Comparison of Outcomes between HSCT Donor Sources for Pediatric Patients with Hematologic Malignancies

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for pediatric patients with hematologic malignancies. Historically, matched sibling donors (MSD) have been the preferred donor source given ease of availability and lower rates of graft-versus-host-disease (GVHD). However, only 30% of patients have a MSD and relapse rates are high after MSD HSCT, raising the question of best donor choice. As conditioning regimens evolve, GVHD management improves and supportive care advances, it is important to evaluate the role of donor source on short and long-term clinical outcomes to inform donor selection. We performed a single-center retrospective analysis comparing post-HSCT outcomes in a cohort of pediatric patients undergoing MSD, matched unrelated donor (MUD), and umbilical cord blood (CB) transplants from 2006 to 2018. Methods: A retrospective analysis was performed on an IRB-approved protocol through Fred Hutchinson Cancer Research Center. 232 patients were included who received MSD (n=56), MUD (n=89) or CB (n=87) transplants. Of note, 24 CB patients received expanded CB cells in addition to unmanipulated unit(s). GVHD prophylaxis in all patients consisted of a calcineurin inhibitor and MMF or methotrexate. The vast majority received a high-intensity conditioning regimen (86%, 96%, and 82% respectively for MSD, MUD and CB). Overall survival (OS) and disease-free survival (DFS) were evaluated using the Kaplan-Meier method. Probabilities of non-relapse mortality (NRM), relapse, and acute GVHD were evaluated using cumulative incidence (CI) estimates with appropriate competing risks. The Cox regression model was used for adjusted analysis for age, year of transplant, sex, CMV status, MRD status, disease risk, and conditioning regimen. Results: Patient/treatment/donor demographics are shown in Table 1. Median follow-up was 2.6, 3.7 and 3.1 years for MSD, MUD and CB respectively. Patient diagnosis, disease risk, gender, age, and CMV serology were balanced between groups. CI of engraftment was similar as well, with only one graft failure in the MUD group (Fig 1). Median time to platelet recovery was significantly faster in MUD and MSD groups as compared to the CB group (p<0.0001; p<0.0001). There was no difference in unadjusted 5 year OS (Fig 2) and NRM (Fig 3) between groups. Five-year DFS was significantly higher in CB v. MSD (71% v. 54%, p=0.03) but not between CB v. MUD (71% v. 61%, p=0.18) or between MSD and MUD (p=0.38) (Fig 4). The CI of relapse at 5 years was 20% for CB patients, significantly lower than that of MSD recipients (49%, p=0.003) and not different from MUD (32%, p=0.11) (Fig 5). After adjusted analysis, the risk of DFS failures was higher among recipients of MSD than CB [HR: 1.88 (CI 95%: 1.01-3.47), p=0.04]. When CB versus MUD groups were compared, there was a trend of higher risk of DFS failures in the MUD group [HR: 1.28 (CI 95%: 0.96-1.66), p=0.09]. No difference was observed in risk of DFS failures between MSD versus MUD groups [HR:0.77 (CI 95%: 0.44-1.4), p=0.43]. Incidence of grade II-IV acute GVHD was 90% (95%CI: 82-95%), 75% (95%CI: 61-84%) and 88% (95%CI: 80-94%), for CB, MSD and MUD, respectively (p=0.25). Incidence of grade III-IV acute GVHD was 33% (95%CI: 23-43%) for CB, 9% (95%CI: 3-18%) for MSD, and 11% (95%CI: 5-18%) for MUD. Incidence of grade III-IV was significantly higher for the CB group compared to the other groups (p=0.001); however, nearly 60% of CB recipients with grade III-IV acute GVHD were diagnosed before engraftment had occurred and in retrospect met criteria for pre-engraftment syndrome. Among surviving patients, 23 CB recipients developed chronic GVHD (26% - 15 mild, 4 moderate, 4 severe) as compared to 14 MSD patients (25% - 13 mild, 1 moderate) and 40 MUD patients (45% - 27 mild, 11 moderate, 2 severe). Conclusions: Our data demonstrate no difference in unadjusted OS between MSD, MUD and CB recipients. Importantly, despite this equivalence, 5-year DFS was significantly better in the CB v. MSD group, reflecting the lower relapse rate observed in CB patients and seen previously by us and others. CB continues to be viewed as an "alternative" donor for HSCT due to the low stem cell dose in a CB graft resulting in delayed neutrophil recovery, primary graft failure and increased NRM. However, this was not observed herein, supporting the use of CB for pediatric HSCT perhaps especially in patients at high risk of post-transplant relapse. Disclosures Milano: ExCellThera: Research Funding; Amgen: Research Funding. Delaney:Nohla Therapeutics: Employment, Equity Ownership; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees. Bleakley:HighPass Biotherapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

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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.

