Multicenter Investigation Of Unrelated Donor Hematopoietic Cell Transplantation (HCT) For Thalassemia Major After a Reduced Intensity Conditioning Regimen (URTH Trial)

Abstract Background HCT cures thalassemia major (TM). In the absence of a family donor, marrow or less frequently umbilical cord blood (UCB) from unrelated donors (URD) has been used. Due to risks of graft rejection, myeloablative preparative regimens are primarily utilized. URD marrow and UCB HCT have 65-90% and 21-74% event free survival (EFS) and rejection rates of 9-17% and 17-57% respectively. The URTH trial was developed in collaboration with the Thalassemia Clinical Research Network (TCRN), National Heart, Lung and Blood Institute (NHLBI), Pediatric Blood and Marrow Transplant Consortium (PBMTC) and New England Research Institutes (NERI) to explore URD HCT for TM as a strategy to expand availability of HCT. It employed reduced intensity conditioning (RIC) as a means to decrease early and late toxicities. The study tested our hypothesis that an immunosuppressive RIC regimen was sufficient for engraftment in children with TM (age > 1 year to < 17 years) after URD HCT. The primary objective was to determine EFS at 1 year after URD marrow or UCB HCT. Methods Patients with transfusion dependent beta thalassemia and a suitable URD (matched at 8/8 HLA-alleles in marrow donors or 5 to 6/6 HLA antigens in UCB donors) were conditioned with hydroxyurea (30mg/kg x 30 days) (day -50 to -21), alemtuzumab (48 mg) (-22 to -19), fludarabine (150 mg/m2) (-8 to -4), thiotepa (8mg/kg) (-4), and melphalan (140mg/m2) (-3). Patients received tacrolimus or cyclosporine with methotrexate and methylprednisone (marrow) or mycophenolate mofetil (UCB) after HCT to prevent graft-versus-host disease (GVHD). Suitable UCB units were defined as having a pre-thaw total nucleated cell content >4.0x10E7/Kg recipient weight. Patients were eligible irrespective of Pesaro classification but the presence of liver fibrosis by histology was an exclusion criterion. Results Twenty-three patients from 11 US centers (11M: 12F) with a median age of 10 years (2–17 years) received unrelated donor allografts: marrow (14) or UCB matched at 6/6 (1) or 5/6 HLA antigens (8). The median follow up time was 12 months (range 120 days-2 years). The median time to neutrophil engraftment was 13 days (range 10-25) and 34 days (range 12-46) after marrow and UCB HCT respectively. The median time to platelet engraftment after marrow and UCB HCT was 24 days (range 18-34) and 54.5 days (range 32-234) respectively. Primary graft rejection occurred in 1 patient (4% of all patients) following UCB HCT and was accompanied by autologous hematopoietic recovery 35 days after HCT. All others had >90% donor chimerism and achieved transfusion independence. There were no late graft rejections. The overall and EFS probabilities were 82% and 78% respectively at the most recent encounter. One patient developed mild VOD which resolved uneventfully. Of 15 patients who had CMV reactivation, 13 responded to pre-emptive therapy and had no progression to CMV disease. The probabilities of grade II-IV and grade III-IV acute GVHD were 30% and 9% respectively. Limited chronic GVHD was noted in 35% of the cohort; 9% developed extensive cGVHD. Four patients died on days 25, 86, 106 and 366. The causes of death included 1) pulmonary hemorrhage associated with CMV, adenovirus, and Pneumocystis jiroveci infections, 2) diffuse alveolar pulmonary hemorrhage, 3) cGVHD with pneumonia associated with CMV and adenovirus infections, and 4) cGVHD with pulmonary failure associated with CMV and EBV infections and presumed central nervous system post-transplantation lymphoproliferative disease. Conclusion HCT after RIC for thalassemia is feasible and sufficient for engraftment after URD marrow and UCB transplantation with survival exceeding 80%. The principal transplant- related complications we observed were early opportunistic viral reactivations; otherwise the preparative regimen was tolerated well with very little early toxicity. Fatal and late viral infections were noted only in the setting of severe GVHD. Patients should be monitored carefully and treated promptly for infectious complications after HCT until there is adequate immune reconstitution. The risk of severe GVHD was low despite unrelated and mismatched (UCB) donor sources. Longer follow up will determine if this regimen can reduce late toxicities. An extension of this trial is ongoing and currently recruiting patients to evaluate additional HCT related and quality of life measures. Disclosures: Neufeld: Shire: Consultancy. Kwiatkowski:Resonance Health: Research Funding; Shire: Consultancy. Thompson:Novartis: Consultancy, Research Funding; ApoPharma: Consultancy, Honoraria; Glaxo Smith Kline: Research Funding; Eli Lilly: Research Funding; Amgen: Research Funding; bluebird bio: Research Funding.

Download Full-text

Phase II Prospective Multicenter Study of Treosulfan Based Reduced Intensity Conditioning In Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies From 10/10 HLA Identical Unrelated Donor

Blood ◽

10.1182/blood.v116.21.2353.2353 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2353-2353 ◽

Cited By ~ 1

Author(s):

Mauricette Michallet ◽

Mohamad Sobh ◽

Stephane Morisset ◽

Nathalie Tedone ◽

Jacques-Olivier Bay ◽

...

Keyword(s):

Stem Cell ◽

Median Time ◽

Cumulative Incidence ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Cd34 Cells ◽

