) and the median follow-up was 23 months (range: 0-125). The three groups shared similar characteristics (gender, type of MDS, disease status, disease risk index, CMV status, ABO compatibility, peripheral blood stem cells graft count, conditioning regimen) except median recipient age which was younger in matched patients ( 61 vs 65 MUD vs 65 Haplo, p=0,04) and median donor age which was older in matched transplant ( 61 vs 34 MUD vs 42 Haplo, p< 0,001) (Table 1). With a median follow-up of 46,4 months, the 4-year OS (Figure 1) was comparable between the three groups (haplo: 60.1 % ± 11,0 % , MSD: 59,0 % ±9,4 % and MUD: 61.2 % ± 7,2 %, p = 0.88) as well as the 4-year DFS (Figure 2) (55.9 % ± 11,1 % vs 51,2 % ±9,2 % vs 59.6 % ± 7,2 %, p = 0.78) and the cumulative incidence (CI) of NRM (34.6 % ±12,4 % , 15,4% ± 6,4% and 23.8 % ± 6,4 %, p = 0.21). Also, the 4-year CI of acute grade 3-4 GVHD (14,3% vs 15,2% vs 20,8%, p=0.79) and of moderate/severe chronic GVHD (14,3% vs 24.2% vs 27,1%, p=0.56) were not significantly different. The 4-year GRFS seemed better with haplo (Figure 3) but this was not statistically significant (56,1 % ± 11,0% vs 28,1% ±9,2 % vs 32,8 % ± 7,4%,p=0 .41). Conclusions: These data suggest that haplo-identical donors represent a valid alternative in MDS patients lacking a MSD or a MUD for allo-SCT. Figure 1 Figure 1. Disclosures Moreau: Oncopeptides: Honoraria; Amgen: Honoraria; Celgene BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria.

The Disease Risk Index Is a Robust Tool for Allogeneic Hematopoietic Stem Cell Transplantation Risk Stratification: An Independent Validation Study on a Large Cohort of the European Society for Blood and Marrow Transplantation (EBMT)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 988-988 ◽  
Author(s):  
Roni Shouval ◽  
Joshua Fein ◽  
Myriam Labopin ◽  
Nicolaus Kroger ◽  
Rafael F. Duarte ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Hematological Malignancies ◽  
Disease Risk ◽  
Risk Index ◽  
Risk Groups ◽  
Advisory Committees ◽  
Very High

