Comparison Between Related T-Cell Depleted HLA-Haploidentical Stem Cell Transplantation (TCD-Haplo) and Umbilical Cord Blood Transplantation (UCBT) in Pediatric Patients with Acute Leukemia, a Eurocord, PDWP-EBMT Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1215-1215
Author(s):  
Franco Locatelli ◽  
Myriam Labopin ◽  
Gerard Michel ◽  
Rupert Handgretinger ◽  
Cristina Diaz de Heredia ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Acute Leukemia ◽  
Advanced Disease ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Gvhd Prophylaxis ◽  
Risk Of Relapse

Abstract Both TCD-Haplo and UCBT are used for treating children with either acute lymphoblastic (ALL) or myeloid (AML) leukemia in need of an allograft and lacking a suitable donor. Although both these types of HSCT have been shown to be effective in curing children with acute leukemia, to date, no study has compared the outcomes of these two types of transplant. We performed a retrospective registry-based study on children (less than 18 years) with either ALL or AML, receiving, after a myeloablative conditioning regimen, a TCD-Haplo (CD34+ cell positive selection, CD3+ negative or TCR alpha/beta+ cell depletion) or single unit UCBT. Patients given pharmacological graft-versus-host disease (GVHD) prophylaxis after graft infusion in haplo HSCT were excluded. Transplants were performed from 2001 to 2012 in EBMT centers; 1067 patients received single UCBT and 266 TCD-Haplo for AML (n=478) or ALL (n=855). Median follow up was 28 (range 1-150) and 20 (range 1-152) months for UCBT and TCD-Haplo, respectively. Compared to TCD-Haplo, UCBT recipients were younger (median age 5.96 years vs 9.6 years, p=<0.0001), were transplanted more frequently in CR1 (42% vs 24%, p=<0.001), less frequently in advanced disease (10% vs 21%, p=<0.001) and had more often negative cytomegalovirus (CMV) serology (45% vs 31%, p=<0.001). Conditioning regimen was mainly total body irradiation (TBI)-based, 56% versus 50% for TCD-Haplo and UCBT, respectively. For UCBT, patients CSA+steroids was the most commonly used (72%) GVHD prophylaxis. A higher proportion of patients transplanted with TCD-Haplo received ATG in the conditioning regimen (90% vs 74%, p=<0.001). Acute GVHD (grade II-IV) incidence was 16% and 28% (p<0.001) while that of chronic GVHD was 14% and 16%, (p=0.40) for TCD-Haplo and UCBT respectively. Since diagnosis was the most important factor influencing outcome, the analysis was performed separately for patients with ALL and AML. For ALL (n=855) in univariate analysis, the 2-year probability of leukemia-free survival (LFS) was 35% and 43% (p=0.08), for TCD-Haplo and UCBT, respectively. The cumulative incidence (CI) of non-relapse mortality (NRM) was 28% and 29% (p=0.57), and relapse incidence (RI) was 36% and 28% (p=0.01) for TCD-Haplo and UCBT, respectively. According to disease status, for patients in CR1 (n=300), 2-year RI was 21% versus 20%, p=0.75; NRM 30% versus 24%, p=0.59; and 2- year LFS 49% versus 56%, p=0.87; for TCD-Haplo and UCBT, respectively. For patients in CR2 (n=478), 2-year RI was 34% versus 29%, p=0.75; NRM 28% versus 32%, p=0.29; and 2- year LFS 38% versus 39%, p=0.63, for TCD-Haplo and UCBT, respectively. For patients in advanced disease (n=77), 2-year LFS was 5% versus 8%, p=0.08 for TCD-Haplo and UCBT, respectively. For patients with AML (n=478), 2-year probability of LFS was 21% and 58% (p=<0.0001), for TCD-Haplo and UCBT, respectively. CI of NRM was 43% and 19% (p=<0.001), and RI was 36% and 23% (p=0.01) for TCD-Haplo and UCBT, respectively. According to disease status, for patients in CR1 (n=207), 2-year RI was 31% versus 14%, p=0.06; NRM 45% versus 16%, p=0.002; and 2-year LFS 24% versus 69%, p=<0.001; for TCD-Haplo and UCBT, respectively. For patients in CR2 (n=180), 2-year RI was 28% versus 24%, p=0.49; NRM 44% versus 21%, p=0.004; and 2- year LFS 28% versus 55%, p=0.0005, for TCD-Haplo and UCBT, respectively. For patients in advanced disease status (n=91), 2-year LFS was 10% versus 22%, p=0.44 for TCD-Haplo and UCBT, respectively. In multivariate analysis adjusted for differences between the 2 groups, for patients with ALL, no statistically significant differences were observed according to the graft source. Disease status was the only factor associated with better LFS (HR 4.84, p<0.0001). TCD-Haplo was associated with greater risk of RI (HR 1.58, p=0.01). For AML, in multivariate analysis, TCD-Haplo was associated with greater risk of relapse (HR 1.67, p=0.05) and of NRM (HR= 1.94; p=<0.001), and worse LFS (HR 1.94, p=<0.001) when compared to UCBT. Advanced disease at transplantation (HR 2.89, p=<0.001) was the other factor associated with LFS and RI. This retrospective analysis demonstrates that children with ALL have comparable probability of LFS after either UCBT or TCD-Haplo. By contrast, in children with AML, UCBT is associated with lower risk of relapse and NRM than TCD-Haplo, this translating into better LFS. These results may help guide physician choices for transplanting children with acute leukemia. Disclosures No relevant conflicts of interest to declare.