Grade Ii ◽

Reduced Intensity

Abstract Abstract 2353 Background: The key point in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to find the optimal balance between the graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect particularly in the unrelated HSCT settings, without forgetting the important role of conditioning. Objective: To evaluate the toxicity and efficacy of a new reduced intensity conditioning regimen including Treosulfan, followed by allo-HSCT from a 10/10 HLA identical unrelated donor. Materials and Methods: This prospective study included adult patients presenting a hematological malignancy in need of allo-HSCT using a 10/10 HLA identical unrelated donor. Accepted diagnoses were: CML in 1st chronic phase (CP) resistant to imatinib, in 2nd CP or in complete remission (CR) after blast crisis. Multiple myeloma (MM) or chronic lymphocytic leukemia (CLL) in stage B or C in response after relapse post-auto-HSCT. Acute lymphocytic or myeloid leukemia (ALL, AML) patients in CR1 at high risk or <CR1. Myelodysplasic syndrome (MDS) with poor prognostic factors. The conditioning included: Treosulfan 12g/m2/day intra-venous (day-6 to day-4), fludarabine 30mg/m2/day intra-venous (day-6 to day -2) and ATG 2.5 mg/kg/day (day-2 to day-1). GVHD prophylaxis used cyclosporine A oral (5mg/kg/day) or iv. (3mg/kg/day) from day-1. Peripheral stem cells after mobilization by G-CSF were used as HSC source. Results: Between February 2005 and July 2009, 56 patients were included in 5 different French centers, 30 (54%) males and 26 females with a median age of 57 years (18-65.5). There were 38 (68%) myeloproliferative disorders [29 AML (14 in CR1, 14 CR2 & 1<CR), 8 MDS (1CR1 and 7<CR) and 1 CML in CR1] and 18 (32%) lymphoprolifative disorders [9 MM in PR, 6 CLL (2CR1 & 4PR) and 3 ALL(1CR1 & 2CR2)]. Among 45 explored for cytogenetics, 23 (51%) were normal and 22 with poor prognostic. Before transplantation, two patients did not receive any previous treatment, 21 received 1 line, 22 two lines and 11 > 2 lines. For sex-matching, 49% of patients were sex-mismatched (half of them were F>M). For CMV, 43% were -/-, 25% +/+, 28% +/− and 1% -/+. For ABO matching, 52% were compatible, 24% major incomp. & 24% minor incopm. The median time between diagnosis and allograft was 15 months (4-168). The median number of infused CD34+ cells was 6.5 × 106/Kg(1-17.2) Fifty-four (96%) patients engrafted with a median time to neutrophils (>0.5G/l), and platelets (>50G/l) recovery of 16 days (4-86), 11 (4-82) respectively. Seventeen patients developed aGVHD grade ≥II (8 grade II, 2 grade III & 7 grade IV) with a cumulative incidence at 3 months of 31% (25-38). The cumulative incidence of cGVHD was, at 12 months: 32% (25-39) limited and 6% (2-10) extensive; at 18 months: 34% (27-47) limited and 8% (5-12) extensive. After a median follow-up of 13 months (1-57), the median overall survival (OS) was not reached with a 3 years probability of 52% (38-71). The median time of event free survival (EFS) was 15 months (8 - 57) with a 3-years probability of 47% (35-64). The cumulative incidence of relapse at 3 years was 25% (19-31) and the cumulative incidence of transplant-related mortality (TRM) at 12, 18 and 36 months was 20% (16-27), 23% (16-29) (same at 18 & 36 months) respectively. At the last follow-up, 22 patients died, 7 due to relapse and 15 due to TRM (5 pneumonia, 4 GVHD, 1 secondary malignancy and 6 other causes). We showed in a univariate analysis a higher 3-years OS of patients in CR1 (65%) compared to those <CR1 (44%) at transplantation with a significant better benefit for AML patients (76%). Patients with active cGVHD seem to benefit for the GVL effect on OS with a high significant difference (HR=0.2 (0.1-0.6) p=0.002). The multivariate analysis studying age, sex matching, ABO compatibility, CMV matching, type of disease, CD34+ cells number, cytogenetics, number of previous treatments, disease status and interval diagnosis-allo-HSCT showed: a negative significant impact of both minor ABO incompatibility (p<0.001) and CMV+/− (p=0.01) on OS, a negative significant impact of patients <CR (p=0.03) on relapse. There was no impact of studied factors on TRM. Conclusion: We showed very promising results in terms of OS, relapse and TRM with an impressive GVL effect, in heavily pre-treated patients and transplanted using unrelated donors. Treosulfan appears to be a good choice for conditioning especially with a better outcome in AML patients in CR1. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Reduced-Intensity Conditioning with FBA/FBAA Regimen Is Feasible for Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia (AML): Interim Results of a Multicenter Clinical Trial in China.

Blood ◽

10.1182/blood.v114.22.196.196 ◽

2009 ◽

Vol 114 (22) ◽

pp. 196-196 ◽

Cited By ~ 1

Author(s):

Jianmin Wang ◽

Jiong Hu ◽

Chun Wang ◽

Xinghua Chen ◽

Jian Hou ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Graft Rejection ◽

Myeloid Leukemia ◽

Unrelated Donor ◽

Donor Group ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Reduced Intensity ◽

Acute Myeloid

Abstract Abstract 196 Reduced-intensity conditioning (RIC) regimens have emerged as an attractive modality to decrease transplant-related mortality (TRM). However, the potential higher relapse rate and graft rejection after RIC allogeneic hematopoietic stem cell transplant (allo-HSCT) are still under considerable debate. To further optimize the outcome of RIC allo-HSCT, we designed a novel RIC regimen called FBA/FBAA. Fludarabine (Flu) and cytosine arabinoside (Ara-C) have a synergistic effect on leukemia cells and regimens such as FLAG (Flu+Ara-C+G-CSF) have been proven to be effective in the treatment of acute myeloid leukemia (AML). The nonmyeloablative regimen comprising Flu and busulfan (Bu) has been demonstrated to have favorable effects on engraftment, overall survival (OS) and disease-free survival (DFS). Therefore, we assume that the combination of Flu, Bu and Ara-C as a novel RIC regimen for allo-HSCT would further enhance the transplant efficacy for AML patients. We report here 52 AML patients treated with allo-HSCT from HLA identical siblings (26/52, 50%) and unrelated donors (26/52, 50%) enrolled from March 2007 to March 2009. There were 31 male and 21 female patients with median age of 33 years (range:14∼60). At the time of conditioning, 47 patients were in CR1 (1 AML-M1, 8 M2, 21 M4, 15 M5, 2 M6) and 5 in CR2 (2 M2, 3 M5). HLA typing was performed with high-resolution technology. Amongst 52 patients, 42 had donors matched for HLA-A, -B and -DRB1 alleles, while 10 had 1 allele mismatched donor. In the sibling donor group, the patients received Flu 30 mg/m2x5d, Bu 0.8 mg/kg q6h×3d and Ara-C 1.5g/m2×5d (FBA). In the unrelated donor group, ATG-Fresenius 5 mg/kg×4d was combined with FBA conditioning (FBAA). GVHD prophylaxis consisted of mycophenolate mofetil, cyclosporin and methotrexate. The median dose of mononuclear cells infused was 5.95 ×108/kg (0.77∼20.10×108/kg), with 5.08 (0.29∼18.0) ×106 CD34+ cells/kg. All patients successfully achieved hematopoietic reconstitution. The median time to engraftment of neutrophils >0.5×109/L and platelet >20×109/L were 14.3 (8∼25) days and 16.5 (9∼30) days post- transplantation, respectively. The chimeric status measured by short tandom repeat (STR)-PCR showed that the complete chimeras at day +30 and day +90 were 86.1% and 92.1%, respectively. No graft rejection occurred. During the median follow-up of 9.1 months (1∼28 months), only 8 patients (15.4%) developed acute GVHD (aGVHD grade II: 7, grade III∼IV:1). Chronic GVHD (cGVHD) occurred in 23 of 48 patients (47.9%) who survived more than 3 months, with only 4 (8.3%) extensive type. 8 patients (15.4%) relapsed, and were treated with chemotherapy combined with infusion of frozen G-CSF mobilized donor peripheral blood stem cells or donor lymphocytes. 4 of these patients went into complete remission (1 relapsed after 3 months). During the follow-up period, a total of 9 (17.3%) deaths from transplant-related pneumonia (4, 7.7%) and relapsed disease (5, 9.6%) occurred. The probability of OS at +100 days, 1 year and 2-years were 100%, 78.0% and 73.9%, respectively, while the probability of DFS were 100%, 78.0% and 65.9%, respectively. The OS were 81.8% and 74.1% respectively at 1 year, 81.8% and 67.4% (P=0.352) respectively at 2 years for related and unrelated donor group. Similarly, the DFS were 81.8% and 74.1% respectively at 1 year, 71.5% and 60.6% (P=0.439) respectively at 2 years for related and unrelated donor group. In conclusion, these interim results demonstrate that the FBA/FBAA regimen is a safe and effective conditioning regimen for allo-HSCT for AML patients, with effective engraftment, low incidence of graft rejection and relapse as well as decreased incidence of severe aGVHD and cGVHD. We await the complete analyses of the results and verification of the above results. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia (AML) with FBA/FBAA Regimen Based Reduced-Intensity Conditioning: A Multicenter Clinical Trial in China