Abstract Background: Allogeneic stem cell transplantation is a potentially curative procedure to a long list of hematological malignancies, but involves substantial risk of morbidity and mortality. Means for accurately predicting outcome and assessing risk are thus greatly needed. The Disease Risk Index (DRI) is a prognostic tool developed and validated by Armand et al. across a wide range of hematological malignancies (Blood 2012, Blood 2014) on cohorts of American patients. The Index stratifies patients into 4 distinct risk groups (low, intermediate, high, very high) and has yet to be validated in an international cohort. We sought to evaluate the validity of the DRI in a large cohort of European patients. Methods: This was a retrospective validation study on an independent cohort of patients undergoing allogeneic HSCT and reported the European Society for Blood and Marrow Transplantation (EBMT). Patients included had a hematological malignancy and underwent allogeneic transplantation between the years of 2000 and 2015. Risk groups were coded in accordance with the refined DRI (Blood, 2014). Outcomes were evaluated 4 years after the allogeneic HSCT. Overall survival (OS) was calculated with the Kaplan-Meier method. The log-rank test was used for comparisons of Kaplan-Meier curves. Cumulative incidence curves for nonrelapse mortality (NRM) and relapse with or without death were constructed reflecting time to relapse and time to NRM, respectively, as competing risks. The difference between cumulative incidence curves in the presence of a competing risk was tested with the Gray method. The prognostic effect of the DRI strata was estimated using a Cox proportional hazard model for OS and a Fine and Gray model for NRM and relapse. Results: A total of 89,061 patients from 423 transplantation centers were included in the analysis. Median age was 48.3 (IQR 36.2-57.5). The most frequent indication for transplantation was AML (39,530 patients) followed by ALL (16,206) and MDS (9,750); other indications spanned the spectrum of hematological malignancies. The majority of patients were in 1st or 2nd complete remission (54%). The median follow-up period was 3.6 years. Approximately 63% of patients were classified as intermediate risk by DRI, suggesting that this group could be further partitioned. The 4 year overall survival (95% CI) of the low, intermediate, high, and very high risk groups was 60.8% (59.9-61.8), 51.3% (50.8‐51.8), 27.0% (26.1‐27.8), 18.4% (17.1-19.8) (Figure 1). The same groups corresponded with increasing cumulative incidence of relapse; 8.9% (8.3-9.4), 19.3% (18.9-19.7), 39.0% (37.8-39.6), 45.1% (43.4-46.7), respectively. The DRI groups also showed increasing hazard between strata in the overall survival setting; intermediate risk was associated with a hazard ratio of 1.32, high risk 2.67 and very high risk 3.71 relative to low risk. Relapse showed a similar pattern. NRM was less strongly stratified by DRI (Table 1). The DRI groups maintained a similar risk, regardless of whether the transplantation was performed prior or after 2008. DRI was the strongest determinant of overall survival and relapse when introduced to a multivariable model with additional covariates. AUC for the index at 4 years was 62.5 for OS, 58.5 for NRM and 68.2 for relapse. Conclusions: We have validated the Disease Risk Index in a massive European data set. The groupings suggested by the DRI corresponded with distinct risk groups for overall mortality and relapse. Overall, our results indicate the international applicability of this robust prognostic tool. Figure 1. Kaplan-Meyer survival curves for overall survival, stratified by DRI Figure 1. Kaplan-Meyer survival curves for overall survival, stratified by DRI Table 1 Table 1. Disclosures Bader: Medac: Consultancy, Research Funding; Riemser: Research Funding; Neovii Biotech: Research Funding; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Bonini:Molmed SpA: Consultancy; TxCell: Membership on an entity's Board of Directors or advisory committees. Dreger:Gilead: Consultancy; Janssen: Consultancy; Novartis: Speakers Bureau; Gilead: Speakers Bureau; Novartis: Consultancy; Roche: Consultancy. Kuball:Gadeta B.V,: Membership on an entity's Board of Directors or advisory committees. Montoto:Roche: Honoraria; Gilead: Research Funding.

scholarly journals A Phase II Trial of Melphalan Based Reduced Intensity Conditioning and Transplantation of Partially HLA-Mismatched Peripheral Blood Stem Cells for Patients with Hematologic Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3333-3333
Author(s):  
Melhem Solh ◽  
Scott R. Solomon ◽  
Xu Zhang ◽  
H. Kent Holland ◽  
Lawrence E Morris ◽  
...  
Keyword(s):  
Graft Failure ◽  
Phase Ii Trial ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Myeloablative Conditioning ◽  
Peripheral Blood Stem Cells ◽  
Free Survival ◽  
Blood Stem Cells ◽  
Disease Free ◽  
Very High