Are Outcomes After Myeloablative Conditioning Regimen in Double Cord Blood Transplantation (UCBT) Better Than Single UCBT for Adults with Acute Leukemia in Remission?.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3083-3083
Author(s):  
Annalisa Ruggeri ◽  
Henrique Bittencourt ◽  
Guillermo Sanz ◽  
Alessandro Rambaldi ◽  
Ibrahim Yakoub-Agha ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Acute Leukemia ◽  
Conflicts Of Interest ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Grade Ii ◽  
Group 2

Abstract Abstract 3083 Allogeneic hematopoietic stem cell transplantation (HSCT) is indicated for patients (pts) with acute leukemia (AL) with poor-risk cytogenetics or refractoriness to chemotherapy. For adults requiring HSCT urgently, such as pts in first complete remission (CR1), a single (s) or double unit (d) UCBT is a valid stem cells source. In the sUCBT setting, type of conditioning regimen seems to be associated with better outcome (Sanz BMT 2012). With the aim to compare single vs double UCBT after myeloablative conditioning regimen (MAC) in a homogeneous series of pts, we analyzed 239 adults (>18years) with AL in CR1. Pts were transplanted with sUCBT (n=156) or dUCBT (n=83) from 2005–2011 in EBMT centers for ALL (n=101) and AML (n=138). Type of MAC was statistically associated with outcomes therefore pts were analyzed in 3 different groups: Group 1: pts receiving sUCBT with TBI-based+Cy (+Flu) (n=68) (performed in 42 transplant centers (TC)), Group 2: pts receiving sUCBT with Bu+Flu+Thiotepa (n=88) (performed in 23 TC) and Group 3: pts receiving dUCBT with Cy+TBI+Flu (n=83) (performed in 47 TC). No statistical differences were found among the 3 groups for pts and disease characteristics (diagnosis, risk, gender, weight, CMV status, year of UCBT and time from diagnosis to UCBT) however pts in group2 were older than in group1 and 3 (median age 38 vs 33 vs 31 years) (p=0.03). Cytogenetic at diagnosis was available for 176 pts, 39% of pts were classified in the intermediate risk and 56% in unfavorable risk group. Forty-two pts had t(9;22) and 26 FLT3/ITD mutation. No differences on cytogenetic were found among the 3 groups. Thirty one percent of CB units were identical to recipient or had 1 HLA disparity (antigen level typing for HLA-A and B and allelic level for DRB1) while 69% had 2–3 HLA disparities. There was no difference on HLA disparities among the 3 groups. Median infused TNC was 2.9×107/kg for group1, 3×107/kg for group2, and 3.7×107/kg for group3 (p=0.01) and median CD34 was 1.2×105/kg, 1.6×105/kg and 1.5×105/kg, respectively (p=0.32). ATG was part of conditioning regimen in 73% of pts. The use of ATG was different in the 3 groups (70%, 90% and 40% for group1, 2 and 3, respectively p<0.001). GVHD prophylaxis consisted either of CSA±MMF or CSA±steroids in 46% and 22% of pts, respectively. All groups had the same median follow-up time: 24 (range 3–74) months. For group1, group2 and group3, the cumulative incidence (CI) of 60 days neutrophil recovery was 82%, 89% and 87% (p=0.15), with median time of 27, 21 and 24 days, respectively (p<0.001). Chimerism analysis performed at day 100 showed full donor chimerism in 87% of pts (data available for 80% of pts who engrafted). No differences in chimerism status were found between the 3 groups (p=0.47). At day 100, CI of acute GVHD (grade II-IV) was 30% vs 20% vs 45% for group1, group2 and group3, respectively (p=0.001). Pts receiving a dUCBT who developed aGvHD (n=38), experienced mainly grade II aGvHD with skin involvement (grade II (n=25), grade III (n=10), grade IV (n=3)). CI of chronic GvHD at 1 year was 29%, with no differences in the incidence among the groups. At 1 year, CI of TRM was 44% for group1, 33% for group2 and 36% for group3 (p=0.46). In multivariate analysis, two factors were associated with higher TRM: diagnosis of ALL (p=0.048) and age>35 years (p=0.049). One-Hundred-six pts died and the causes of death were infection (n=38), GvHD (n=18), other transplant-related events (n=31) or relapse (n=18). CI of 2y relapse was 25% for group1, 18% for group2 and 16% for group3 (p=0.22). No factors were found to be associated with increase relapse incidence in multivariate analysis. The 2y probability of leukemia-free-survival (LFS) was 31% for group1 (sUCBT-TBI based), 48% for group2 (sUCBT-BuFluTT), and 47% for group3 (dUCBT) (p=0.03). No center effect was found for LFS. In multivariate analysis, use of sUCBT using TBI based MAC (HR=0.9, p=0.003), diagnosis of ALL (HR=0.69, p=0.04) and age>35years (HR=1.4, p=0.04) were independently associated with decreased LFS. In this retrospective based registry analysis, in the myeloablative setting for adults with AL in CR1, outcomes (TRM, RI and LFS) after dUCBT were not statistically different from sUCBT using iv-BuFluTT. However, compared to sUCBT using TBI-based MAC, dUCBT was associated with lower RI and better LFS rates. In the MAC setting, the combination of conditioning regimens and type of graft (single vs. double) may have different impact UCBT outcomes. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Unrelated Cord Blood Versus Non-T Cell Depleted Haploidentical Stem Cell Transplantation: Comparable Results in Adults with Acute Leukemia, a Eurocord and ALWP-EBMT Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1227-1227
Author(s):  
Annalisa Ruggeri ◽  
Myriam Labopin ◽  
Guillermo F. Sanz ◽  
Simona Piemontese ◽  
William Arcese ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Gvhd Prophylaxis ◽  
Unrelated Cord Blood