Blood ◽

10.1182/blood.v118.21.1953.1953 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1953-1953

Author(s):

Jianmin Wang ◽

Weiping Zhang ◽

Jiong Hu ◽

Chun Wang ◽

Xinghua Chen ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Graft Rejection ◽

Myeloid Leukemia ◽

Unrelated Donor ◽

Donor Group ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Reduced Intensity ◽

Acute Myeloid

Abstract Abstract 1953 Reduced-intensity conditioning (RIC) regimens have emerged as an attractive modality to decrease transplant-related mortality (TRM). However, the potential higher relapse rate and graft rejection after RIC allogeneic hematopoietic stem cell transplant (allo-HSCT) are still under considerable debate. To further optimize the outcome of RIC allo-HSCT, we designed a novel RIC regimen called FBA/FBAA. Fludarabine (Flu) and cytosine arabinoside (Ara-C) have a synergistic effect on leukemia cells and regimens such as FLAG (Flu+Ara-C+G-CSF) have been proven to be effective in the treatment of acute myeloid leukemia (AML). The nonmyeloablative regimen comprising Flu and busulfan (Bu) has been demonstrated to have favorable effects on engraftment, overall survival (OS) and disease-free survival (DFS). Therefore, we assume that the combination of Flu, Bu and Ara-C as a novel RIC regimen for allo-HSCT would further enhance the transplant efficacy for AML patients. We reporthere 69 AML patients enrolled in the study from March 2007 to July 2011, among which 69 AML patients treated with allo-HSCT from HLA identical siblings (35/69, 50.72%) or unrelated donors (34/69, 49.28%). There were 38 male and 31 female patients with median age of 33 years (range:14□'61). At the time of conditioning, 60 patients were in CR1 (1 AML-M1, 11 M2, 24 M4, 22 M5, 2 M6) and 9 in CR2 (3 M2, 1 M4, 5 M5). HLA typing was performed with high-resolution technology. Amongst 66 patients, 50 had donors matched for HLA-A, -B and -DRB1 alleles, while 16 had 1/2 allele mismatched donor. In the sibling donor group, the patients received Flu 30 mg/m2x5d, Bu 0.8 mg/kg q6h×3d and Ara-C 1.5g/m2×5d (FBA). In the unrelated donor group, ATG-Fresenius 5 mg/kg×4d was combined with FBA conditioning (FBAA). GVHD prophylaxis consisted of mycophenolate mofetil, cyclosporin and methotrexate. The median dose of mononuclear cells infused was 6.04 ×108/kg (0.8∼20.1×108/kg), with 4.91 (0.3□18.0) ×106 CD34+ cells/kg. All patients successfully achieved hematopoietic reconstitution. The median time to engraftment of neutrophils >0.5×109/L and platelet >20×109/L were 13.07 (1.0∼22.0) days and 14.08 (0.0∼30.0) days post- transplantation, respectively. The chimeric status measured by short tandom repeat (STR)-PCR showed that the complete chimeras and mix-chimeras at day +30 and day +90 were 92.75%, 7.25% and 94.20%, 5.80% respectively. No graft rejection occurred. During the median follow-up of 24.6 months (0.8∼51.6 months), 16 patients (23.19%) developed acute GVHD (aGVHD grade II□F9 patients, grade III∼IV: 3 patients. Chronic GVHD (cGVHD) occurred in 26 of 67 patients who survived more than 3 months, with only 9 extensive types. During the follow-up period, death patients were 19, 9 patients died of non-relapse causes, 8 died from pneumonia. The probability of OS at +100 days, 1 year and 2-years were 97.10%, 81.84% and 75.07%, respectively, while the probability of DFS were 97.10%, 80.27% and 73.62%, respectively. The OS at 1 year and 2-years for related and unrelated donor groups were 83.40%, 80.52% and 83.40%, 66.74% (P=0.263), respectively, and the DFS were 83.40%, 77.42% and 83.40%, 64.18% (P=0.431). In conclusion, these interim results demonstrate that the FBA/FBAA regimen is a safe and effective conditioning regimen for allo-HSCT for AML patients, with effective engraftment, low incidence of graft rejection and relapse as well as decreased incidence of severe aGVHD and cGVHD. The trial comparing this regimen with standard Bu-Cy +/− ATG are ongoing. Disclosures: Hou: Novartis: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Results of a Two-Arm Phase II Clinical Trial Using Post-Transplantation Cyclophosphamide for Prevention of Graft-Versus-Host Disease in Haploidentical and Mismatched Unrelated Donors Hematopoietic Stem-Cell Transplantation

Blood ◽

10.1182/blood.v126.23.152.152 ◽

2015 ◽

Vol 126 (23) ◽

pp. 152-152 ◽

Cited By ~ 2

Author(s):

Sameh Gaballa ◽

Isabell Ge ◽

Riad O. El Fakih ◽

Jonathan E. Brammer ◽

Sa A. Wang ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Disease Risk ◽

Risk Index ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Equity Ownership ◽

