Comparing transplant outcomes in ALL patients after haploidentical with PTCy or matched unrelated donor transplantation

Abstract We compared outcomes of 1461 adult patients with acute lymphoblastic leukemia (ALL) receiving hematopoietic cell transplantation (HCT) from a haploidentical (n = 487) or matched unrelated donor (MUD; n = 974) between January 2005 and June 2018. Graft-versus-host disease (GVHD) prophylaxis was posttransplant cyclophosphamide (PTCy), calcineurin inhibitor (CNI), and mycophenolate mofetil (MMF) for haploidentical, and CNI with MMF or methotrexate with/without antithymoglobulin for MUDs. Haploidentical recipients were matched (1:2 ratio) with MUD controls for sex, conditioning intensity, disease stage, Philadelphia-chromosome status, and cytogenetic risk. In the myeloablative setting, day +28 neutrophil recovery was similar between haploidentical (87%) and MUD (88%) (P = .11). Corresponding rates after reduced-intensity conditioning (RIC) were 84% and 88% (P = .47). The 3-month incidence of grade II-IV acute GVHD (aGVHD) and 3-year chronic GVHD (cGVHD) was similar after haploidentical compared with MUD: myeloablative conditioning, 33% vs 34% (P = .46) for aGVHD and 29% vs 31% for cGVHD (P = .58); RIC, 31% vs 30% (P = .06) for aGVHD and 24% vs 29% for cGVHD (P = .86). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 44% and 51% with haploidentical and MUD (P = .56). Corresponding rates after RIC were 43% and 42% (P = .6). In this large multicenter case-matched retrospective analysis, despite the limitations of a registry-based study (ie, unavailability of key elements such as minimal residual disease testing), our analysis indicated that outcomes of patients with ALL undergoing HCT from a haploidentical donor were comparable with 8 of 8 MUD transplantations.

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HLA-Mismatch Is Associated With Worse Outcomes After Unrelated Donor Reduced Intensity Conditioning Hematopoietic Cell Transplantation: A Cibmtr Analysis

Blood ◽

10.1182/blood.v122.21.547.547 ◽

2013 ◽

Vol 122 (21) ◽

pp. 547-547 ◽

Cited By ~ 2

Author(s):

John Koreth ◽

Kwang Woo Ahn ◽

Joseph Pidala ◽

James L. Gajewski ◽

Hailin Wang ◽

...

Keyword(s):