Abstract Unrelated cord blood transplantation (UCBT) and related Haploidentical non T-cell depleted stem cell transplantation (Haplo) are alternative options to treat patients with high risk acute leukemia. Both techniques have shown encouraging results. The current retrospective analysis aimed to compare the outcomes of both approaches in adults with ALL and AML receiving either UCBT (n=928) or Haplo (n=518) reported to EBMT centres between 2007 and 2011. Diagnosis was ALL for 716 patients (Haplo=158 and UCBT=558) and AML for 730 (Haplo=360, UCBT=370). Haplo grafts were not T-cell depleted, with 236 patients receiving unmanipulated bone marrow (BM), 253 receiving peripheral blood stem cells (PBSC) and 29 receiving BM+PBSC. For UCBT, 431 patients were treated with a single unit, while 497 received double unit UCBT. Compared with recipients of UCBT, Haplo recipients were more likely to have AML (69% versus 40%, p=<0.001), and were transplanted more recently (2011 versus 2009, p=0.001), had a longer median interval from CR1 to transplant (139 versus 126 days, p=0.07), and had more frequently advanced phase of disease at time of transplant (35% versus 17%, p=0.001). Median follow-up was 19 months and 25 months, (p=0.007) for Haplo and UCBT, respectively. The type of conditioning regimen (MAC or RIC) was similar between both groups, with MAC representing 60% and 56% for Haplo and UCBT, respectively. For Haplo, the most frequently used regimens were Thiotepa-Busulfan-Fludarabine (TBF) for MAC and Treosulfan-based regimens for RIC. Graft versus host disease (GVHD) prophylaxis included CsA+MMF (41%), Sirolimus (15%), while 163 patients received post-transplant Cyclophosphamide (Cy). For UCBT cases, the most common MAC regimens were TBF for 33% of cases, CyFluTBI-12Gy for 27% and CyTBI12Gy for 17%. The most frequently used RIC was CyFluTBI-2Gy in 72% of the cases. GVHD prophylaxis was CsA+MMF in 70% of cases. In univariate analysis, cumulative incidence (CI) of neutrophil engraftment was 92% vs 84% (p=<0.001) for Haplo and UCBT; CI of acute GVHD was 27% vs 32% (p=0.11) and for chronic GVHD it was 30% vs 25% (p=0.06) for Haplo and UCBT. For non-relapse mortality (NRM), relapse incidence (RI) and leukemia-free survival (LFS) outcomes were analyzed separately according to disease status, and no statistically significant differences were observed between Haplo and UCBT. According to disease status, for patients in CR1 (n=610), 2 years RI was 27% versus 28%, p=0.67; NRM 26% versus 29%, p=0.30; and 2 years LFS 48% versus 43%, p=0.16; for Haplo and UCBT, respectively. For patients in CR2 (n=502), 2 years RI was 33% versus 28%, p=0.51; NRM 33% versus 33%, p=0.93; and 2 years LFS 34% versus 39%, p=0.61, for Haplo and UCBT, respectively. For patients in advanced disease status (n=334), 2 years LFS was 11% versus 14%, p=0.92 for Haplo and UCBT, respectively. Infections and GVHD were the most common causes of transplant-related deaths in both groups, (infection 30% in both groups, GVHD 15% and 9%, after Haplo and UCBT, respectively), and 40% of deaths were due to disease recurrence in both Haplo and UCB recipients. In multivariate analysis, UCBT was associated with lower incidence of chronic GVHD (HR= 0.62; p<0.001) and higher NRM (HR= 1.28; p=0.04) when compared to Haplo. No statistically significant differences were observed between Haplo and UCBT for RI (HR= 0.87; p=0.24) and LFS (HR= 1.06; p=0.47). Factors independently associated with lower LFS were disease status at transplant (HR 2.69, p=<0.001), and use of ATG (HR 1.28, p=0.001). In conclusion, in this retrospective analysis, non TCD Haplo and UCBT showed similar RI, NRM, and LFS, highlighting that both approaches are valid for this population of patients. Longer follow-up, more homogeneous transplant strategies (stem cell source, type of conditioning regimen and GVHD prophylaxis) are needed for further evaluation. While waiting for the results of the BMT CTN trial on non TCD Haplo using post-transplant Cy and double UCBT both in the RIC setting, the choice of the specific approach for Haplo or UCBT should be likely based on transplant centre expertise and policy. Disclosures No relevant conflicts of interest to declare.

Hematopoietic Stem Cell Transplantation (HSCT) as Curative Therapy for Fanconi Anemia (FA) Patients with Acute Leukemia or Advanced Myelodysplasia (MDS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5464-5464
Author(s):  
Christopher J. Fraser ◽  
John E. Wagner ◽  
Margaret L. MacMillan
Keyword(s):  
Acute Leukemia ◽  
Hemorrhagic Cystitis ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Curative Therapy ◽  
Disease Characteristics ◽  
Gvhd Prophylaxis ◽  
Preparative Regimen ◽  
Total Body