Reduced Intensity

Abstract Allogeneic stem cell transplantation offers curative therapy for many patients (pts) with high-risk hematologic malignancies. Donor availability remains a major limitation for many pts. The introduction of high-dose post-transplant cyclophosphamide (PTCy) has significantly improved the outcomes of pts undergoing haploidentical (HAPLO) stem cell transplants. The choice between a HAPLO or a one-antigen HLA mismatched unrelated donor (9/10 MUD) for pts lacking an HLA-matched donor remains unclear. Methods: We conducted a prospective non-randomized phase 2 clinical trial with two parallel arms, HAPLO (n=60) and 9/10 MUD (n=46) transplants, for pts with advanced hematologic malignancies or aplastic anemia who lacked an HLA-matched unrelated donor type at 10 loci (HLA-A, -B, -C, -DRB1, and -DQB1) using a MEL-based reduced-intensity conditioning regimen. The regimen included a single intravenous dose of MEL 140 mg/m2 (day -7), thiotepa 5 mg/kg (day -6), and four daily IV doses of fludarabine 40 mg/m2 (day -5 to day -2) (FM140). Thiotepa was intermittently available and was replaced by total body irradiation at a dose of 2 Gy on day -1. Pts >55 years (yr) old or with significant comorbidities received a lower MEL dose (100 mg/m2) (FM100). All pts with CD20-positive lymphoma received rituximab (375 mg/m2) on days -13, -6, +1 and +8. GVHD prophylaxis consisted of PTCy 50 mg/kg on day +3 and +4, and tacrolimus and mycophenolate for 6 and 3 months (mo), respectively. The stem cell source was unmodified bone marrow for both arms. Results: Patient characteristics are shown in Table 1. The median follow-up duration was 24 mo in the HAPLO arm and 29 mo in the 9/10 MUD arm. The cumulative incidence (CI) of neutrophil (ANC) recovery at day 45 was 95% and 98% in the HAPLO and 9/10 MUD arm, respectively. The median time to ANC recovery was 18 days in both arms; the median time to platelet recovery was 25 days in the HAPLO arm and 28 days in the 9/10 MUD arm. Primary graft failure developed in two pts in the HAPLO arm (one due to anti-donor HLA antibodies) and one patient in the 9/10 MUD arm. One pt in both arms developed mixed donor chimerism at day 100; otherwise, all pts in both arms achieved full (>95%) donor chimerism. Bone marrow was the graft source in all pts except 2 in the HAPLO arm and 8 in the 9/10 MUD arm who received a peripheral blood graft. The 1-yr overall and progression free survival were 70% and 60%, respectively, in the HAPLO arm (Fig. 1A) and 60% and 47%, respectively, in the 9/10 MUD arm (Fig. 1B). Day 100 CI of grade II-IV aGVHD and III-IV aGVHD were 28% and 3%, respectively, in the HAPLO arm versus 33% and 13%, respectively, in the 9/10 MUD arm; the 2-yr CI of chronic extensive GVHD was 13% and 14% in the two groups, respectively. The 1-yr CI of non-relapse mortality was 21% in the HAPLO arm and 31% in the 9/10 MUD arm, while the 1-yr relapse rate was 19% and 25% in the two groups, respectively. Conclusions: This study establishes PTCy, tacrolimus, and mycophenolate as an effective regimen for GVHD prevention in mismatched transplantation using both haploidentical and mismatched unrelated donor sources. Melphalan-based reduced-intensity conditioning is an effective regimen for a broad range of hematologic malignancies. Prospective randomized studies comparing haploidentical and unrelated donor sources are needed. Table 1. HAPLO (n=60) 9/10 MUD (n=46) Median Age, years (Range) 45 (20-63) 51 (20-64) Sex (M/F) 29/31 23/23 KPS ³90 53 (88%) 40 (87%) <90 7 (12%) 6 (13%) HCT-CI 0-3 50 (83%) 38 (83%) >3 10 (17%) 8 (17%) Disease Risk Index* Very high 5 (8%) 3 (7%) High 18 (30%) 15 (33%) Intermediate 29 (48%) 12 (26%) Low 8 (13%) 12 (26%) NA 0 4 (9%)** Conditioning Regimen FM100 20 (33) 18 (39%) FM140 40 (67%) 28 (61%) Diagnosis AML/MDS 33 (55%) 18 (39%) ALL 7 (11%) 5 (11%) Lymphoma 10 (17%) 13 (28%) Others 10 (17%) 10 (22%) Disease Stage Acute Leukemia CR1/CR2 24 (66%) 9 (56%) CR3 or higher/ CRpx 6 (17%) 5 (31%) Active disease 6 (17%) 2 (13%) Lymphoma CR 3 (30%) 8 (62%) PR 5 (50%) 3 (23%) Chemoresistant 2 (20%) 2 (15%) *Disease Risk Index by Armand et al; xCRp: Complete Remission with incomplete count recovery; **Patients had aplastic anemia. Figure 1. Figure 1. Disclosures Brammer: Celgene: Research Funding. Lee:Ziopharm: Equity Ownership; Cyto-Sen: Equity Ownership; Intrexon: Equity Ownership. Rezvani:Pharmacyclics: Research Funding. Alousi:Therakos, Inc: Research Funding.

Download Full-text

CloB2A2 Reduced-Intensity Conditioning (RIC) Regimen Prior to Allogeneic Stem Cell Transplantation Provides Significant Better Survival Compared to FB2A2 RIC Regimen in Adults with Acute Myeloid Leukemia (AML): A Study on Behalf of the SFGM-TC

Blood ◽

10.1182/blood.v126.23.1908.1908 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1908-1908

Author(s):

Patrice Chevallier ◽

Myriam Labopin ◽

Regis Peffault de la Tour ◽

Bruno Lioure ◽

Jean-Yves Cahn ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Median Time ◽