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Results from REACH1, a Single-Arm Phase 2 Study of Ruxolitinib in Combination with Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Vs-Host Disease

Blood ◽

10.1182/blood-2018-99-116342 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 601-601 ◽

Cited By ~ 8

Author(s):

Madan Jagasia ◽

Miguel-Angel Perales ◽

Mark A Schroeder ◽

Haris Ali ◽

Nirav N Shah ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hematologic Malignancies ◽

Phase 2 ◽

Advisory Committees ◽

Graft Vs Host Disease ◽

Phase 2 Study ◽

Grade Ii ◽

Equity Ownership ◽

Grade Iii

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with high-risk or relapsed hematologic malignancies. Development of acute graft-vs-host disease (aGVHD) is a risk factor for nonrelapse mortality after allo-HSCT. Systemic corticosteroids (CS) are recommended first-line treatment for aGVHD, but <50% of patients (pts) achieve sustained responses, and there are no approved therapies for steroid-refractory (SR) aGVHD. Ruxolitinib (RUX) is an oral, selective inhibitor of Janus kinase (JAK)1/JAK2 signaling, implicated in GVHD pathogenesis. Retrospective studies showed clinical benefit from RUX in pts with SR aGVHD. Here, we report results from the REACH1 trial (NCT02953678) evaluating RUX plus CS in SR aGVHD. Methods: REACH1 was an open-label, single-cohort, multicenter, phase 2 study. Eligible pts were ≥12 years old, had an allo-HSCT from any donor source for hematologic malignancies, developed grade II-IV SR aGVHD per Mount Sinai Acute GVHD International Consortium criteria, and had ≤1 systemic treatment in addition to CS for aGVHD. SR aGVHD was defined as GVHD that progressed after 3 days or had not improved after 7 days of primary treatment with methylprednisone ≥2 mg/kg/d (or equivalent), development of GVHD in another organ after receiving CS (≥1 mg/kg/d methylprednisone) for skin or skin plus upper gastrointestinal GVHD, or inability to tolerate CS taper. Pts received RUX 5 mg twice daily (BID), with optional increase to 10 mg BID in the absence of cytopenias. The primary endpoint was overall response rate (ORR) at Day 28, defined as the proportion of pts having complete response (CR), very good partial response, or partial response (PR). The key secondary endpoint was 6-month duration of response (DOR; time from first response to GVHD progression or death). Results: At the primary analysis of ORR (02 Apr 2018), 71 pts received ≥1 dose of RUX. Mean (range) age was 52.9 (18-73) years; 49.3% of pts were men. Acute myeloid leukemia (AML) and myelodysplastic syndrome were the most common primary malignancies (28.2% each). Most pts (80.3%) received peripheral blood stem cells; 18.3% received bone marrow, and 1.4% received cord blood as the stem cell source. Treatment was ongoing in 17 pts (23.9%) at data cutoff. At baseline, 23 pts (32.4%) had grade II aGVHD, 34 (47.9%) had grade III, and 14 (19.7%) had grade IV; 36 pts (50.7%) had ≥2 organs involved. Before starting RUX, 19 pts (26.8%) had progressive aGVHD after 3 days of CS treatment, 30 (42.3%) had no response after 7 days of CS, 8 (11.3%) developed new organ involvement on CS <2 mg/kg, and 14 (19.7%) were taper intolerant. At Day 28, ORR (95% CI) was 54.9% (42.7%-66.8%) with responses observed irrespective of grade or SR criteria (Table 1). Median DOR among Day 28 responders has not been reached (lower limit, 159 days; Figure 1). Event-free probability estimates (95% CI) for Day 28 responders at 3 and 6 months were 79.0% (62.3%-88.9%) and 67.0% (47.3%-80.7%), respectively. Best ORR at any time was 73.2% (CR, 56.3%). Median (range) time to response was 7.0 (6-49) days. Two pts had malignancy relapse (AML in both). At Day 28, 43 pts were on RUX and CS treatment; 55.8% (24/43) of these pts had a 50% reduction from baseline in CS dose (Figure 2). Most pts (69/71) initiated RUX at 5 mg BID. At Day 28, 46.5% of pts (20/43) received RUX 10 mg BID. The most common treatment-emergent adverse events (TEAEs; any grade, grade 3/4) were anemia (60.6%, 46.5%), hypokalemia (47.9%, 18.3%), decreased platelet count (43.7%, 38.1%), peripheral edema (43.7%, 11.3%), and decreased neutrophil count (36.6%, 31.0%). Cytomegalovirus (CMV) infection, viremia, and chorioretinitis occurred in 9 (12.7%), 4 (5.6%), and 1 (1.4%) pts, respectively (43.7% of pts were CMV+ at baseline). Fatal treatment-related TEAEs were sepsis and pulmonary hemorrhage (1 pt each) and were attributed to both RUX and CS. Conclusion: In this first prospective trial of RUX in pts with SR aGVHD, RUX treatment resulted in overall responses in 54.9% of pts with SR aGVHD by Day 28, many of whom (68%) had grade III/IV disease at baseline. Best ORR at any time was 73.2% (CR, 56.3%). Responses were rapid and durable. Most pts achieved sustained reductions in CS dose. The AE profile was consistent with expectations for RUX and pts with SR aGVHD. RUX represents a promising therapeutic strategy; a phase 3 trial of RUX vs best available therapy in SR aGVHD is underway. Disclosures Jagasia: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Perales:Merck: Other: Personal fees; Abbvie: Other: Personal fees; Takeda: Other: Personal fees; Novartis: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support. Schroeder:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Shah:Lentigen Technology: Research Funding; Miltenyi: Other: Travel funding, Research Funding; Juno Pharmaceuticals: Honoraria; Geron: Equity Ownership; Exelexis: Equity Ownership; Oncosec: Equity Ownership. Chen:Magenta Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; REGiMMUNE: Consultancy. Arbushites:Incyte Corporation: Employment, Equity Ownership. Dawkins:Incyte Corporation: Employment. Tian:Incyte Corporation: Employment. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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The Use of Anti-Thymocyte Globulin Is Associated with Increased Chance of Survival Free from Relapse and Graft-Versus-Host Disease after Allogeneic Peripheral Blood Stem Cell Transplantation for Adults with Philadelphia-Negative Acute Lymphoblastic Leukemia: An Analysis By the Acute Leukemia Working Party of the EBMT