Abstract Historically outcomes have been very poor for FA patients with advanced MDS or leukemia. It remains controversial as to whether HSCT is indicated for such patients and there is no consensus as to the optimal conditioning regimen in this setting. Traditionally, conditioning for FA patients has incorporated total body irradiation (TBI). Here, we report results of a pilot study in which we have substituted busulfan for TBI, designed for FA patients with one or more high risk features, identified following analysis of 42 previous consecutive URD FA transplants: advanced MDS or leukemia, age &gt;18 years, or previous proven fungal or gram negative infection. Between 12/02–08/04 6 patients were enrolled, 5 with acute leukemia. Patient and disease characteristics are presented in Table 1. Conditioning consisted of busulfan (total 3.2mg/kg), cyclophosphamide (total 40mg/kg), fludarabine (total 140 mg/m2) and ATG (total dose 75mg/kg); GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. All patients received prophylactic voriconazole for one month prior to transplant. BM was T cell depleted with CD34 selection by Isolex 300i. Five out of six patients achieved neutrophil engraftment. Median time to an ANC&gt;500 was 16 days (range: 11–20 days). One patient developed Grade I acute GVHD; no patient has developed chronic GVHD. The preparative regimen was well tolerated. Toxicities included Grade IV mucositis (n=1), VOD (n=2), hemorrhagic cystitis (n=1) and CMV pneumonia (n=1). Three patients are alive and in remission with a median follow-up of 575 days. Table 1 Age Diagnosis FANC group Remission status Donor source D+21 chimerism D+60 chimerism Vital status Patient and disease characteristics 5.9 ALL BRCA2 treated; CR 5/6 related BM 100% donor 100% donor alive d+894 21.7 AML A untreated 5/6 URD BM 99.1% donor 100% donor died resp. failure d+99 20.8 SAA A N/A 5/6 URD BM insufficient cells N/A died VOD d+24 6.6 ALL,MDS,Wilm’s BRCA2 ALL treated CR; MDS (7.5% blasts) 6/6 URD UCB 100% donor 100% donor alive d+575 7.1 AML A treated; refractory 4/6 UCB + 5/6 UCB 100% donor #2 54.7% #2; 45.3% recipient died AML relapse d+60 17.3 AML A treated; refractory 5/6 UCB x2 66.7% #1; 31.3% #2; 2% recipient 100% donor #1 alive d+423 These results suggest TBI is not required to achieve durable engraftment and leukemia control, busulfan 3.2 mg/kg is tolerable, and advanced MDS or acute leukemia does not preclude HSCT in FA patients.

Umbilical Cord Blood (UCB) Transplantation in Children with Acute Leukemia: Impact of Conditioning Regimen on Transplant Outcomes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1231-1231 ◽  
Author(s):  
Mary Eapen ◽  
Joanne Kurtzberg ◽  
Mei-Jie Zhang ◽  
Adam M. Mendizabal ◽  
Ka Wah Chang ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Cord Blood ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Survival Rates ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Marrow Transplant ◽  
Blood And Marrow Transplant ◽  
Hematopoietic Recovery

Abstract The Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0501; NCT00412360) randomized children with hematologic malignancy to one or two cord blood unit transplantation between December 2006 and February 2012. While the trial concluded that survival was similar regardless of number of units infused, results were generally better than those previously reported after single UCB transplant. The apparently improved survival in recipients of BMT CTN 0501 compared to prior studies in children transplanted with a single UCB unit prompted a comparison of trial versus non-trial treatment outcomes to determine 1) the generalizability of trial results and 2) whether survival was better for patients treated with the trial regimen. Using data reported to the Center for International Blood and Marrow Transplant Research during the trial period, 396 recipients of one UCB unit transplant met the broad eligibility criteria for BMT CTN 0501 (i.e. aged 1- 21 years, high-risk acute leukemia, performance score ≥70). Trial and non-trial patients were comparable in their HCT-CI score. Trial patients (n=100) received total body irradiation (TBI) 1320 cGy, cyclophosphamide 120 mg/kg, and fludarabine 75 mg/m2 (TCF). Non-trial patients either received the same regimen as in the trial (N=62; non-trial TCF) or an alternative regimen (N=334; non-trial non-TCF regimen). Excluded were 13 patients on BMT CTN 0501 randomized to receive a single UCB unit for malignant diseases other than acute leukemia. Patient and disease characteristics of those treated on BMT CTN 0501 and others were similar except that those who received non-trial TCF regimen were more likely to report performance scores of 80 or 70 (24% versus 11%, p=0.04) and transplanted in relapse (18% vs. 5%, p=0.02) and those that received non-TCF regimens were more likely to 1-10 years of age (76% versus 53%, p<0.0001). Sixty-three percent of non-trial non-TCF regimens included TBI (≥1000 cGy) and the predominant non-TBI regimen was busulfan and cyclophosphamide. All patients received a calcineurin inhibitor for graft-versus-host disease (GVHD) prophylaxis. Donor-recipient HLA-match, median infused total nucleated cells and median follow up times were similar across the groups. Three-year survival rates were similar between patients receiving TCF regimen either on (A) or off trial (B), Figure1A, p=0.83. Similarly, there were no differences in hematopoietic recovery, relapse or non-relapse mortality between trial and non-trial TCF. However, compared to TCF on trial (A), overall survival rates were significantly lower with non-TCF non-TBI (C) and TBI (D) containing regimens after adjusting for age, CMV serostatus, disease and disease status; Figure 1B, 68% versus 55% (p=0.001) and 68% versus 50% (p=0.04), respectively. Results of multivariate analysis are shown in Table 1. Compared to patients treated on trial (TCF regimen; 20% at 3-years) relapse rates were higher with non-TCF non-TBI (42%, p=0.003) but not TBI-containing regimens (25%, p=0.38) after adjusting for age, disease, disease status and CMV seropositivity. Among non-TCF patients, relapse risk was higher for non-TBI compared to TBI-containing regimens (hazard ratio [HR] 1.61, p=0.02) but not mortality risk (HR 0.93, p=0.74). Cytogenetic risk features were not associated with relapse or survival. There were no differences in hematopoietic recovery, acute and chronic GVHD. The results of BMT CTN 0501 appear generalizable to the population of trial eligible patients. The survival differences between the trial specified and other conditioning regimens support use of the TCF regimen to improve survival. It also indicates the importance of conditioning regimen for outcome and may serve as a stimulus to design trials to identify the optimal regimen for children with acute leukemia undergoing UCB transplantation. Disclosures No relevant conflicts of interest to declare.