T Cell ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Cell Depletion ◽

Unrelated Donor ◽

T Cell Depletion ◽

Gvhd Prophylaxis ◽

Conditioning Intensity

Abstract In myeloablative unrelated donor allogeneic hematopoietic cell transplantation (HCT) a 1-locus HLA-mismatch (-A, -B, -C, -DRB1) is associated with lower survival compared to fully matched pairs. However data in reduced-intensity and non-myeloablative conditioning (together called RIC) HCT are limited. We analyzed adult AML/ALL/CML/MDS recipients of first 8/8 HLA-matched or 1-locus mismatched unrelated donor (MUD, MMUD) RIC HCT performed in the period 1999-2011 and registered in the CIBMTR. HLA-A, -B, -C and -DRB1 loci were typed in all pairs at high resolution; -DQB1 and -DPB1 loci could not be evaluated in all pairs. Transplants involving ex-vivo T-cell depletion, CD34+ selection, or post-transplant cyclophosphamide were excluded. Overall survival (OS) was the primary outcome. Secondary outcomes included non-relapse mortality (NRM), relapse, disease-free survival (DFS) and acute and chronic GVHD. Individual locus mismatch was also assessed. Apart from HLA matching, variables related to patient (age, race, sex, KPS, diagnosis, disease-risk), donor (age, parity), both (sex match/ABO match/CMV match) treatment (conditioning intensity, TBI use, in-vivo T-cell depletion (ATG), graft source (PB, BM) and GVHD prophylaxis (CyA-, Tac-based)) were considered. 2588 RIC HCT (8/8 MUD: 2025; 7/8 MMUD: 563) from 144 centers and 12 countries were analyzed. Median follow up in 8/8 MUD and 7/8 MMUD was 38 and 48 months respectively. Diagnoses were AML (65%), ALL (8%), CML (7%), MDS (20%). Conditioning intensity was RIC (79%), NMA (21%). 58% received in-vivo T-cell depletion. Graft source was PBSC (85%), BM (15%). GVHD prophylaxis was Tac-based (70%), CyA-based (27%). Mismatches involved HLA-A (188), -B (81), -C (219), and -DRB1 (75); with -DPB1 and -DQB1 typing available in 1382 and 2502 cases respectively. Compared to 8/8 MUD, 7/8 MMUD recipients were more likely to be younger and ethnic minorities and to have older and parous donors. In univariate analyses DQB1- and -DPB1 mismatch was not associated with worse OS, DFS, or NRM and was not further evaluated. There was a trend toward more grade II-IV acute GVHD in -DPB1 double (p=0.02) but not single mismatches. In multivariate models 7/8 MMUD RIC HCT had worse grade II-IV and III-IV acute GVHD, NRM, DFS and OS, but not relapse or chronic GVHD (Table). No significant interactions were identified between degree of HLA matching and other clinical variables. Adjusted 1- and 3-year NRM for 8/8 MUD vs. 7/8 MMUD was 20.4% vs. 28.9% (p<0.0001) and 29.2% vs. 38.1% (p<0.0007) respectively. Adjusted 1- and 3-year OS was 54.7% vs. 48.8% (p=0.01) and 37.4% vs. 30.9% (p=0.005) respectively (Figure). There was no difference between allele and antigen mismatches. HLA-A, -B, -C, and -DRB1 locus mismatches were each associated with 1 or more impaired outcomes (acute GVHD, NRM, DFS, and/or OS). Table 1 7/8 vs. 8/8 HLA HR (95% CI) p-value Acute GVHD II-IV 1.29 (1.09-1.53) 0.003 Acute GVHD III-IV 1.69 (1.00-3.36) 0.05 Chronic GVHD 1.11 (0.96-1.28) 0.15 Relapse 1.01 (0.87-1.17) 0.92 NRM 1.52 (1.29-1.79) <0.0001 DFS 1.20 (1.07-1.34) 0.0015 OS 1.25 (1.11-1.40) 0.0001 Compared to 8/8 MUD, both 7/8 allele and antigen MMUD RIC HCT have greater treatment toxicity and worse survival, of a magnitude similar to that seen in myeloablative transplantation. An isolated mismatch at HLA-A, -B, -C, or -DRB1 was associated with 1 or more adverse outcomes. In unrelated donor RIC HCT, matching for all alleles of HLA-A, -B, -C and -DRB1 loci results in superior outcomes. Disclosures: No relevant conflicts of interest to declare.

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Alternative donor transplantation for myelodysplastic syndromes: haploidentical relative and matched unrelated donors

Blood Advances ◽

10.1182/bloodadvances.2020003654 ◽

2021 ◽

Vol 5 (4) ◽

pp. 975-983

Author(s):

Michael R. Grunwald ◽

Mei-Jie Zhang ◽

Hany Elmariah ◽

Mariam H. Johnson ◽

Andrew St. Martin ◽

...

Keyword(s):

Calcineurin Inhibitor ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Disease Free Survival ◽