Blood ◽

10.1182/blood.v128.22.666.666 ◽

2016 ◽

Vol 128 (22) ◽

pp. 666-666

Author(s):

Sebastian Giebel ◽

Myriam Labopin ◽

Wlodzimierz Mendrek ◽

Gerard Socie ◽

Liisa Volin ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Lymphoblastic Leukemia ◽

Conditioning Regimen ◽

Advisory Committees ◽

Graft Versus Host ◽

Grade Ii ◽

Grade Iii

Abstract BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-SCT) is considered a standard of care for adults with high risk Philadelphia-negative acute lymphoblastic leukemia (Ph-neg ALL). During the last decade mobilized peripheral blood stem cells (PBSCT) has become predominant source of graft for allo-SCT. However, as compared to bone marrow, PBSCT is associated with increased risk of chronic graft-versus-host disease (cGVHD). Attempts to reduce the cGVHD rate include the addition of anti-thymocyte globulin (ATG) to the conditioning regimen. The goal of this registry-based, retrospective study was to analyze the effect of ATG on results of allo-PBSCT in adults with Ph-neg ALL. PATIENTS AND METHODS: 682 patients, aged 18-74 years, with Ph-neg ALL, treated with un-manipulated allo-PBSCT in first complete remission between 1997-2014 were included in the analysis. Conditioning regimen was myeloablative in 550 (81%) cases. Among 339 transplantations from matched sibling donors, ATG was used in 57 (22%) cases. In the 8/8 HLA-matched unrelated setting 204/343 (78%) patients were treated with ATG. Survival free from grade III-IV acute GVHD, cGVHD and relapse (GRFS) was the primary study end-point. RESULTS: In a univariate analysis the use of ATG was associated with increased probability of GRFS at 3 years (46% vs 38%, p=0.02) as well as decreased incidence of the overall cGVHD (34% vs. 51%, p=0.0001) and extensive cGVHD (12% vs. 25%, p<0.0001). No significant difference could be demonstrated with regard to the incidence of grade II-IV acute GVHD (30% vs. 33%, p=0.41), grade III-IV acute GVHD (8% vs. 11%, p=0.12), relapse (28% vs. 26%, p=0.38) and non-relapse mortality (NRM, 15% vs. 17%, p=0.21) as well as probability of leukemia-free survival (LFS, 57% vs. 57%, p=0.89) and overall survival (OS, 65% vs. 65%, p=0.54). In a multivariate model adjusted for other potential risk factors, the use of ATG was associated with reduced risk of grade II-IV aGVHD (HR=0.64, p=0.007), grade III-IV aGVHD (HR=0.52, p=0.03), overall cGVHD (HR=0.61, p=0.001), extensive cGVHD (HR=0.4, p<0.0001), and NRM (HR=0.62, p=0.04). No significant effect was found with regard to the incidence of relapse (p=0.27), LFS (p=0.7) and OS (p=0.16). GRFS was significantly increased with the use of ATG (HR=0.74; p=0.009). Among other factors a chance of GRFS was significantly decreased with increasing patient age (HR=1.1 for each 10 years, p=0.02), transplantations with reduced-intensity conditioning (HR=1.61, p=0.0009) and positive recipient CMV serological status (HR=1.3, p=0.02). CONCLUSIONS: Patients with Ph-neg ALL treated with allo-PBSCT benefit from the use ATG in terms of survival free from GVHD and relapse. The use of ATG should therefore be recommended in this setting. Further studies are needed to explore potential role of the ATG brand and dose. Disclosures Masszi: Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Maertens:Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy.

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Impact of Antithymocyte Globulin-Containing Conditioning Regimens on Patients Undergoing Allogeneic Stem Cell Transplantation for Progressive Myelodysplastic Syndrome: A Report From the SFGM-TC Group

Blood ◽

10.1182/blood.v118.21.3035.3035 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3035-3035

Author(s):