scholarly journals From Ex-Vivo T-Cell Depletion to Post-Transplant Cyclophosphamide: Improved GvHD-Free & Relapse-Free Survival but Comparable Chronic GvHD Incidence in Haploidentical Transplantation. A 15 Years EBMT Registry Analysis on Behalf of the TCWP-EBMT

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 876-876
Author(s):  
Maria Teresa Lupo-Stanghellini ◽  
Christophe Peczynski ◽  
Hildegard T. Greinix ◽  
Emmanuelle Polge ◽  
Mohamad Mohty ◽  
...  
Keyword(s):  
Research Funding ◽  
Ex Vivo ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Disease Status ◽  
Free Survival ◽  
Patient Gender ◽  
Gvhd Prophylaxis ◽  
Grade 3

Background: Haploidentical stem cell transplantation (Haplo HSCT) has emerged in the past three decades as an alternative curative option when an HLA match donor is not available. Over time, the use of Haplo has increased dramatically, reaching superimposable results when compared to unrelated and related HSCT strategies, confirming its validity. The widespread use of Haplo mainly relies upon technical advances, control of alloreactivity through graft-versus-host disease (GvHD) prophylaxis combined with a rapid and almost universal probability to find an Haplo donor for any candidate patient. The aim of our study was to provide a picture of acute (aGvHD) and chronic GvHD (cGvHD) incidence in Haplo HSCT across different platform in the past 15 years, where Haplo moved from ex-vivo T-cell depleted (TCD) platform to in-vivo TCD platform to the post-transplantation cyclophosphamide (PTCy). Methods: We compared the outcomes of adult patients receiving a 1st Haplo HSCT for any hematological malignancy according to GvHD prophylaxis - ex-vivo + in-vivo TCD (n=160), in-vivo only TCD (n=507) or PTCy (n=2593) - and reported to the EBMT registry in 2004-2016. Patients with missing data on disease status at last follow-up and GvHD information were excluded. Primary endpoint was GvHD-free & Relapse-free survival (GRFS) with events defined by death or relapse or grade ≥3 aGvHD or extensive (ext) cGvHD. Secondary endpoints were progression-free survival (PFS), overall survival (OS), aGvHD and cGvHD, incidence of relapse (IR) and non-relapse-mortality (NRM). Due to sample size in the first cohort of ex-vivo TCD, multivariate analysis compared only in-vivo TCD vs PTCy cohorts. Table 1 illustrates patients' characteristics. Results: Univariate analysis for 3-year outcomes are reported on table 2. PTCy provides better GRFS, OS, PFS, NRM versus ex-vivo or in-vivo. IR was not significantly different. Likewise, the 3-year CI of cGvHD and ext cGvHD were similar between PTCy, in vivo TCD and ex-vivo TCD (cGvHD 27% [25-29%], 25% [21-29%], 18% [12-25%], p 0.03; ext cGvHD 11% [10-12%], 10% [8-13%], 8% [4-13%], p 0.45). On the contrary the 100-day CI of grade ≥2 aGvHD were lower in the ex-vivo TCD vs PTCy and in-vivo TCD (19% [14-26%], 28% [26-30%], 32% [28-36%], p 0.002) while grade ≥3 aGvHD were lower in the PTCy group vs ex-vivo and in-vivo TCD (9% [8-10%], 11% [7-17%], 14% [11-18%], p &lt;0.001). After adjustment for diagnosis, patient age, disease status, Karnofsky PS, donor/patient gender and CMV, cell source, conditioning intensity, previous auto and year of transplant, the multivariable model comparing in-vivo TCD and PTCy showed better outcome for PTCy. Compared to in-vivo TCD, the hazards for GRFS was 0.76 for PTCy (p 0.004), the HR for PFS was 0.71 (p 0.001) and the HR for OS was 0.7 (p 0.0008), the HR for NRM was 0.63 (p 0.001). Moreover, compared to in-vivo TCD, PTCy yielded similar hazards for grade≥2 aGvHD (HR: 1.02, p 0.89), grade≥3 aGvHD (HR 0.79, p 0.27), cGvHD (HR 1.17, p 0.37), ext cGvHD (HR 1.18, p 0.52) and relapse (HR 0.8, p 0.1). Variables associated with GRFS were active disease, Karnofsky PS ≥90%, diagnosis, donor/patient gender and CMV. An ancillary analysis evaluating the stem cell source effect in the PTCy cohort only, demonstrates comparable outcome endpoints (OS, PFS, NRM, IR) at 2-year between bone marrow (BM) and peripheral blood (PB) PTCy. In univariate analysis GRFS and the 2-year CI of cGvHD were not different between BM and PB (GRFS 47% [45-50%], 46% [44-49%], p 0.085; 2-year CI of cGvHD 25% [23-28%], 27% [25-30%], p 0.2) while ext cGvHD, 100-day CI of grade ≥2 aGvHD and grade ≥3 aGvHD were lower in BM PTCy vs PB PTCy (ext cGvHD 8% [7-10%], 12% [10-14%], p &lt;0.001; grade ≥2 aGvHD 20% [18-22%], 36% [33-38%], p &lt;0.001; grade ≥3 aGvHD 6% [5-7%], 12% [10-14%], p &lt;0.001). Compared to BM PTCy, the HR for cGvHD was 1.55 for PB PTCy (p 0.001), the HR for ext cGvHD was 2.04 (p 0.0003), the HR for grade ≥2 aGvHD was 1,94 (p &lt;0.0001), the HR for grade ≥3 aGvHD was 2.01 (p 0.0001). Conclusions: In the present EBMT registry study on more than 3000 patients transplanted from an Haplo donor, we report improved outcome (better GRFS - in spite of comparable chronic GvHD - OS and PFS, lower NRM) and widespread use in different diagnosis setting other than acute leukemia in PTCy platform. PTCy strategy provides a concrete progress into the field: even if cGvHD still represent a major issue, exploitation of BM PTCy seems to protect against most severe GvHD manifestation. Disclosures Mohty: Jazz Pharmaceuticals: Honoraria, Research Funding. Kröger:Sanofi-Aventis: Honoraria; Riemser: Research Funding; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Medac: Honoraria; JAZZ: Honoraria; DKMS: Research Funding; Celgene: Honoraria, Research Funding. Basak:Celgene: Honoraria; Teva: Honoraria.