Marrow Transplant ◽

Unrelated Donor ◽

Research Database ◽

Matched Unrelated Donor ◽

Gvhd Prophylaxis ◽

Total Body

Abstract We compared outcomes in 603 patients with myelodysplastic syndrome (MDS) after HLA-haploidentical relative (n = 176) and HLA-matched unrelated (n = 427) donor hematopoietic cell transplantation (HCT) from 2012 to 2017, using the Center for International Blood and Marrow Transplant Research database. All transplantations used reduced-intensity conditioning regimens. Total-body irradiation plus cyclophosphamide and fludarabine was the predominant regimen for HLA-haploidentical relative donor HCT, and graft-versus-host disease (GVHD) prophylaxis was uniformly posttransplantation cyclophosphamide, calcineurin inhibitor, and mycophenolate. Fludarabine with busulfan or melphalan was the predominant regimen for HLA-matched unrelated donor HCT, and GVHD prophylaxis was calcineurin inhibitor with mycophenolate or methotrexate. Results of multivariate analysis revealed higher relapse (hazard ratio [HR], 1.56; P = .0055; 2-year relapse rate, 48% vs 33%) and lower disease-free survival (DFS) rates after HLA-haploidentical relative donor HCT (HR, 1.29; P = .042; 2-year DFS, 29% vs 36%). However, overall survival (OS) rates did not differ between donor type (HR, 0.94; P = .65; 2-year OS, 46% for HLA-haploidentical and 44% for HLA-matched unrelated donor HCT) because of mortality associated with chronic GVHD. Acute grade 2 to 4 GVHD (HR, 0.44; P < .0001) and chronic GVHD (HR, 0.36; P < .0001) were lower after HLA-haploidentical relative donor HCT. By 2 years, probability of death resulting from chronic GVHD was lower after HLA-haploidentical relative compared with HLA-matched unrelated donor HCT (6% vs 21%), negating any potential survival advantage from better relapse control. Both donor types extend access to transplantation for patients with MDS; strategies for better relapse control are desirable for HLA-haploidentical relative donor HCT, and effective GVHD prophylaxis regimens are needed for unrelated donor HCT.

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Protmune, a Next-Generation Graft for GvHD Prophylaxis in Allogeneic Hematopoietic Cell Transplantation: 1-Year Safety and Efficacy Phase 1 Data

Blood ◽

10.1182/blood-2018-99-115088 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2167-2167

Author(s):

Richard T. Maziarz ◽

John Edwards ◽

James Essell ◽

Cesar Freytes ◽

Chatchada Karanes ◽

...

Keyword(s):

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Ex Vivo ◽

Phase 1 ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Matched Unrelated Donor ◽