Myeloid Leukemia ◽

Research Funding ◽

Prospective Trial ◽

International Congress ◽

White Blood Count ◽

Reduced Intensity Conditioning ◽

Reduced Intensity ◽

Acute Myeloid

Abstract Purpose: The FB2A2 (fludarabine, intermediate doses of busulfan and ATG) reduced-intensity conditioning (RIC) regimen is considered as a standard RIC regimen in many centers worldwide. Recently, we have reported the prospective good results of a clofarabine-busulfan containing RIC regimen (CloB2A2) in adults with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in complete remission (CR) at time of transplant (Chevallier et al, Haematologica, 2014). Thus, this regimen may prove to be superior to the FB2A2 regimen in patients with AML/MDS. Patients and Methods: The aim of this study was to compare outcomes between adult AML/MDS patients who have received, between 2009 and 2015, in 26 French centers, either a FB2A2 RIC regimen (n=170, male 61%, median age: 58 years, AML 86%, CR1 79%) or the CloB2A2 RIC regimen (n=39, including the 16 cases treated within the prospective trial mentioned above, male 62%, median age: 61 years, AML 62%, CR1 64%). The FB2A2 and CloB2A2 regimens consisted of either 30 mg/m²/day Fludarabine for 5 days or 30mg/m²/day Clofarabine for 4 or 5 days, each combined with 3.2 mg/kg/day Busulfan for 2 days and 2.5 mg/kg/day Anti-thymocyte globulin (ATG, Thymoglobuline) for 2 days. As GVHD prophylaxis, cyclosporine (CsA) alone was used in case of related donor in both groups, and for the 16 CloB2A2 patients treated within the prospective trial, while CsA+ MMF were used in case of unrelated donors. The two groups were not statistically different in term of gender, median age and performans status at transplant, median white blood count at diagnosis, median time between diagnosis and transplant, type of donors or cytogenetics for AML patients. Conversely, there were more AML patients (86% vs 62%, p=0.0004) and more patients in CR1 (79% vs 64%, p=0.04) in the FB2A2 group. Also, CloB2A2 patients were transplanted more recently (median year of transplant: 2014 vs 2011, p<0.0001). Results: All patients engrafted, except one in the FB2A2 group. Median time of neutrophils recovery was similar between both groups (FB2A2: 17 days vs CloB2A2: 18 days, p=0.10). With a median follow-up of 28 and 14 months in the FB2A2 and the CloB2A2 groups, respectively, 2-year overall survival (OS) were 59% (51.4-66.7) for the former vs 77% (62.8-91.1) for the latter, p=0.07, 2-year leukemia-free survival (LFS) were 52.7% (44.9-60.4) vs 64% (48.1-79.9), p=0.23, 2-year relapse incidence were 31.1% (24.2-38.4) vs 27.5% (14-42.9), p=0.58, 2-year non relapse mortality were 16.2% (5.8-31.3) vs 8.5% (2.1-20.7), p=0.26 and 2-year chronic GVHD were 13.8% (8.3-20.5) vs 23.9% (8.1-44.2), p=0.12. Incidences of grade 2-4 or grade 3-4 acute GVHD were similar between both groups: FB2A2 22% vs CloB2A2 23%, p=0.86,and 8% vs 3%, p= 0.31. In multivariate analysis, FB2A2 RIC regimen was significantly associated with lower OS and LFS (HR: 2.45; 95%CI: 1.08-5.55, p=0.03; and HR: 2.32; 95%CI: 1.12-4.79, p=0.02) contrary to CR1 status which was associated with significant higher survivals (HR: 0.48; 95%CI: 0.28-0.83, p=0.008 and HR: 0.42; 95%CI: 0.25-0.70, p=0.001). MDS (HR: 1.88; 95%CI: 1.03-3.43, p=0.03) and higher WBC at diagnosis (>median) (HR: 1.76; 95%CI: 1.10-2.82, p=0.01) were also significantly associated with lower LFS. However, when considering AML and MDS patients separately, benefit of CLOB2A2 RIC regimen appears to be restricted to AML patients (2-year OS FB2A2: 58.1% vs CloB2A2: 80.2%; HR: 2.45; 95%CI: 1.08-5.55, p=0.03; and 2-year LFS FB2A2: 53.6%, vs CloB2A2: 76.9%; HR: 2.32; 95%CI: 1.12-4.79, p=0.02). Conclusion: Thisretrospective comparison suggests thattheCloB2A2 RIC regimen can likely provide a higher survival compared to the use of a FB2A2 RIC regimen for AML patients. A prospective phase 3 randomized study is warranted. Disclosures Deconinck: JANSSEN: Other: Travel for international congress; NOVARTIS: Other: Travel for international congress; ALEXION: Other: Travel for international congress; ROCHE: Research Funding; PFIZER: Research Funding; CHUGAI: Other: Travel for international congress; LFB loboratory: Consultancy. Mohty:Janssen: Honoraria; Celgene: Honoraria.

Download Full-text

Impact of Genomic Alterations on Outcomes in Myelofibrosis Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v128.22.2301.2301 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2301-2301 ◽

Cited By ~ 1

Author(s):

Raajit K. Rampal ◽

Roni Tamari ◽

Nan Zhang ◽

Caroline Jane McNamara ◽

Franck Rapaport ◽

...

Keyword(s):

Bone Marrow ◽

Research Funding ◽

Triple Negative ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Disease Characteristics ◽

Donor Type ◽

The Impact ◽

Reduced Intensity

Abstract Introduction: The impact of genomic alterations, such as mutations in ASXL1, on the risk of disease progression and leukemic transformation in patients with myelofibrosis (MF) is well established. Further, emerging data suggests that the number and type of mutations may impact response to therapies such as ruxolitinib or imetelstat. Allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only potentially curative treatment for MF patients. However, the impact of somatic mutations on overall survival (OS) and relapse-free survival (RFS) is poorly understood. Using next-generation sequencing of pre-transplant blood and bone marrow samples from a well clinically-annotated cohort of MF patients who underwent allo-HSCT, we sought to determine the impact of mutational burden on outcomes. Methods: A multicenter retrospective analysis of a cohort of 84 patients was carried out. This included 52 patients treated on the MPD-RC 101 prospective study (NCT00572897), 18 patients treated at Prince Margaret Hospital, and 14 patients treated at Memorial Sloan Kettering Cancer Center. Patient and transplant characteristics are displayed in Table 1. DNA was extracted from pre-transplant bone marrow aspirate samples or peripheral blood samples. High-throughput sequencing of a panel of genes was performed. Average coverage of 829x (standard deviation of ±130) was obtained. Mutect was utilized to call single point variants (comparing our samples to a pool of normal samples) and PINDEL was used to call short insertions and deletions. We excluded all mutations present in at least one database of known non-somatic variants (DBSNP and 1000 genomes) and absent from COSMIC. Univariate Cox regression and Kaplan-Meier graphics were used to investigate the association of patient, transplant, and disease characteristics with OS and RFS. Results: JAK2V617F was the most frequent mutation detected in 41(48.8%) patients (Table 2). Eighteen patients (21.4%) had triple negative disease (negative for JAK2, MPL, and CALR mutations). Univariate analysis included the following: patient characteristics (age, gender), transplant characteristics (related vs. unrelated donor, matched vs. mismatched donor and myeloablative vs. reduced intensity conditioning) and disease characteristics (DIPSS and presence of mutations). Decreased OS was associated with unrelated donor status (HR 2.09, 95% CI: 1.03-4.23, p=0.04), reduced intensity conditioning (HR 4.21, 95% CI: 1.01-17.59, p=0.049), triple negative disease (HR 2.09, 95% CI: 1.02-4.30, p=0.04), and presence of U2AF1 (HR 2.53, 95% CI: 1.10-5.81, p=0.03) or SUZ12 mutations (HR 3.92, 95% CI: 1.19-12.21, p=0.02). Decreased RFS was associated with unrelated donor status (HR 2.27, 95% CI: 1.16-4.45, p=0.02), and the presence of SUZ12 mutation (HR 6.97, 95% CI: 2.37-20.49, p<0.001). A descriptive decrease in RFS in patients with U2AF1 (HR 2.15, 95% CI: 0.94-4.88, p=0.07) was observed but did not reach statistical significance. Importantly, mutations previously reported to be associated with reduced OS and RFS in the non-transplant setting, such as ASXL1, EZH2, IDH1/2, and SRSF2, were not associated with poorer outcomes in this analysis in transplanted patients. In an exploratory multivariate analysis including donor type (related vs. unrelated) and presence of U2AF1 and SUZ12 mutations, there was a significantly reduced OS and RFS in patients who harbor these mutations regardless of donor type (OS: HR 5.30, 95% CI: 2.08-13.47, p<0.001; RFS: HR 5.49, 95% CI: 2.27-13.30, p<0.001). In patients without the above mutations, having an unrelated donor was associated with worse OS (HR 2.55, 95% CI: 1.09-5.96, p=0.03) and RFS (HR 2.61, 95% CI: 1.17-5.83, p=0.02, Figure 1). Conclusions: Our analysis demonstrates that mutations previously associated with poor prognosis in MF, such as ASXL1, do not appear to confer a worsened prognosis in patients undergoing allo-HSCT, suggesting transplant may be able to overcome the impact of these mutations. However, mutations in SUZ12 and U2AF1 are associated with reduced OS in univariate and multivariate analysis (together with donor type). Further studies with larger cohorts of patients are indicated to validate these findings, and to elucidate the impact of these mutations on disease biology. Disclosures Rampal: Incye and CTI: Consultancy. Mascarenhas:Janssen: Research Funding; CTi Biopharma: Research Funding; Promedior: Research Funding; Merk: Research Funding; Incyte: Research Funding. Mesa:Galena: Consultancy; Gilead: Research Funding; Promedior: Research Funding; Incyte: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Ariad: Consultancy; Novartis: Consultancy. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