A phase II trial 90y-ibritumomab tiuxetan in combination with reduced intensity regimen of fludarabine (flu) and melphalan (mel) followed by allo-HCT in patients with refractory B-cell lymphoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6545-6545 ◽  
Author(s):  
Auayporn Nademanee ◽  
Andrew Antony Raubitschek ◽  
Ni-Chun Tsai ◽  
Jennifer Simpson ◽  
Neil Martin Kogut ◽  
...  
Keyword(s):  
Disease Control ◽  
B Cell ◽  
Median Time ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
B Cell Lymphoma ◽  
Disease Status ◽  
Gvhd Prophylaxis ◽  
Transformed Lymphoma ◽  
Grade Ii

6545 Background: RIC allo-HCT has reduced transplant-related mortality (TRM) in patients with relapsed NHL. However, relapses do occur despite potential graft vs. lymphoma (GVL) effect. We hypothesized that adding Zevalin to Flu/Mel may improve disease control and reduce relapse post allo-HCT. Methods: Patients received In- Zevalin on day -21 followed by 90Y- Zevalin 0.4mCi/kg on day -14, flu 25 mg/m2 daily on days -9 to -5 and mel 140 mg/m2 on day -4. Rituximab (R) level was measured on Day -22 and -15 and if the level was ≥ 10 μg/ml, R was not given prior to In-Zevalin or 90Y- Zevalin to enhance biodistribution. Tacrolimus and sirolimus was used for GVHD prophylaxis. Between 10/2007 and 11/2011, 31 were treated. Median age 55 (range 27-67), median regimen =3 (range 2-8). Median time from diagnosis to HCT was 20 mo (range 5-105). Histology: DLBCL (including transformed lymphoma)=14 (45%), MCL=7 (23%), FL=5 (16%) and SLL/CLL=5 (16%). Disease status at HCT: 1CR=7, Relapse=9, ≥2CR=5, primary refractory =10. Fifteen had chemoresistant and 19 had FDG PET+ at HCT. Donors: sib=13, URD=18. Results: All patients engrafted with the median time to ANC ≥500 and platelet ≥ 20,000 was 14 (range 10-28) and 13.5 days (range 11-28), respectively. There were 10 deaths from disease progression (2) infection (5) GVHD (1) and multi-organ failure (2). TRM at day +100 and at 1 yr was 6.5% and 17%, Five with DLBCL relapsed between 3-7 mos. Grade II-IV acute GVHD was 65%, Grade III-IV was 16%, chronic GVHD was 65%. Fifteen became PET- at day +100 while 4 remained PET+ and relapsed. Twenty-one are alive at a median followup of 24 mos (range 2-46). The 2 yrs OS and PFS was 65% (95% CI, 51-75%) and 57% (95% CI, 46-67%), respectively. Univariate analysis identified disease status predict for OS and PFS while histology predict for PFS. Conclusions: This study demonstrates the feasibility of adding Zevalin to flu/mel in the allo-HCT setting for B-cell NHL and suggest that this approach could be used to provide early disease control before GVL effect takes place. Innovative approaches should be explored in DLBCL.

Reduced-Intensity Unrelated Cord Blood Transplantation (RICBT) for Adults with Hematological Diseases.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2763-2763 ◽  
Author(s):  
Shigesaburo Miyakoshi ◽  
Koichiro Yuji ◽  
Eiji Kusumi ◽  
Daisuke Kato ◽  
Syouhei Koyama ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Significant Prognostic Factor ◽  
Platelet Recovery ◽  
Hematological Diseases ◽  
Blood Transplantation ◽  
Sex Risk