Ibrahim Yakoub-Agha ◽

Gandhi Damaj ◽

Marie Robin ◽

Stephane Vigouroux ◽

Alice Garnier ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Acute Gvhd ◽

Conditioning Regimen ◽

Refractory Disease ◽

Advisory Committees ◽

Grade 3

Abstract Abstract 3035 Background: due to a risk of relapse of underlying disease in patients transplanted with progressive malignancy, the use of antithymocyte globulins (ATG), incorporated within the conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT), is still controversial. We report here on a study of 245 consecutive patients transplanted between January 1999 and December 2009 in 26 French and Belgian centers for progressive MDS, defined as stable, untreated, relapsed or refractory disease. Patients and Methods: Inclusion criteria included patients aged over 18 who received allo-SCT from either a sibling (n=153) or HLA-A, -B, -C, -DRB1 and -DQB1 allele matched unrelated donor (10/10) (n=86) for MDS or AML/RAEB-t (with 20–30% BM blasts). Data quality was ensured using computerized discrepancy errors and vigorous on-site data verification of every single file. A qualified research technicien has been appointed by the University-Hospital of Lille to assist on-site centers that couldn't meet data quality requirements. HLA matching was double-checked by the French Bone Marrow Donor Registry. Results: The first 239 files analyzed until now are presented, including 154 males and 85 females. According to the WHO classification at diagnosis, 85 patients had RA/RARS/RCMD, 86 RAEB1, 62 REAB2 and 6 RAEB-t/AML. Sixty-six patients had progressed to a more advanced disease before allo-SCT. At diagnosis, 102 patients had an IPSS int-2 or higher. Cytogenetic IPSS was recorded as favorable (n=109), intermediate (n=61), unfavorable (n=63) and missing (n=6). Disease status at transplant was established as follows: relapsed or refractory disease (n=106) and untreated or stable disease without hematological improvement (n=133). Median age at transplantation was 53 years (range, 20–70). Patients received myeloablative conditioning (n=105) and nonmyeloablative (n=134) including busulfan-based regimens (n=127), TBI-based regimens (n=92) or other alkylating-agent-based regimens (n=20). In this series, 95 patients (40%) received ATG as part of conditioning ('ATG' group), whereas 144 did not ('no-ATG' group). The analysis reference date of April 1st 2011, median follow-up in survivors was 50 months (IQR, 33–92) with 59 patients having died of relapse and 77 of TRM. The estimated 3-year OS and EFS was respectively 42.3%, and 32.4%. The probability of relapse, overall and event-free survival at 3 years was not significantly different between the two groups. In contrast, the cumulative incidence of grade 2–4 acute GVHD was 48% in the no-ATG group and 30% ATG group (P <.001) and the cumulative incidence of grade 3–4 acute GVHD was 24% and 11% respectively (P <.001). Although the cumulative incidence of chronic GVHD was similar in the no-ATG and ATG groups (64% vs 46%, p=.15), a trend for a lower TRM was observed in the ATG group (22% vs 31%, p=.06). In multivariate analysis, the absence of use of ATG was the strongest parameter associated with an increased risk of acute grade 2–4 [HR = 2.28, 95% CI: 1.39–3.74, p=.001] and grade 3–4 GVHD [HR = 2.19, 95% CI: 1.04–4.61, p=.035]. In conclusion, the addition of ATG to the conditioning regimen resulted in a decreased incidence of acute GVHD without increasing relapse rates and compromising patient survival undergoing allo-SCT for progressive MDS. Disclosures: Yakoub-Agha: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; Fresinus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Michallet:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fresinus: Honoraria, Membership on an entity's Board of Directors or advisory committees. Deconinck:Celgene: Honoraria. Mohty:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Subset Analysis of Response to Treatment of Chronic Phase CML in a Phase 1 Study of Ponatinib in Refractory Hematologic Malignancies

Blood ◽

10.1182/blood.v118.21.602.602 ◽

2011 ◽

Vol 118 (21) ◽

pp. 602-602 ◽

Cited By ~ 3

Author(s):