Myeloablative Conditioning ◽

Gvhd Prophylaxis ◽

Mobilized Peripheral Blood

Abstract ProTmune is an ex vivo pharmacologically-modulated, next-generation mobilized peripheral blood (mPB) cell graft with FDA fast track designation for the reduction of incidence and severity of acute graft versus host disease (GvHD) in patients undergoing allogeneic hematopoietic cell transplantation (HCT). Here we report the 1-year safety and efficacy data from the Phase 1 stage of PROTECT, an ongoing Phase 1 open-label / Phase 2 blinded, randomized and controlled trial of ProTmune in adult subjects with hematologic malignancy undergoing matched unrelated donor HCT following myeloablative conditioning and receiving standard GvHD prophylaxis of methotrexate and tacrolimus. Seven subjects were administered ProTmune in the Phase 1 stage of PROTECT. Underlying hematologic diseases included ALL (n=3), AML (n=3) and MDS (n=1). Subjects were predominantly female (n=5) with a median age of 56 (range 34 to 69) and a median weight of 79 kg (range 53 to 133). As of July 23, 2018, five subjects remain on study with a median follow up of 390 days (range 342 to 490 days). ProTmune was manufactured on-site on the day of HCT by pharmacologically-modulating a conventional mobilized peripheral blood (mPB) cell graft ex vivo with 16,16-dimethyl prostaglandin E2 and dexamethasone, to enhance the biologic properties and therapeutic function of the graft. All ProTmune units were manufactured successfully with a mean of 6.6 (range 3.0 to 11.0) x106 CD34+ cells/kg and 2.3 (range 1.2 to 3.1) x108 CD3+ cells/kg. ProTmune was well tolerated. ProTmune-related AEs were all mild to moderate and consisted of nausea, vomiting and non-cardiac chest pain on the day of administration. No ProTmune-related SAEs have been reported. All subjects engrafted with no primary or secondary graft failure. Average time to neutrophil engraftment was 17 days (range 14 to 22). Day 100 acute GvHD assessment revealed three of the seven subjects had steroid responsive acute CIBMTR Grade 2-4 GvHD with median time of seven days [range 5 to 8 days] to resolution of the maximum GvHD grade. Since therapeutic approaches intended to reduce acute GvHD may increase disease relapse risk, composite endpoints are being explored by the HCT community to more thoroughly define transplant success. 1-year current GvHD-free, relapse-free survival (CGRFS) is one endpoint under study measuring proportion of subjects that are alive without relapse and without active moderate or severe chronic GvHD per NIH consensus criteria at Day 365. We intend to present final 1-year CGRFS on the seven Phase 1 subjects at the ASH Annual Meeting. To date, non-relapse mortality, deemed not attributable to ProTmune, occurred in two subjects (Subject 1 on Day 228 from pulmonary edema; Subject 3 on Day 151 from cardiac arrhythmia). There has been no disease relapse, and no moderate / severe chronic GvHD at Day 365. Two subjects are pending the 1-year assessment. The Phase 2 stage of PROTECT is currently enrolling a planned 60 subjects at 15 U.S. centers. Subjects with hematologic malignancies undergoing matched unrelated donor HCT following myeloablative conditioning are randomized 1:1 to receive in a blinded manner, either ProTmune or a conventional matched unrelated donor mPB unit as the cell graft. Table Table. Disclosures Maziarz: Athersys, Inc.: Patents & Royalties; Incyte: Consultancy, Honoraria; Kite Therapeutics: Honoraria; Juno Therapeutics: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Saad:Actinium: Consultancy. Diaz:Fate Therapeutics, Inc.: Employment. Medcalf:Fate Therapeutics, Inc.: Employment. Storgard:Fate Therapeutics, Inc.: Employment, Equity Ownership. Deol:Kite Pharmaceuticals: Consultancy; Novartis: Consultancy.

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Comparable Long-Term Outcomes of Reduced-Intensity and Myeloablative Conditioning Allogeneic Hematopoietic Cell Transplantation By Minimal Residual Disease Kinetics during the Tyrosine Kinase Inhibitor-Based Chemotherapy Courses in Adults with Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia in First Remission

Blood ◽

10.1182/blood.v128.22.3979.3979 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3979-3979

Author(s):

Jae-Ho Yoon ◽

Sung-Soo Park ◽

Young-Woo Jeon ◽

Sung-Eun Lee ◽

Byung-Sik Cho ◽

...

Keyword(s):

Research Funding ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Unrelated Donor ◽