Download Full-text

Early Results from a Phase 1/2 Study of Aru-1801 Gene Therapy for Sickle Cell Disease (SCD): Manufacturing Process Enhancements Improve Efficacy of a Modified Gamma Globin Lentivirus Vector and Reduced Intensity Conditioning Transplant

Blood ◽

10.1182/blood-2020-140963 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 20-21

Author(s):

Michael Grimley ◽

Monika Asnani ◽

Archana Shrestha ◽

Sydney Felker ◽

Carolyn Lutzko ◽

...

Keyword(s):

Gene Therapy ◽

Safety Profile ◽

Manufacturing Process ◽

Research Funding ◽

Phase 1 ◽

Reduced Intensity Conditioning ◽

F Cells ◽

Favorable Safety ◽

Reduced Intensity

Introduction: ARU-1801 is a gene therapy consisting of autologous CD34+ hematopoietic stem cells and progenitors (HSCPs) transduced with a lentiviral vector (LV) encoding a modified γ-globinG16D gene. Preclinical studies in SCD mice have shown that g-globinG16D binds α-globin with higher affinity; hence, the g-globinG16D LV produces 1.5-2x more HbF/vector copy number (VCN) than a g-globin LV. Preliminary studies also show greater reduction in reticulocytes in SCD mice expressing HbFG16D compared to those expressing the same level of HbF, suggesting that HbFG16D may have a more potent anti-sickling effect than HbF. We hypothesized a high potency anti-sickling globin would allow ARU-1801 to be effective with reduced intensity conditioning (RIC). RIC would result in lower toxicities and resource utilization compared to myeloablative approaches, allowing access of gene therapy to a broader group of SCD patients. We previously reported early data from patient 1 (P1) and 2 (P2) in the ongoing Phase 1/2 study (NCT02186418), who were treated with drug product (DP) from the initial ARU-1801 manufacturing process (Process I). We now present the long-term data on these patients and early data from P3, the first patient treated with our new manufacturing process (Process II). Methods: Adults with severe SCD, as defined by recurrent vaso-occlusive events (VOE) and acute chest syndrome deemed eligible were enrolled. Manufacturing process improvements in Process II included optimized timing of HSCP collection after plerixafor mobilization, LV production and improved HSCP transduction. Prior to DP infusion, all patients received a single dose of IV melphalan (140 mg/m2 BSA) and were weaned off transfusions 3-6 months after DP infusion. Patients were monitored for safety, engraftment, VCN, anti-sickling Hb (ASG) expression, and hematological and clinical manifestations of SCD. Levels of ASG (including HbFG16D) are presented as fractions of endogenous Hb. Results: As of 28 July 2020, data from 3 patients treated with ARU-1801 are available. P1 (34yr old) has HbSβ0- and P2 (24yr old) has HbSβ+ thalassemia (2-3% HbA). Both have 30 months (mo) post-transplant (PT) follow up. P3 (19yr old) has HbSS genotype with 6 mo PT follow up. ARU-1801 demonstrated a favorable safety profile with no treatment-related adverse events to date. Time to neutrophil engraftment (ANC ≥500) was 9, 7, and 7 days PT, and time to platelet recovery (Plt >50,000) was 12, 7, and 6 days PT, in P1, P2, and P3, respectively. Figure 1 shows HSPC dose, conditioning exposure and gene transfer; Figure 2 shows ASG over time. Using Process I, P1 has shown stable expression of 20% HbFG16D, 31% ASG and 31%à64% F-cells over 2.5 years, despite a low DP VCN of 0.2 and low HSPC dose of 1.4 x106 cell/kg. P2 received a higher cell dose of 7.1 x106 cell/kg with a DP VCN of 0.47 but had below target melphalan exposure, likely due to rapid clearance from hyperfiltration (GFR= 200 mL/min/1.73m2). Despite lower engraftment and HbFG16D level, P2 maintains stable total ASG of 22% at 30 mo due to a compensatory increase in HbF. Using Process II, P3 received DP of 6.8 x106 cells/kg with a VCN of 1.0, and demonstrated an engrafted VCN of 0.74, 71% F-cells and 91% F-reticulocytes at 6 mo. As P3 is being weaned off transfusions, HbFG16D is progressively rising, showing the selective advantage to HbFG16D-containing RBCs. P1 and P2 have maintained improvements in VOEs, no VOE in P3 so far (data will be presented). Conclusion: We show that engraftment of ARU-1801 and amelioration of disease is possible with RIC using IV melphalan, with persistent stable ASG expression and meaningful improvement in VOEs in P1 and P2. P1 shows stable HbFG16D and high ASG despite low, albeit stable VCN. P2 had lower HSCP engraftment, which we hypothesize was due to below target melphalan exposure. Nevertheless, significant clinical benefit was observed in P2 due to stable ASG of 22% at mo 30. It is likely that the presence of this amount of HbFG16D has provided enough ASG to prevent sickling/ineffective erythropoiesis, resulting in the preferential survival of HbF+HbFG16D-expressing RBC. Process II DP in P3 resulted in 2-4X higher engraftment of transduced HSCPs at 6 mo. Additional process enhancements are under development for future treated patients. ARU-1801, administered with RIC, holds significant promise for achieving durable responses with a favorable safety profile in patients with severe SCD. Disclosures Asnani: Aruvant Sciences: Research Funding; Avicanna Ltd.: Research Funding. Lutzko:Aruvant Sciences: Patents & Royalties: pre-clinical vector development. Lo:Aruvant Sciences: Current Employment. Little:Aruvant Sciences: Current Employment. McIntosh:Aruvant: Current Employment, Current equity holder in private company. Malik:Aruvant Sciences, Forma Therapeutics, Inc.: Consultancy; Aruvant Sciences, CSL Behring: Patents & Royalties. OffLabel Disclosure: Plerixafor - stem cell mobiliziation Melphalan - chemotherapy conditioning pre autologous transplant with ARU-1801

Download Full-text

Reduced Intensity Conditioned Bone Marrow Transplant with Post-Transplant Cyclophosphamide and Donor-Derived Mesenchymal Stromal Cell Infusions for Recessive Dystrophic Epidermolysis Bullosa

Blood ◽

10.1182/blood-2018-99-113035 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2165-2165 ◽

Cited By ~ 1

Author(s):

Christen L. Ebens ◽

John A McGrath ◽

Katsuto Tamai ◽

Hovnanian Alain ◽

John E. Wagner ◽

...