Jorge E. Cortes ◽

Hagop M. Kantarjian ◽

Neil Shah ◽

Dale Bixby ◽

Michael J. Mauro ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Phase 1 ◽

Chronic Phase ◽

Hematologic Malignancies ◽

Employment Equity ◽

Advisory Committees ◽

Mutation Status ◽

Equity Ownership

Abstract Abstract 602 Background: Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Initial findings of a phase 1 trial in patients (pts) with refractory hematologic malignancies have been reported. The effect of duration of treatment, prior treatment, and mutation status on response to treatment was examined in CML chronic phase (CP) pts who responded to ponatinib. Methods: An open-label, dose escalation, phase 1 trial of ponatinib in pts with hematologic malignancies is ongoing. The primary aim is to assess the safety; anti-leukemic activity is also being investigated. Pts resistant to prior treatments or who had no standard treatment available were enrolled to receive a single daily oral dose of ponatinib (2 mg to 60 mg). Subset analyses of factors impacting cytogenetic and molecular response endpoints (MCyR and MMR) were performed for pts with CP-CML. Data are presented through April 15, 2011. Results: In total, 81 pts (54% male) received ponatinib. Overall, 43 pts had CP with 34 ongoing at analysis. MCyR was observed as best response in 31/43 (72%), 27 (63%) CCyR. The median time to MCyR was 12 (3 to 104) wks. Response rates were assessed by duration of treatment (1 pt in CCyR at entry was excluded; 6 pts in PCyR had to achieve CCyR). At the 3 month assessment, 22/42 (52%) CP pts achieved MCyR; at 6 months, 24/42 (57%); at 12 months, 29/42 (69%) had MCyR. The impact of prior treatment on response and time to response was assessed. 42 pts (98%) had >2 prior TKIs and 28 (65%) ≥3 prior TKIs, including investigational agents. Of approved TKIs, all pts were previously treated with imatinib, 19 dasatinib or nilotinib after imatinib, and 21 both dasatinib and nilotinib after imatinib. MCyR rate decreased with number of prior TKIs (2 prior TKIs 13/14 [93%], ≥3 prior TKIs 17/28 [61%]) and number of approved TKIs (imatinib followed by dasatinib or nilotinib 17/19 [90%], or by both dasatinib and nilotinib 12/21 [57%]). Time to response was prolonged in pts more heavily treated with prior TKIs. Median time to MCyR increased with the number of prior TKIs and approved TKIs (2 TKIs 12 wks, ≥3 TKIs 32 wks). The effect of mutation status on response and time to response was also evaluated. At entry, 12 pts had the T315I mutation, 15 had other BCR-ABL kinase domain mutations, 12 had no mutations detected, 4 did not allow sequencing. MCyR response rate for CP pts with T315I was 11/12 (92%); for other mutations, 10/15 (67%); and no mutation, 7/12 (58%). Similarly, mutation status had an impact on time to response: median time to MCyR was 12 wks for those with T315I or other mutations and 32 wks in resistant pts with no mutation. All CP patients were evaluable for MMR. At analysis, MMR was 17/43 (40%). MMR rate was inversely related to number of prior TKIs (2 TKIs 10/14 [71%], ≥3 TKIs 6/28 [21%]), approved TKIs (imatinib followed by dasatinib or nilotinib 12/19 [63%], or by both dasatinib and nilotinib 4/21 [19%]), and was higher for T315I pts (7/12, 58%) and those with other mutations (7/15, 47%) compared with no mutation (2/12, 17%). Median time to MMR for CP pts was 97 wks; median time to MMR was shorter for pts who were less heavily treated (2 prior TKIs 24 wks) and those with T315I or other mutations (63 wks). Conclusion: In this subset analysis of the phase 1 data, ponatinib had substantial activity in all subgroups analyzed. Time on treatment, less prior therapy and kinase domain mutations were associated with higher response rates and early responses in CP pts. Cytogenetic responses improved over the first 12 months of treatment and were higher in less heavily treated pts. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding. Shah:Ariad: Consultancy, Research Funding. Bixby:Novartis: Speakers Bureau; BMS: Speakers Bureau; GSK: Speakers Bureau. Mauro:ARIAD: Research Funding. Flinn:ARIAD: Research Funding. Hu:ARIAD: Employment. Clackson:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Druker:MolecularMD: OHSU and Dr. Druker have a financial interest in MolecularMD. Technology used in this research has been licensed to MolecularMD. This potential conflict of interest has been reviewed and managed by the OHSU Conflict of Interest in Research Committee and t. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Talpaz:ARIAD: Research Funding.

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Higher Incidence of Hemorrhagic Cystitis after Haploidentical Compared to Matched Sibling Donor Transplantation

Blood ◽

10.1182/blood-2018-99-119612 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3380-3380

Author(s):

Srinivasa Reddy Sanikommu ◽

Olivia Copelan ◽

Jiaxian He ◽

Candace M. Butler ◽

Michael R. Grunwald ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Hemorrhagic Cystitis ◽

Advisory Committees ◽

Conditioning Regimens ◽

Matched Sibling ◽

Donor Source ◽

Severe Grade

Abstract Introduction: Hemorrhagic cystitis (HC) causes significant morbidity following allogeneic hematopoietic cell transplantation (HCT). Reactivation of BK polyoma virus frequently occurs following transplantation and appears to be the most commonly associated factor, although high dose cyclophosphamide, other viruses, and numerous other factors contribute. A higher incidence of BK HC was reported with the use of matched unrelated or cord blood donors compared to HLA-matched siblings (El-Zimaity M, et al. Blood. 2004), however, the intensity of GVHD prevention regimens varied according to cell source complicating interpretation of these data. The effect of HLA-mismatched donors on the incidence of BK HC has been disputed and a large study of mismatched donors detected no association of HC with mismatched compared to matched donors (Giraud G, et al. Bone Marrow Transplant, 2008; Gilis L, et al. Bone Marrow Transplantation, 2014.) We analyzed a cohort of patients biologically assigned to matched sibling (MSD) or haploidentical family donor (based on presence of a suitable MSD donor) who received identical myeloablative or nonablative conditioning regimens and identical PTCy-based GVHD prevention to directly analyze the association of donor source with HC. Methods : To evaluate the role of haploidentical vs MSD donor source, we analyzed all patients undergoing haploidentical or MSD HCT at the Levine Cancer Institute between March 2014 and June 2018. Patients received identical myeloablative (BuCy) or nonmyeloablative (Flu/Cy/TBI) conditioning regimens followed by peripheral blood stem cell grafts and identical PTCy-based regimens which included tacrolimus and mycophenolate for GVHD prevention. The cumulative incidence of HC was calculated in a competing risk setting with death from any cause as a competing event. Group comparisons of incidences were determined by a Gray's test. Cox regression was conducted to evaluate risk factors for the development of HC. It was also used to evaluate HC as a time-dependent risk factor for overall survival. Fisher's exact test was used to analyze categorical patient characteristics, and two-sample t-test was employed for continuous variables. Results : From March 2014 to June 2018, 39 patients (32%) underwent MSD transplantation and 84 patients (68%) received transplants from haploidentical donors. Baseline characteristics were similar except for younger donor age of haploidentical donors (median 40 yrs vs 54 yrs P< .001). The rates of acute GVHD, Chronic GVHD, NRM and overall survival were similar between the two groups. The cumulative incidence of HC was higher in patients who received cells from haploidentical donors when compared to matched related donors (p=0.05). In multivariate analysis of risk factors associated with HC (Table 1), haploidentical donor (HR: 1.80, 95% CI 0.95-3.44, P= .07) and, grade III-IV acute GVHD (HR: 4.93, 95% CI 1.01-23.93 P = .05), were associated with development of HC. 33/53 HC patients (62%) were tested positive for BK virus. The intensity of the conditioning regimen, disease status at transplant, donor and recipient age were not associated with development of HC. For patients who received cells from haploidentical donors, there was a trend towards severe (grade 3-4) HC, but this did not reach statistical significance (HR 2.71, 95% CI 0.59-12.24 P=.19). The incidence of HC was not associated with overall survival (HR 0.58 95% CI 0.3-1.15 P=0.12), even when severe (grade III-IV) HC events were evaluated (HR 1.79 95% CI 0.75-4.3 P=0.19). Conclusions: In adults undergoing allogenic transplantations using identical conditioning regimens and PTCy based GVHD prevention, the use of a haploidentical donor results in a higher incidence of HC than does a MSD. Disclosures Grunwald: Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medtronic: Equity Ownership; Genentech: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding. Jacobs:Genentech: Honoraria. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding.