Long Term Outcomes ◽

Matched Unrelated Donor ◽

Sibling Donor ◽

Matched Sibling

Abstract Background: The use of tyrosine kinase inhibitor (TKI)-based chemotherapy has demonstrated improved complete remission (CR) rates and increased applicability to allogeneic hematopoietic cell transplantation (HCT), thus allowing better survival in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). However, the sensitivity of Ph-positive ALL to reduced-intensity conditioning (RIC) versus myeloablative conditioning (MAC) by minimal residual disease (MRD) kinetics is not well established. Previously, we have confirmed that monitoring MRD kinetics is very important to predict long-term outcomes. Here, we examined a cohort of patients with Ph-positive ALL in CR1 and tried to compare the long-term outcomes of RIC-HCT vs MAC-HCT according to pre-HCT MRD kinetics. Methods: During the period between 2000 and 2014, 173 adults (median age, 39 years [range, 16-65 years]) with Ph-positive ALL were included in this analysis. All patients received allogeneic HCT (68 RIC [fludarabine 150mg/m2 + melphalan 140mg/m2] and 105 MAC [total body irradiation 13.2Gy + cyclophosphamide 120mg/kg]) in CR1 following two courses of first-line TKI (138 imatinib and 35 dasatinib)-based chemotherapy and had data on prospectively determined quantitative MRD kinetics. A total of 52 patients were excluded because of >CR1 pre-HCT status (n=26), transplants receiving umbilical cord blood grafts (n=14), and no TKI use before HCT (n=12). All but one RIC transplants received peripheral blood stem cells as a graft source (40 matched sibling donor, 11 matched unrelated donor, 17 mismatched unrelated donor), while MAC transplants used either bone marrow (n=73; 57 matched sibling donor, 8 matched unrelated donor, 6 mismatched unrelated donor) or peripheral blood stem cells (n=32; 2 matched sibling donor, 20 matched unrelated donor, 10 mismatched unrelated donor). The median time to transplant was 154 days (range, 119-291 days) in RIC transplants and 141 days (range, 112-280 days) in MAC transplants, respectively. Calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) and methotrexate was used for graft-versus-host disease (GVHD) prophylaxis and 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. MRD monitoring was centrally evaluated by real-time quantitative PCR (4.5 log sensitivity) through handling of bone marrow samples. Results: After a median follow-up of 70.4 months (range, 16.0-176.8 mo), RIC regimen showed comparable 5-year cumulative incidence of relapse (CIR; 30.2% vs 27.9%, P=0.750), non-relapse mortality (NRM; 20.3% vs 15.5%, P=0.318), disease-free survival (DFS; 49.7% vs 56.6%, P=0.296), and overall survival (OS; 59.3% vs 62.1%, P=0.540) compared to MAC regimen. We further analyzed the impact of conditioning intensity on CIR and DFS according to MRD kinetics. Based on the MRD kinetics during the pre-HCT TKI-based chemotherapy courses, we classified patients into 3 subgroups: early-stable molecular responders (EMR, n=59), late molecular responders (LMR, n=57), and poor molecular responders (PMR, n=53). In all MRD-based subgroups of patients, no significant difference in CIR (EMR: 16.3% vs 6.2%, P=0.280; LMR: 10.5% vs 21.4%, P=0.334; PMR: 63.6% vs 59.4%, P=0.372) or DFS (EMR: 68.1% vs 78.1%, P=0.381; LMR: 49.6% vs 59.5%, P=0.369; PMR: 27.3% vs 34.2%, P=0.250) was observed between RIC and MAC. In multivariate analysis, LMR (HR, 2.36; 95% CI, 0.81-6.86; P=0.114) or PMR (HR, 9.05; 95% CI, 3.40-24.1; P<0.001) had higher relapse risk than EMR. Consequently, compared with EMR, LMR (HR, 2.02; 95% CI, 1.01-4.02; P=0.046) or PMR (HR, 3.79; 95% CI, 1.92-7.50; P<0.001) had poorer DFS. The presence of chronic GVHD, especially mild to moderate grade, was also independently associated with better DFS (HR, 0.28; 95% CI, 0.14-0.53; P<0.001). In addition, patients older than 40 years had higher risk of treatment failure in terms of NRM (HR, 4.25; 95% CI, 1.69-10.6; P=0.002). Conclusion:RIC-HCT showed comparable long-term outcomes to MAC-HCT in all MRD-based subgroups of patients with Ph-positive ALL in CR1. Our data suggest that RIC-HCT is worthy of further investigation in prospective trials of adult Ph-positive ALL. 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.

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Conditioning Intensity in Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽

10.1182/blood.v118.21.501.501 ◽

2011 ◽

Vol 118 (21) ◽

pp. 501-501 ◽

Cited By ~ 1

Author(s):

Ulrike Bacher ◽

Evgeny Klyuchnikov ◽

Jeanette Carreras ◽

Jennifer Le-Rademacher ◽

Ginna G. Laport ◽

...