HLA-haploidentical (haplo) stem cell transplantation is now widely used for patients lacking a suitably matched related or unrelated donor (MUD). Conventionally, T-replete Haplo transplantation has been performed using non-myeloablative conditioning and a bone marrow graft. Subsequently, our group has developed the use of myeloablative conditioning and PBSC grafts for Haplo (Solomon et al BBMT 2015, 2019). However, some patients with hematologic malignancies who are unable to tolerate a fully myeloablative regimen may benefit from intermediate intensity conditioning. We conducted a prospective phase II trial utilizing melphalan based preparative regimen ( fludarabine 30mg/m2 days -6 to -2, melphalan 140 mg/m2 day -1) followed by infusion of unmanipulated peripheral blood stem cells (PBSCs) ,capped at 5x10 6 CD34+/kg,from a haploidentical first degree family donor. Graft-versus-host disease (GVHD) prophylaxis consisted of Cy 50mg/kg on days 3 and 4, MMF through day 35, and tacrolimus through day 180. The primary endpoint was to estimate the incidence of graft rejection following Fludarabine/Melphalan conditioning. For the graft failure endpoint we tested the hypotheses H0: p=10% versus Ha: p<10% using a one-sided exact Binomial test. Assume that none of patients undergoing the proposed regimen will have graft failure, the power for confirming p less than 15% is always 100% if the null hypothesis is rejected. The population enrolled was needed to achieve rejection of the null hypothesis at the 5% significance level. Twenty-five patients had their first allogeneic transplant on this study, and their characteristics were as follows: median age 57 years (range 35-68), male sex 44%, transplant diagnosis included AML [11], ALL [3], MDS/MPN [7], NHL [3], and multiple myeloma [1]. Using disease risk index (DRI), patients were classified as low [1], intermediate [13], or high/very high [11]. Twenty patients (80%) had a comorbidity index (HCT-CI) of ≥ 3. Median follow up for survivors was 28.3 (range 8.7-43.9) months. Post infusion fevers that subsided after receiving Cytoxan were seen in 93% and two patients had grade 2 cytokine release syndrome. Median time to ANC and platelet engraftment was 18 days (13-32) and 36 days (21-224), respectively. Three patients failed to engraft with spontaneous count recovery in one of them. Two of the three graft failures ended up engrafting after a second transplant. All engrafting patients had sustained complete donor myeloid and T cell chimerism by day 30. Acute GVHD grade II-IV and III-IV was seen in 20% and 8% respectively. The cumulative incidence of chronic GVHD was 16% (moderate-severe 12%). The estimated 2-year overall survival (OS) was 56%, disease-free survival (DFS) 44%, non-relapse mortality (NRM) 20%, relapse rate 36% and GVHD-, relapse-free survival (GRFS) 41%. For patients with high/very high DRI, the 2 year OS was 53%. For patients with HCT-CI 0-2, 2 year OS and DFS were at 75%. When compared to a contemporaneous cohort of patients receiving haplo transplant using fludarabine, Cytoxan and low dose TBI (Baltimore regimen), outcomes were not significantly different for OS, DFS, NRM and relapse. Patients receiving Flu/Mel had lower incidence of acute II-IV GVHD at 100 days (16% vs 44%). A matched pairs comparison (n=18) using matching at age range, DRI and HCT-CI between Flu/Mel and patients receiving Flu/Cy/TBI at our center, showed significant difference in OS, DFS, NRM and relapse (graph 1) between Flu/Mel and flu/Cy/TBI. All patients with primary MPD (n=4) had successful engraftment on this protocol which historically had a high graft failure rate on the non-ablative flu/Cy/TBI. Haplo transplant using fludarabine/melphalan with PBSCs is a valid option for some patients lacking a timely access to a matched donor. It is well tolerated and provides full and rapid donor myeloid and T-cell chimerism. Figure 1:Overall Survival and Disease Free Survival In Matched Cohorts of Flu/Mel versus Flu/Cy/TBI Figure 1 Disclosures No relevant conflicts of interest to declare.

scholarly journals Posttransplant cyclophosphamide as GVHD prophylaxis for peripheral blood stem cell HLA-mismatched unrelated donor transplant

2021 ◽  
Vol 5 (12) ◽  
pp. 2650-2659
Author(s):  
Monzr M. Al Malki ◽  
Ni-Chun Tsai ◽  
Joycelynne Palmer ◽  
Sally Mokhtari ◽  
Weimin Tsai ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Unrelated Donor ◽  
Peripheral Blood Stem Cells ◽  
Entire Cohort ◽  
Gvhd Prophylaxis ◽  
Blood Stem Cells

Efficacy of PTCy after mismatched unrelated donor (MMUD) HCT is unknown. In this pilot clinical trial, we enrolled 38 patients with hematologic malignancies scheduled to undergo MMUD-HCT (≥6/8 HLA-matched donors) onto 1 of 2 conditioning strata: myeloablative using fludarabine and fractionated total body irradiation (n = 19) or reduced intensity with fludarabine/melphalan (n = 19). Graft source was peripheral blood stem cells (PBSCs), and GVHD prophylaxis was PTCy, tacrolimus, and mycophenolate mofetil. Patients’ median age was 53 years (range, 21-72 years). Median number of HLA mismatches was 2 (range, 1-4) of 12 loci. Twenty-three patients (61%) were considered racial (n = 12) or ethnic (n = 11) minorities. Median time to neutrophil engraftment was 16 days (range, 13-35 days). With a median follow-up of 18.3 months (range, 4.3-25.0 months) for surviving patients, 1-year overall survival (OS) and GVHD-free/relapse-free survival (GRFS) were 87% (95% confidence interval [CI]: 71-94) and 68% (95% CI: 51-81), respectively. Cumulative incidence of nonrelapse mortality at 100 days and 1 year were 0% and 11% (95% CI: 4-27), respectively, whereas relapse/progression was 11% (95% CI: 4-27). Cumulative incidence of 100-day acute GVHD grades 2-4 and 3-4 and 1-year chronic GVHD were 50% (95% CI: 36-69), 18% (95% CI: 9-36), and 48% (95% CI: 34-68), respectively. The rate of moderate/severe chronic GVHD was 3% in the entire cohort. We showed highly promising OS/GRFS rates with an acceptable risk profile after PBSC-MMUD-HCT with PTCy. This trial was registered at www.clinicaltrials.gov as #NCT03128359.