Keyword(s):

Disease Activity ◽

Research Funding ◽

Reduced Intensity Conditioning ◽

Dystrophic Epidermolysis Bullosa ◽

Type Vii Collagen ◽

Medical Photography ◽

Recessive Dystrophic Epidermolysis Bullosa ◽

Skin Biopsies ◽

Reduced Intensity

Abstract Introduction: Recessive dystrophic epidermolysis bullosa (RDEB) is a severe, life-limiting systemic genodermatosis, characterized by COL7A1 mutation(s) yielding inadequate type VII collagen to maintain the integrity of the cutaneous basement and mucosal membranes. The mainstay of therapy for RDEB is supportive care to minimize the daily morbidity of blistering/scarring, pain/pruritis, systemic inflammation, and high metabolic demand. Leveraging the pluripotency of bone marrow cells, investigations of BMT as a systemic therapy for RDEB showed promise in pre-clinical murine (Tolar J, et al., Blood 2009, 113(5): 1167-74) as well as early phase human clinical trials utilizing fully myeloablative conditioning (Wagner J, et al., NEJM 2010, 363(7): 629-39). However, regimen-rated toxicity limited dampened enthusiasm for the clinical approach. Methods: In an effort to modulate disease activity with decreased toxicity, we investigated the safety of and preliminary responses to BMT with a reduced-intensity conditioning regimen (rabbit anti-thymocyte globulin 2.5 mg/kg with a methylprednisolone taper, cyclophosphamide 28 mg/kg, fludarabine 150 mg/m2, and low dose total body irradiation 300-400 cGy). Graft-versus-host disease (GvHD) prophylaxis included post-transplant cyclophosphamide (PTCy, 50 mg/kg recipient weight/dose on days +3 and 4) and mycophenylate mofetil from day +5 to 35. All except HLA-matched related donor recipients received tacrolimus from day +5 until tapered at day +100. Immunomodulatory donor-derived mesenchymal stromal cells (MSCs, 2 x 106 cells/kg recipient weight/dose) were infused at 60, 100 and 180 days post-BMT. Skin biopsies, medical photography, and dynamic assessments of RDEB disease activity by providers and parents were completed at baseline, day +100, +180 and 1 year post-BMT. Results: Ten RDEB patients were transplanted at a median age of 9.9 years (range 1.8 to 22.1), with a median follow-up of 16 months (1 year evaluations available for only 4 of 10). Donors were haploidentical related (n=6), HLA-matched related (n=3), and HLA-matched unrelated (n=1). BMT complications included graft failure in 3 patients (2 elected to pursue a 2nd PTCy BMT), veno-occlusive disease in 2, posterior reversible encephalopathy in 1, and chronic GvHD in 1, the latter deceased. Infectious complications in the first 100 days were limited to 3 viremia, 7 bacteremia, and 0 fungemia episodes. No serious adverse events were observed with MSC infusions. In the 9 ultimately engrafted patients, median donor chimerism at day +180 was 100% in both myeloid and lymphoid fractions of peripheral blood and 27% in skin. Skin biopsies at day +180 show stable (n=7) to improved (n=2) type VII collagen protein expression by immunofluorescence (IF) and gain of anchoring fibril components by transmission electron microscopy in 4 of 9 patients. Early clinical response included a trend toward reduced body surface area of blisters/erosions from a median of 45.5% at baseline to 27.5% at day +100 (p=0.05), with parental measures indicating stable quality of life. Select medical photography and skin biopsy results are shown for Patient 1 [IF: 40x merged dapi (blue) and C7 collagen antibody (red); immunoelectron microscopy with C7 collagen-directed immunostain (black)]. Conclusions: BMT using reduced-intensity conditioning, PTCy and donor-derived MSC infusion for RDEB was largely well tolerated with low rates of GvHD and death from regimen-related toxicity in 1 of 10 patients undergoing 12 total BMTs. Early follow-up suggests this treatment modulates RDEB disease activity but requires longer follow-up for evaluation of efficacy. Importantly, the PTCy BMT platform provides a means of attaining immunotolerance for future donor-derived cellular grafts. Figure Figure. Disclosures Wagner: Magenta Therapeutics: Consultancy, Research Funding; Novartis: Research Funding.

Download Full-text

Outcomes with Mismatched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation Following Reduced Intensity Conditioning: A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood-2021-146051 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2863-2863

Author(s):

Moazzam Shahzad ◽

Sibgha Gull Chaudhary ◽

Ezza Tariq ◽

Naira Fatima ◽

Muhammad Arslan ◽

...

Keyword(s):

Cell Transplantation ◽

Research Funding ◽

Acute Gvhd ◽

Meta Analysis ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Unrelated Donors ◽