Keyword(s):

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Multivariable Analysis ◽

B Cell Lymphoma ◽

Marrow Transplant ◽

P Value ◽

Unrelated Donor ◽

Resistant Disease ◽

Conditioning Regimens ◽

Conditioning Intensity

Abstract Abstract 501 Non-myeloablative (NMC) and reduced intensity (RIC) conditioning approaches rely primarily on a graft-vs-lymphoma (GVL) effect and aim at reducing transplant-related mortality (TRM) associated with myeloablative conditioning (MAC). We analyzed outcomes for 396 adults (228 male) receiving alloHCT for DLBCL following MAC (n=165), RIC (n=143) or NMC (n=88) regimens between 2000 and 2009 and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Conditioning regimens were classified using consensus criteria. Engraftment, cumulative incidences of acute and chronic graft-vs-host disease (GvHD), TRM, progression and probabilities of progression-free (PFS) and overall survival (OS) were compared between MAC and NMC/RIC. Common MAC regimens were cyclophosphamide (CY) + total body irradiation (TBI) (54%) and busulfan (BU) + CY (23%). Common RIC regimens were fludarabine (Flu) with melphalan (44%) or BU (39%) and for NMC, Flu with CY (48%) and low dose TBI (33%). Practice patterns changed with declining use of MAC regimens after 2003 (> 66% of total being MAC pre-2003 and <33% after). Donors were HLA matched siblings in 40%, 26%, 30% of MAC, RIC and NMC recipients, respectively, with 67% overall receiving unrelated donor (URD) grafts. Significant (p <0.05) baseline differences between the cohorts included: RIC and NMC recipients were older (54% and 58% >50 yrs vs 39% for MAC), more likely to have received prior autoHCT (36% and 51% vs 18%), prior radiation and more prior chemotherapy regimens (55 and 70% vs 44% with >3 regimens) than those with MAC. Recipients of RIC and NMC were less likely to have chemotherapy resistant disease (30% and 26% vs. 42% for MAC); and had a longer median interval from diagnosis to alloHCT (median 27 and 36 mo vs. 17 mo). Day 100 engraftment was more frequent in RIC and NMC recipients (99% and 97% with ANC >500/cu.mm vs. 88% for MAC, p <0.001). Acute (43–44%) and chronic GvHD incidence (37–42% at 5 years) was similar across the groups. Outcomes are summarized in Table 1. TRM at day +100 and at 5 years was significantly higher for MAC compared with RIC and NMC groups (See Table 1). Lymphoma relapse/progression at 5 years was significantly lower for MAC vs. RIC and NMC but 5 year PFS and OS at 5-years did not differ significantly. In multivariable analysis, NMC (HR 0.58, p=0.026) and later year of alloHCT (HR 0.49, p<0.001) were associated with lower TRM while Karnofsky status <90 (HR 1.51, p=0.011), chemo-resistant relapse (HR 2.79, p<0.001) and URD (HR 2.32, p<0.001) were associated with higher TRM. Higher incidence of relapse/progression was associated with NMC (HR 2.14, p=0.003), non-receipt of rituximab prior to alloHCT (HR 1.69, p=0.008) and chemo-resistant disease (HR 2.06, p=0.006). Conditioning intensity did not impact OS and PFS. In selected patients with advanced DLBCL, allogeneic HCT can induce long-term PFS irrespective of the intensity of conditioning with a lower incidence of TRM with RIC and NMC regimens. Due to increased toxicity, the use of MAC regimens has been declining in recent years. However, the incidence of RIC/NMC, risk of relapse/progression was concordantly higher in the RIC/NMC recipients so that survival did not differ significantly between conditioning regimens. Further studies are needed to clarify optimal conditioning strategies for advanced DLBCL aiming to further reduce TRM. Table 1: Parameter Intensity of Conditioning (95% CI) p-value MAC RIC NMC TRM @day +100 at 5 yrs 32% (25–39%) 24% (17–31%) 17% (10–26%) 0.029 56% (48–64%) 47% (38–56%) 36% (26–46%) 0.007 Relapse @ 5 yrs 26% (19–33%) 38% (30–46%) 40% (30–50%) 0.031 OS @ 5 yrs 18% (12–25%) 20% (13–29%) 26% (17–36%) 0.365 PFS @ 5 yrs 18% (12–24%) 15% (9–23%) 25% (16–34%) 0.309 Disclosures: Montoto: Genentech: Research Funding; Roche: Honoraria.