Abstract &lt;Introduction&gt;The potential role of RICBT in adults remains unclear. This study reports the results of RICBT for adults with hematological diseases. &lt;Objective&gt;The 1st purpose of this report was to investigate the risk factors of non-relapse mortality (NRM) within day 100 of RICBT and the 2nd was to identify its prognostic factors. &lt;Patients and Methods&gt;We reviewed medical records of 107 patients with advanced hematological diseases who had received RICBT between March 2002 and June 2004 at Toranomon Hospital, Tokyo, Japan. Median age of the patients was 55 years (17–79). Primary diseases were advanced (n=88) or standard (n=19). Median follow-up was 14 months (0.5–27). Conditioning regimen was fludarabine 125 mg/m2, melphalan 80 mg/m2 and TBI 4 Gy. GVHD prophylaxis was cyclosporine (n=87) or tacrolimus (n=26). Median total nucleated cells (TNC): 3.2 x 10^7 cells (1.7–4.3); Median CD34+: 1.4 x 10^5 cells (0.21–3.28); HLA match: 6/6 (n=4), 5/6 (n=3), 4/6 (n=95), 3/6 (n−1). Time to event curves were plotted by using the actuarial method of Kaplan-Meier, and differences between curves were analyzed by log-rank tests. The following factors were considered potential predictors of outcomes about 1st and 2nd purpose: age, weight, sex, risk, HLA disparities, TNC, CD34+, GVHD, pre-engraftment reactions (PER) that we have reported (Clin Cancer Res.10:3586-92, 2004), and use of steroids for PER. All factors were tested for the proportional hazards assumption. &lt;Results&gt;Neutrophile (&gt;500/μL) and platelet recovery (&gt;20,000/μL) were observed in 77.9% at day 60 (median; 19.5 day), 48.7% at day 100 (45.5 day), respectively. Primary graft failure was occurred in 8% of all cases. Cumulative incidence of acute GVHD (II-IV) and chronic GVHD were 39.8% and 21.1%, respectively. Causes of NRM included infections (n=30), regimen related mortality (RRM) (n=19), and GVHD (n=6). Incidence of NRM at day 100 was 51.6% (95% CI: 42–61), 33 patients with use of steroids for PER had NRM at day 100 of 75% (95% CI: 67–94), as compared to 39% (95% CI: 25–48) in 77 patients without use of steroids (p&lt;0.05). The estimated OS was 29.9% (95% CI: 17.8–40.2) in all cases, 54.5% (95% CI: 29.8–78.4) in standard, and 21.2% (95% CI: 6.7–35.7) in advanced (p&lt;0.05), respectively. In multivariate analysis, the most important risk factor of NRM was use of steroids for PER (p&lt;0.05), while other factors did not influence. As for OS, disease status and use of steroids for PER were significant predictors of OS (p&lt;0.05). &lt;Discussion and Conclusion&gt; RICBT is associated with a high NRM. This study has demonstrated status of underlying diseases and use of corticosteroid for PER as a significant prognostic factor. Eligibility of RICBT needs to be investigated, and further studies are warranted to clarify the pathogenesis of PIR and its optimal management. Figure Figure

Risks and Benefits of Unrelated Donor Peripheral Blood Progenitor Cells (PBPC) in Children and Adolescents with Acute Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 977-977
Author(s):  
Mary Eapen ◽  
Olle Ringden ◽  
Franco Locatelli ◽  
Haydar Frangoul ◽  
Mats Remberger ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Unrelated Donor ◽  
Platelet Recovery ◽  
Free Survival ◽  
Grade 3

Abstract Although PBPC is an acceptable alternative to bone marrow (BM) for transplanting children with leukemia, there are no published studies describing outcomes after unrelated donor PBPC transplants. We compared the results of 385 unrelated donor BM transplants that were allele-matched (n=186) or mismatched (n=199) at HLA A, B, C, DRB1 and 110 PBPC transplants that were matched (n=60) or mismatched (n=50) at HLA A, B, C, DRB1 in patients younger than 18 years of age. All patients had acute leukemia and were transplanted in 2000–2006. Median follow up of surviving patients was 2 years in both treatment groups. There were no significant differences in patient and disease characteristics, transplant conditioning regimen, graft-versus-host disease (GVHD) prophylaxis and donor-recipient HLA disparity by graft type. Though the early probability of neutrophil recovery (³500/ul) was faster after transplantation of PBPC (31% vs. 10% at day-14, p<0.001) the probability of recovery by day-28 was similar after PBPC and BM transplants (94% and 91%, p=0.391). In contrast, platelet recovery (³20,000/ul) was better after PBPC transplants (86% vs. 76% at day-60, p=0.022). Risks of grade 2–4 (hazard ratio [HR] 1.24, p=0.147) and grade 3–4 (HR 1.07, p=0.785) acute GVHD were similar after PBPC and BM transplants. The risk of developing chronic GVHD was significantly greater after PBPC transplants compared to BM transplants (HR 2.36, p<0.001). After adjusting for disease status, donor-recipient HLA disparity and age, the of transplant-related mortality (TRM) relapse, treatment failure (relapse or death from any cause; inverse of leukemia-free survival and overall survival were similar after PBPC and BM transplants. The Table below shows the day-100 probability of grade 2–4 acute GVHD and the 3-year probabilities of chronic GVHD, TRM, relapse, leukemiafree survival and overall survival by graft type. These results differ from transplantation of PBPC from HLA-matched siblings where higher chronic GVHD translated into higher TRM and lower LFS. It remains to be seen whether the observed higher chronic GVHD after PBPC transplants will eventually result in the long term in higher mortality or fewer leukemia recurrence. PBPC BM Grade 2–4 acute GVHD 53% 49% Chronic GVHD 58% 33% TRM 20% 24% Relapse 34% 28% Leukemia-free survival 46% 48% Overall survival 49% 49%

Haploidentical Transplantation (HAPLO) with Post-Transplant High-Dose Cyclophosphamide for Graft Vs Host Disease (GVHD) Prevention in the Treatment of High Risk Hematological Neoplasms

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4545-4545
Author(s):  
Jorge Gayoso ◽  
Mi Kwon ◽  
David Serrano ◽  
Pascual Balsalobre ◽  
Javier Anguita ◽  
...  
Keyword(s):  
High Risk ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Allogeneic Transplantation ◽  
High Dose ◽  
Unrelated Donor ◽  
Haploidentical Transplantation ◽  
Gvhd Prophylaxis