Low Incidence Of Severe Cgvhd and Late NRM In a Phase II Trial Of Thymoglobulin®, Tacrolimus and Sirolimus For Gvhd Prevention

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5471-5471
Author(s):  
Zaid Al-Kadhimi ◽  
Alireza Eghtedar ◽  
Zartash Gul ◽  
Wei Chen ◽  
Daryn Smith ◽  
...  
Keyword(s):  
Phase Ii ◽  
Cumulative Incidence ◽  
Bronchiolitis Obliterans ◽  
Phase Ii Trial ◽  
Performance Status ◽  
Chronic Gvhd ◽  
Low Incidence ◽  
Nih Consensus Criteria

Abstract Introduction Chronic graft-versus-host disease (cGVHD) is a major factor determining long term outcome and quality of life following allogeneic hematopoietic cell transplantation (AHSCT). In fact, cGVHD is the leading cause of late non-relapse mortality (NRM) and morbidity after AHSCT. The rates of severe cGVHD using NIH consensus criteria reported in the literature are 15-38%. Effective regimens are needed to reduce the severity of cGVHD and improve NRM. We analyzed and updated the long term outcomes of our phase 2 trial evaluating the efficacy of intermediate dose rabbit anti-thymocyte globulin (Thymo) in combination with tacrolimus and sirolimus for the prevention of acute and chronic GVHD after unrelated donor transplantation. Methods In a Phase II trial, 47 adult patients (pts) underwent AHSCT from unrelated donors using Thymo, tacrolimus, and sirolimus for GVHD prophylaxis. Thymo was given as follows: 0.5 mg/kg day -3, 1.5mg/kg day -2, and 2.5mg/kg day -1. Chronic GVHD was measured using NIH consensus criteria. Results Twenty-two pts received 8/8 and 25 received 7/8 HLA matched unrelated grafts. Thirteen pts received a reduced intensity preparative regimen, while 34 pts received a full intensity regimen. The median follow-up duration was 45.2 months (95% CI 37.7-48.8), with minimum follow up of 30 months. At 4 years of follow up, the cumulative incidence of NIH severe cGVHD a, was 6.4 % (95% CI 1.6-15.9), and overall cumulative incidence of cGVHD was 48.9% (95% CI 33.6-62.6). Of 20 pts who are alive and disease free, only 4 pts continue to need systemic immune suppression at the last follow up. At 4 years of follow-up, the cumulative incidence of NRM and disease relapse were 27.7% (95% CI 15.7- 41.0) and 30.0% (95% CI 17.5- 43.6), respectively. There has been one non relapse death beyond 12 months and none after 18 months of follow up. Only one pt died from cGVHD and bronchiolitis obliterans, while two other pts had minimal symptoms from bronchiolitis obliterans. Progression free survival (PFS) and overall survival (OS) at 2 years were 50% (95% CI 35-64) and 56% (95% CI 42-70). Median OS is 33.9 months [95% CI (9.8 -*) *the upper limit of the CI was not calculated due to the pattern of censoring] All patients were censored after 40 months, so PFS and OS could not be calculated at 48 months. The median karnofsky performance status at 2 years was 90%. Conclusion At long term follow up, the combination of Thymoglobulin, Tacrolimus, and Sirolimus was associated with low incidence of severe cGVHD, low incidence of late NRM, and good performance status. Further validation of these results in randomized phase III trials is needed. Disclosures: Al-Kadhimi: Genzyme: Research Funding. Off Label Use: The use of Thymoglobulin® for GVHD prevention.

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