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First Results of a Prospective I/II Clinical Trial in Adult Patients Using TCR Alpha/Beta Depleted Stem Cell Transplantation from Matched Related and Unrelated Donors

Blood ◽

10.1182/blood-2018-99-112758 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2164-2164

Author(s):

Moniek De Witte ◽

Anna Van Rhenen ◽

Geerte Van Sluis ◽

Rick Admiraal ◽

Lotte van der Wagen ◽

...

Keyword(s):

Research Funding ◽

Immune Reconstitution ◽

Acute Gvhd ◽

Conditioning Regimen ◽

Myeloablative Conditioning ◽

Post Transplant ◽

Kaplan Meier ◽

Unrelated Donors ◽

Male Patients ◽

Grade Iii

Abstract Introduction: We report the first analysis of a multicenter prospective single-arm phase I/II study that assesses the safety and feasibility of transplantation of TCRalpha/beta depleted stem cells from matched related or unrelated donors using the CliniMACS plus System (Miltenyi Biotec, Germany) in combination with a non-myeloablative conditioning in adult patients (trial nr NL48606.000.14). The conditioning regimen consisted of ATG (Thymoglobulin®) 1.5mg/kg i.v. days -12 to -9; fludarabine i.v. 40 mg/m2 days -5 to -2 and busulfan i.v. (Busivex®) days -5 to -2 (cumulative AUC of 80-90mg*h/L), followed by 28 days of mycophenolic acid. All 35 subjects were eligible to address the primary endpoint which is the incidence of acute GVHD at day 100. Results: 2 centers enrolled 10 female and 25 male patients (median age 59 years, range 19 - 69 years), including 9 AML, 4 ALL, 2 CML, 5 MM, 1 NHL, 10 MDS, 4 MPN. Diseases were in CR (n=17), VGPR (n=1), PR (n=5) or non-remission (n=12). 4 subjects had one or more previous allogeneic SCTs. Donors included 4 MRD, 24 10/10 matched MUD and 7 9/10 matched MUD. 8 male patients received stem cells of female donors. The median number of CD34+ cells and αβ TCR cells/kg was 6.1x 10^6 (range, 1.9-10) and 14.5x10^3 (range, 0-136), respectively. One primary graft failure was observed. Primary engraftment of ANCs > 500 cells/μL was reached at a median of 14 days (range 9 - 48 days) and of platelets > 20 at a median of 17 days (range 10 - 99) days. The median time of follow-up of this first analysis was 190 days (range 110-400 days). 3/35 patients developed acute GVHD grade III-IV during the first 100 days, 9/35 patients developed acute GVHD grade II-IV and 16/35 patients grade I-IV at day 100. At day 100 the cumulative incidence (CI) of CMV was 31%, of EBV 36% and of BK cystitis 20%. The combined CI of CMV/EBV/BK infections with a CTC-AE grade III-V was 53% at day 100. Immune reconstitution was rapid with a median of 227 (range 34 - 1626) CD3+ cells/µl on day 100 but varied substantially between patients. The median numbers of CD3/CD4+ and CD3/CD8+ at day 100 post transplant were 60 (range 30 - 120) and 124 (range 5 - 1450) cells/µl. The median numbers of NK were 289 (range 32-1140) at day 30 and 128 (range 24 - 1228) cells/µl at day 100 post transplant. The median numbers of γδ T cells were 38 (range 4-143) at day 30 and 50 (range 8-556) cells/µl at day 100 post transplant. 26 out of 35 patients were alive, 2 patients died of a relapse, 2 of GVHD and 5 of infectious complications. Kaplan Meier estimates of the OS are 88% (+/- 6%) at day 100 and 68% (+/- 9%) at 1Y. Kaplan Meier estimates of the EFS are 77% (+/- 7%) at day 100 and 52% (+/- 10%) at 1Y. 2 patients developed a relapse before day 100 and 5 patients before 1Y. It is noted that the outcome of 5 patients with MM was very poor in this cohort (3 patients developed a relapse and 2 patients died of complications). Conclusion: Allo-SCT of αβ T cell depleted PBMCs form matched related or unrelated donors, in combination with early ATG and a non-myeloablative conditioning regimen, resulted in favorable rates of primary engraftment (34/35), a CI of aGVHD II-IV of 26% with only minimal immuno-suppression and an encouraging early disease control (Fig 1). OS survival was mainly impacted by NRM (Fig 1), by which the majority of complications were of infectious nature. While all patients with MM suffered from NRM or relapse, all other disease categories had a rather favorable outcome. Reducing inter-individual variations in immune reconstitution early after transplantation will be key to further improve outcomes. Disclosures Minnema: Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Servier: Consultancy. Kuball:Novartis: Research Funding; Miltenyi Biotec: Research Funding; Gadeta (www.gadeta.nl): Consultancy, Equity Ownership, Patents & Royalties: on gd T cells and receptors and isolation strategies, Research Funding.