Abstract Abstract 4545 Introduction: Allogeneic transplantation is the only curative option in the treatment of multiple high risk hematologic neoplasms. Only 25–30% of patients have an HLA identical sibling donor and searching for a compatible unrelated donor or cord blood renders satisfactory results in around 60–70%. Haploidentical transplantation (HAPLO) offers a therapeutic alternative to more than 95% of such patients with the advantages of quick availability, easy programming and a committed donor. Patients and Methods: We evaluate the results of HAPLO with a reduced intensity conditioning regimen (Fludarabine 30 mg/m2 ×5 days (-6 to -2), Cyclophosphamide 14,5 mg/kg ×2 days (-6 and -5), IV Busulfan 3,2 mg/kg × 1–3 days (BUX, days -4 to -2) employing high doses of Cyclophosphamide post graft infussion (50 mg/kg days +3 and +4) as GVHD prophylaxis together with standard doses of cyclosporine and mycophenolate from day +5. Results: From Dec-2007, we have done 26 HAPLO in 4 spanish centers. Median age was 38 years (16–57), 20 were male and all were in advanced phases of their diseases (12 Hodgkin′s, 6 AML, 3 ALL, 2 MM, 1 MDS, 1 MF y 1 NHL). Previous autologous HSCT has been employed in 13 and allogeneic HSCT in 6 (2 MURD and 4 UCB). Disease status at HAPLO was CR in 8, PR in 14 and refractory in 4. Bone marrow was used in 16 and unmodified peripheral blood in 10. The haploidentical donor was patient′s mother (8), father (3), siblings (11) or other relatives (4). BUX was used in 1 dose (15), 2 doses (8) or 3 doses (2) and TBI 200 cGy in 1 case. Mean neutrophils engraftment was achieved on day +18 (13–26) and platelets >50K on day +27 (17–150) in all but 2 cases of graft failure (7.7%) due to progression (MF) or relapse (M7-AML). Main toxicities were grade 1–2 mucositis in 50%, febrile neutropenia in 75% and CMV reactivations in 58% with a 100 days NRM of 3.8% (1/26, VOD and MOF) and 10% NRM at 6 months (2/20). Grade II-IV acute GVHD appeared in 10/23 patients at risk (43%) and grade III-IV in 4/23 (17%). Chronic GVHD affected to 4/15 (27%), being extensive in 1/15 (6.7%). With a median follow-up of 9 months (1–38), 13/22 (59%) are alive in CR, progression or relapse has ocurred in 6/24 (25%). Immune reconstitution seems fast and complete in those evaluated. Conclusions: HAPLO with high-dose cyclophosphamide as GVHD prophylaxis is a useful alternative in the treatment of high risk hematologic tumours, with low toxicity, acceptable GVHD incidence and severity, long lasting remissions, and fast immunological reconstitution. Disclosures: No relevant conflicts of interest to declare.

Risk Factors and Outcome of Children with Relapsed/Refractory Acute Leukemia after T-Cell-Rich Haploidentical Hematopoietic Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4604-4604
Author(s):  
Atsushi Kikuta ◽  
Hideki Sano ◽  
Kazuhiro Mochizuki ◽  
Shogo Kobayashi ◽  
Mitsuko Akaihata ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Leukemia ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Disease Free Survival ◽  
T Cell Therapy ◽  
Gvhd Prophylaxis ◽  
Significant Difference

Abstract Background: T-cell rich (TCR) HLA-haploidentical SCT (haplo-SCT) is a form of T-cell therapy that has a high degree of efficacy in hematologic malignancies. Previously we reported the safety profile assessing GVHD prophylaxis that was conducted with anti-human thymocyte immunoglobulin (ATG), tacrolimus, methotrexate (MTX) and prednisolone (PSL) in unmanipulated haplo-SCT (Clin Transplant 2010, Transfus Med 2014). We evaluated efficacy and toxicity of TCR haplo-SCT in children with very high risk refractory/relapsed acute leukemia (VHR-R/R AL). Methods: VHR-R/R AL were defined as: relapse after SCT, very early or early relapse, induction failure(2 or more) and relapse of risk factor with MLL rearrangement, Ph+, Mo7 and 5q-. From Aug 2000 to April 2014, consecutive 38 patients (pts) with VHR-R/R AL who underwent TCR-haplo-SCT were included. The median age of pts was 8.2(0.3-19.1) years old. The diagnosis included ALL (n=27), AML (n=8), M/NKL (n=3). The disease status at TCR-haplo-SCT were 18 in CR (positive MRD: 8 pts), 20 in non-CR. HLA disparities were 2/8 in 1pt, 3/8 in 9 pts, 4/8 in 28 pts. Donors included fathers (n=21), mothers (n=14), and siblings (n=3). Thirty one pts received myeloablative conditioning (TBI based: 20 pts, Bu based: 11 pts) and 34 pts of them received ATG (rabbit, thymoglobulin 2.5mg/kg) containing regimen. The GVHD prophylaxis was conducted with tacrolimus, MTX and PSL. Thirty four pts received peripheral blood stem cells and 4 pts received BM. Results: Neutrophil engraftment (defined as >0.5x109/L) was 95% with a median day of 13 (range, 10-15). With a median 1640 days follow-up (range, 320-5510 days) in pts without events, the actuarial 3-year overall survival (OS) and disease-free survival (DFS) were 57% and 39%, respectively. On competing-risk analysis, 1-year cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 71% and 63%, respectively; 3-year cumulative incidences of relapse and non-relapse mortality (NRM) were 40% and 20%. On univariate analysis, 3-year OS in pts with acute GVHD vs. without acute GVHD were 70% vs. 22% (p=.0006), in pts CR vs. non-CR at TCR-SCT were 83% vs. 32% (p=.007), in pts infused CD3 cell doses >=5 x 108/kg vs. <5 x 108/kg were 83% vs. 25% (p=.005), according to age at TCR-SCT <9 vs. >=9 were 79% vs. 34% (.008), respectively. In contrast, the occurrence of acute GVHD had no significant difference in infused CD3 cell doses. Conclusions: These data suggest that TCR haplo-SCT following low-dose ATG containing conditioning combined with our GVHD prophylaxis is well tolerated, facilitates engraftment, and has significant anti-leukemic activity, particularly in pediatric patients with refractory/ relapsed population. Disclosures No relevant conflicts of interest to declare.

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