Matched Donor ◽

Reduced Intensity

Abstract Background: Allogeneic hematopoietic cell transplantation (HSCT) is often the optimal and only potentially curative therapy in several high-risk hematologic malignancies. Although human leukocyte antigen (HLA)-matched donors remain the preferred choice for HSCT recipients, haploidentical and umbilical cord blood HSCT has increased access to transplantation. Despite these advances, many patients lack an appropriate donor, in particular the ethnic minorities. The use of mismatched unrelated donors (MMUD) has increased over the years but concerns regarding increased risk of graft versus host disease (GVHD) and non-relapse mortality (NRM) limits the utility of MMUD HSCT. The intensity of the conditioning regimen has a significant impact on survival in case of mismatched donors. We conducted a systematic review and meta-analysis aimed to investigate the outcomes with MMUD HSCT using reduced intensity conditioning (RIC). Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was performed on three databases (PubMed, Cochrane Library, and ClinicalTrials.gov) from date of inception through February 2021 using the MeSH and entry terms for "hematopoietic stem cell transplantation", OR "hematologic neoplasms", AND unrelated donors" AND "treatment outcome". A total of 2477 records were identified and primary and secondary screening was done. After excluding review, duplicate, and non-relevant articles, we included 6 (4 retrospective, 2 prospective) studies reporting outcomes following RIC MMUD HSCT. The Joanna Briggs Institute (JBI) critical appraisal checklist for studies reporting prevalence data and randomized control trial was used for quality assessment, and all studies were reported as good. Proportions along with a 95% confidence interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.16-2). The variance between the studies was calculated using Der Simonian Laird Estimator. Results: We identified 895 participants in the 6 studies, who had MMUD HSCT with RIC. (Table 1) Median age was 57.5 (18-76) years and 56% (n= 415) were males as reported by four studies (n=740). In five studies with available data (n=855), source of the primary graft was peripheral blood (PB) and bone marrow (BM) in 72% (n=614) and 28% (n=241) of the HSCT recipients respectively. After a median follow-up of 48 (3-125) months, we estimated a pooled overall survival (OS) of 62% (95% CI 0.52-0.72, I 2=84%, n=895) at one year and 43.5% (95% CI 0.33-0.54, I 2 =84% n=855) at three years. The pooled incidence of acute GVHD (grade II-IV), acute GVHD (grade III-IV), and chronic GVHD were 37% (95% CI 0.26-0.49, I 2=81%, n=610), 16% (95% CI 0.07-0.29, I 2=87%, n=542), and 28% (95% CI 0.13-0.47, I 2=95%, n=848) respectively. Progression free survival (PFS) and relapse rates (RR) were 46% (95% CI 0.30-0.62, I 2=92%, n=814) and 31% (95% CI 0.24-0.39, I 2=65%, n=814) respectively. The pooled incidence of non-relapse mortality (NRM) was 23% (95% CI 0.09-0.40, I 2=91%, n=707). Kasamon et al. and Shaw et al. reported 1-year OS of 75-79% with MMUD HSCT using fludarabine, cyclophosphamide and 2 Gy total body irradiation RIC, bone marrow graft and post-transplant cyclophosphamide, sirolimus and mycophenolate for GVHD prophylaxis. Conclusion: Mismatched unrelated donor HSCT has shown favorable outcomes with reduced intensity conditioning using a post-transplant cyclophosphamide-based regimen, comparable to the historical outcomes with mismatched related donor (haploidentical) HSCT. MMUD HSCT with RIC can be considered in patients lacking an HLA-matched donor. This strategy will expand access to HSCT in patients with ethnic minorities who often lack a matched donor. Figure 1 Figure 1. Disclosures McGuirk: EcoR1 Capital: Consultancy; Allovir: Consultancy, Honoraria, Research Funding; Gamida Cell: Research Funding; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Astelllas Pharma: Research Funding; Fresenius Biotech: Research Funding; Bellicum Pharmaceuticals: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding.

Download Full-text

Impact of Chronic Graft-Versus-Host Disease on Long-Term Outcomes of Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Adults with High-Risk Acute Lymphoblastic Leukemia in First Remission

Blood ◽

10.1182/blood.v128.22.3980.3980 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3980-3980

Author(s):

Jae-Ho Yoon ◽

Sung-Soo Park ◽

Young-Woo Jeon ◽

Sung-Eun Lee ◽

Byung-Sik Cho ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Median Time ◽

Cumulative Incidence ◽

Research Funding ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Advisory Committees

Abstract Background : The role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC-HCT) in adult acute lymphoblastic leukemia (ALL) remains unclear because the interpretation of transplantation outcome is mainly limited by the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of the criteria used to select patients for RIC-HCT. Previously, we conducted a phase 2 trial of RIC-HCT in adults with high-risk ALL who were ineligible for myeloablative conditioning and showed the potential role of this strategy, especially in patients in first complete remission (CR1). Here, we report the long-term outcomes of RIC-HCT by analyzing 122 consecutive adults with high-risk ALL in CR1, particularly focusing on the prognostic relevance of chronic GVHD. Methods: During the period between 2000 and 2014, 122 patients in CR1 (median age, 52 years [range, 15-65 years]; 54 Ph-negative ALL and 68 Ph-positive ALL) were given an identical RIC regimen consisting of fludarabine (150 mg/m2 in total) and melphalan (140 mg/m2in total). The indications for RIC-HCT were advanced age (≥50 years; n=79; 64.8%) and comorbid conditions (n=43; 35.2%). Graft sources were peripheral blood stem cells (n=118; 66 matched sibling donor, 23 matched unrelated donor, 29 mismatched unrelated donor) and bone marrow (n=4; 1 matched sibling donor, 1 matched unrelated donor, 2 mismatched unrelated donor). The median time to transplantation was 155.5 days (range, 103-291 days). GVHD prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) plus methotrexate. Antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued. Results: The median time for neutrophil and platelet recovery was 12 days (range, 8-30 days) and 13 days (range, 5-60 days) after RIC-HCT. Sixty-two patients developed acute GVHD (53 grade II, 5 grade III, 4 grade IV). The cumulative incidence of acute GVHD at 1 year was 50.8% (42.6% for Ph-negative and 57.4% for Ph-positive, P=0.152). Except for 11 patients with early deaths within 100 days, 77 developed chronic GVHD (30 mild, 29 moderate, 18 severe), resulting in a 5-year cumulative incidence of 63.6% (69.1% for Ph-negative ALL and 58.8% for Ph-positive ALL, P=0.319). The median time to onset of chronic GVHD was 140 days (range, 37-843 days) after transplantation. Cytomegalovirus reactivation >10,000 copies/mL was observed in 40.2% (44.4% for Ph-negative ALL and 36.8% for Ph-positive ALL, P=0.447). After a median follow-up duration of 57.9 months (range, 17.7-206.8 months), the 5-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 27.5% (23.9% for Ph-negative ALL and 30.2% for Ph-positive ALL) and 19.0% (17.4% for Ph-negative ALL and 20.3% for Ph-positive ALL), respectively, and the 5-year disease-free survival (DFS) and overall survival (OS) rates were 53.5% (58.4% for Ph-negative ALL and 49.7% for Ph-positive ALL) and 59.8% (60.2% for Ph-negative ALL and 59.3% for Ph-positive ALL). In multivariate analysis, the presence of chronic GVHD lowered CIR (HR, 0.23; 95% CI, 0.10-0.48; P<0.001), but severe chronic GVHD increased NRM (HR, 8.76; 95% CI, 3.39-22.6; P<0.001). Thus, the presence of mild to moderate chronic GVHD was closely related to better outcomes in terms of DFS (HR, 0.45; 95% CI, 0.32-0.64; P<0.001) and OS (HR, 0.44; 95% CI, 0.30-0.64; P<0.001) in all patients as well as in both subgroups of patients. In Ph-positive ALL subgroup of patients, patients without achievement of major molecular response until the time of transplantation had also significantly higher CIR (HR, 7.42; 95% CI, 3.04-18.10; P<0.001) and poorer DFS (HR, 3.47; 95% CI, 1.48-8.14; P=0.004) and OS (HR, 2.58; 95% CI, 1.03-6.47; P=0.043). Conclusion: Our long-term follow-up data with a uniform treatment strategy suggest that RIC-HCT is a valid alternative choice for providing a long-term disease control for adult high-risk ALL patients in CR1. Minimal residual disease-based treatment strategies to reduce leukemia cell burden before HCT and to enhance the graft-versus-leukemia effect are needed in the future. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Download Full-text