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Activating TP53 by Dual Inhibition of MDMX and MDM2

Blood ◽

10.1182/blood-2019-121097 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. SCI-14-SCI-14

Author(s):

Ulrich G. Steidl

Keyword(s):

Research Funding ◽

Hematologic Malignancies ◽

Advisory Committees ◽

Suppressor Activity ◽

Lymphoid Malignancies ◽

Dual Targeting ◽

Selective Targeting ◽

Tumor Suppressor Activity ◽

Equity Ownership ◽

Dual Inhibition

TP53 is often inactivated by mutations or other mechanisms in human cancers. Recent work has demonstrated that its endogenous inhibitor MDMX (or MDM4) is frequently overexpressed in patients with hematologic malignancies including AML, lymphoid malignancies, as well as other cancers. Pharmacological disruption of the interactions of TP53 with both its endogenous inhibitors (MDMX and MDM2) has long been sought after as an attractive strategy to restore p53-dependent tumor suppressor activity. However, selective targeting of this pathway has previously been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. More recently, pharmacological dual targeting of MDMX/MDM2 has become feasible through stapled peptides and is currently being tested in clinical trials. This presentation will discuss such MDMX/MDM2 dual-targeting strategies as well as new insights into MDMX-mediated mechanisms of tumor progression at the stem cell level, which have emerged from recent studies. Disclosures Steidl: Aileron Therapeutics: Consultancy, Research Funding; Stelexis Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Scientific Co-Founder; Pieries Pharmaceuticals: Consultancy; Celgene: Consultancy; BayerHealthcare: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding.

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Prospective, Biological Randomized Study of T-Cell Depleted Nonmyeloablative Allogeneic Transplantation From HLA-Matched Related, Unrelated or Haploidentical Donors for Patients with Hematologic Malignancies

Blood ◽

10.1182/blood.v116.21.3541.3541 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3541-3541

Author(s):

Junya Kanda ◽

Gwynn D. Long ◽

Cristina Gasparetto ◽

Mitchell E. Horwitz ◽

Keith M. Sullivan ◽

...

Keyword(s):

Research Funding ◽

Acute Gvhd ◽

Residual Disease ◽

Fungal Infections ◽

Randomized Study ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Rank Test ◽

Log Rank Test ◽

Grade Iii

Abstract Abstract 3541 We have previously shown that SCT from HLA-haploidentical related donors (HAPLO) after nonmyeloablative conditioning is feasible with a low incidence of grade III-IV acute GVHD or treatment-related mortality (TRM) (Rizzieri et al. JCO 2007). We now report our comparative study in patients who received SCT from a 6/6 HLA-matched related (MRD), 8–10/8 HLA-matched unrelated (MUD), or HAPLO donor, after nonmyeloablative conditioning. Methods: Patients with chemosensitive relapse or high risk disease with minimal residual disease at study entry were eligible. The conditioning regimen consisted of fludarabine, 40 mg/m2 for 4 days; melphalan, 140 mg/m2 for 1 day; and alemtuzumab, 20 mg for 4 days for patients with lymphoid or myelomatous diseases. Fludarabine and alemtuzumab at the same doses with busulfan, 130 mg/m2 for 2 days was used for patients with myeloid diseases. Mycophenolate mofetil was used for GVHD prophylaxis. Donor lymphocyte infusions were performed in 15 MRD patients and 4 HAPLO patients. Disease-free survival (DFS) and overall survival (OS) rates after SCT were estimated using the Kaplan–Meier method, and univariate comparisons were performed using the log-rank test. Cox proportional-hazards regression was used to evaluate variables that potentially affected the survival rates. Results: The lymphoid cohort included 52 patients with ALL (n = 6), lymphoma (n = 42), or myeloma (n = 4), whereas the myeloid cohort included 46 patients with AML/MDS (n = 40), and myeloproliferative disorder (MPD) (n = 6). The median subject age was 56.5 (range, 20–73) years with a median follow-up of 15 months among survivors. A total of 29, 40, and 29 patients received transplants from MRD, MUD, and HAPLO, respectively. All 29 patients engrafted after HCT from MRD. One of 40 patients who received SCT from MUD had a primary graft failure (GF), with 2 secondary GF and 1 early relapse. Two of them were rescued by subsequent nonmyeloablative SCT from the same MUD or new HAPLO donor. Among 28 HAPLO patients evaluable for engraftment, 8 had a primary GF, 6 of these had myeloid disease; 2 additional patients had donor cell recovery but without full recovery of normal blood counts. Three of the 8 were rescued with subsequent nonmyeloablative SCT from the same donor. The transplant regimen resulted in 11% TRM at day 100. Grade III-IV acute GVHD rates were 0/29 (0%), 4/40 (10%), and 5/29 (17%) in patients who received a transplant from a MRD, MUD, or HAPLO, respectively. CMV reactivation occurred in 57% of patients and 6% developed CMV disease. Other infectious complications included polyomavirus in 24% of patients, bacteria in 23%, respiratory viruses in 13%, and fungal infections in 7%. The common causes of death were progressive disease (30% for all cause of death) and infections (32%). The 1-year DFS rate after SCT from MRD, MUD, and HAPLO was 55% (95% CI, 33–73%), 39% (22–56%), and 34% (16–53%), respectively (Log-rank test, P = 0.094) (Figure 1); the corresponding 1-year OS rate was 66% (43–82%), 39% (21–55%), and 34% (16–53%), respectively (Log-rank test, P = 0.012) (Figure 2). Multivariate analysis revealed that SCT from MUD/HAPLO, compared with that from MRD, was the only adverse factor that affected the OS rate (HR for MUD, 2.62 (95% CI, 1.15–5.96), P = 0.022; HR for HAPLO, 3.17 (1.36–7.37), P = 0.007), but the OS rate after SCT from HAPLO did not significantly differ from that after SCT from MUD (P = 0.560). Other variables (recipient age, conditioning regimen, and disease status at transplant) were not significantly associated with the outcome. Conclusions: The results show the feasibility of this approach with this regimen and the clinical outcomes in patients who received transplants from HAPLO are comparable to patients who received transplants from MUD. Development of strategies to improve immune recovery remains a current challenge. Disclosures: Off Label Use: Alemtuzumab for conditioning in allogeneic stem cell transplantation. Horwitz:Genzyme: Honoraria, Research Funding. Chao:Genzyme: Research Funding. Rizzieri:Genzyme: Speakers Bureau.

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Outcomes of Unrelated Umbilical Cord Blood Transplantation Using a Conditioning Regimen of TBI/Ara-c/CY without ATG for Adolescent and Adults Patients with High-Risk Hematologic Malignancies

Blood ◽

10.1182/blood.v120.21.4525.4525 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4525-4525

Author(s):

Zimin Sun ◽

Huilan Liu ◽

Liangquan Geng ◽

Xingbing Wang ◽

Kaiyang Ding ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Acute Gvhd ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Adult Patients ◽

Myeloablative Conditioning ◽

Blood Transplantation

Abstract Abstract 4525 To retrospectively analyze the curative efficacy of umbilical cord blood transplantation (UCBT) using total body irradiation (TBI)-based myeloablative conditioning regimen without antithymocyte globulin (TBI/Ara-c/CY w/o ATG) in adolescent and adult patients with high-risk hematological malignancies. Outcomes of forty-five consecutive adolescent and adult patients with high-risk hematological malignancies treated with TBI-based myeloablative UCBT without ATG in a single center between September 2006 and February 2012 were retrospectively analyzed. The conditioning regimen included TBI/Ara-c/CY:TBI 12GY (four fractionated) + Ara-C 8g/m2 (two days fractionated) + CY 120mg/kg (two days fractionated), and rhG-CSF was administered for myeloid leukemia by continuous infusion at a dose of 5μg·kg−1·d−1. Infusion of G-CSF was started 24 hours before the first dose of Ara-C and stopped at the completion of the last dose. The patients included 31 males and 14 females, with a median age of 21 years (range: 14–40) and a median weight of 58 kg (range: 42–76). Of those, 17 patients (37.8%) had advanced disease. Double UCB grafts were used for 16 patients, while single UCB graft was used for 29 patients. The median number of nucleated cells infused was 3.57 (1.94∼6.76)×107/kg and the median CD34+cells infused was 2.11 (0.71∼4.95)×105/kg. All patients received a combination of cyclosporine (CSA) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis. All patients successfully engrafted. The median times to neutrophil (ANC≥0.5×109/L) and platelet (PLT PLT≥20×109/L) recovery were 19 days (range: 13–35 days) and 36 days (range: 24–90 days) respectively after transplantation in 40 evaluable patients. Acute GVHD occurred in 21 patients and the cumulative incidences of gradeII-‡W and grade III-‡W acute GVHD were 24.4% and 11.1%, respectively. Chronic GVHD occurred in five of 40 evaluable patients (12.5%). Of the 45 patients, 9 (20%) had relapse. After a median follow-up of 25.1 months (range: 6–65.1) among survivors, treatment-related mortality (TRM) within 100 days and within one year was 8.9% and 24.4%, respectively. The main causes of death were pneumonia and severe acute GVHD. The probability of three-year disease-free survival and overall survival (OS) was 53.3% and 57.8%, respectively. The TBI/Ara-c/CY myeloablative conditioning regimen has been well tolerated by patients at our institution and seems to be able to establish sustained donor cell engraftment and decrease the risk of transplant-related death. For high risk patients and patients with advanced disease, this conditioning regimen could reduce relapse and chronic GVHD, indicating the feasibility of TBI/Ara-c/CY as a conditioning regimen for CBT in adolescent and adult patients with hematologic malignancies. Disclosures: Sun: Key Scientific and Technological Project of Anhui province “Twelfth Five-Year Plan” (11010402164): Research Funding; the Fund of the Key Medical Project of Anhui Provincial Healthy Department (2010A005): Research Funding; Anhui Provincial “115” Industrial Innovation Program (2009): Research Funding.

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