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Randomized Trial On GvHD Prophylaxis with or without Anti T Cell Globulin ATG Fresenius (ATG-F) in Allogeneic Hematopoietic Cell Transplantation From Matched Unrelated Donors: Updated Results and Evaluation of the European Group for Blood and Marrow Transplantation (EBMT) Risk Score.

Blood ◽

10.1182/blood.v120.21.3090.3090 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3090-3090

Author(s):

Juergen Finke ◽

Claudia Schmoor ◽

Wolfgang A. Bethge ◽

Hellmut Ottinger ◽

Matthias Stelljes ◽

...

Keyword(s):

Risk Score ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Disease Stage ◽

Trend Test ◽

Donor Age ◽

Blood And Marrow Transplantation ◽

Gvhd Prophylaxis ◽

Explained Variation ◽

Increasing Risk

Abstract Abstract 3090 Background: Previously, in 201 adult patients with allogeneic hematopoietic cell transplantation from matched unrelated donors, we demonstrated that addition of ATG-F to standard cyclosporine, methotrexate GvHD prophylaxis (control) significantly reduces acute and chronic GvHD without negatively affecting non-relapse mortality (NRM), relapse, disease-free survival (DFS) and overall survival (OS) [1,2]. Methods: Now, we present updated results of extended follow-up (median 5.5, Q1 5.0, Q3 6.5 years). Furthermore, we investigated whether the European Group for Blood and Marrow Transplantation (EBMT) risk score (0 to 7 points) based on the sum of points for patient age (20–40y: 1 point, >40y: 2 points), disease stage (intermediate: 1 point, late: 2 points), time interval from diagnosis to transplant (>12m: 1 point), donor type (unrelated: 1 point), and donor-patient sex combination (donor female, patient male: 1 point) [3] was able to predict outcome with respect to OS in our trial. The explained variation R2 of the risk score was calculated by setting the prediction error (Integrated Brier Score) of the score in relation to the prediction error of an overall estimate of OS without dividing the patients into different risk groups. Results: The incidence of extensive chronic GvHD after 5 years was 13.6% in the ATG-F group vs 48.9% in the control group (p<0.0001). The 5-year rates with respect to outcome were: DFS 44.3% vs 37.2% (p=0.67), relapse 35.2% vs 29.9% (p=0.46), relapse mortality 29.7% vs 27.7% (p=0.99), NRM 20.5% vs 32.9% (p=0.15), and OS 49.8% vs 39.1% (p=0.28), ATG-F vs control respectively. Patients' distribution to the EBMT risk score was 1 point 2, 2 points 43, 3 points 59, 4 points 43, 5 points 32, 6 points19, 7 points 1, unknown 2. The trend test for increasing risk with increasing risk score resulted in p=0.006. The risk score is able to separate patients with regard to OS, but in univariate and multivariate analyses of the factors building the score (age, disease stage, time from diagnosis, patient/donor sex) only disease stage showed a significant and relevant effect on OS (hazard ratio: intermediate vs early 1.54 95%-CI [0.92,2.56], late vs early 1.98 [1.30,3.02], trend test p=0.001). Thus, the addition of points to the risk score for factors that do not have a prognostic effect results in a dilution of its prognostic ability. In fact, the explained variation of the factor disease stage alone was higher than that of the risk score (R2=3.8% vs R2=3.4%). The main prognostic factor in our trial besides disease stage was donor age [4]. We therefore analyse the effect of a new risk score based on the sum of points for these two factors: donor age (>40y: 1 point) and disease stage (intermediate: 1 point, late: 2 points). The trend test for increasing risk with increasing score resulted in p<0.0001, and the explained variation was R2=8.1%. Conclusion: After a long-term follow-up of 5.5 years, it could be confirmed that ATG-F GvHD prophylaxis provides a sustained protective effect without compromising relapse and survival. The EBMT risk score is able to separate patients with regard to OS, but in our trial another risk score based on disease stage and donor age can be defined leading to a better prediction of OS. As this score was derived in the same dataset, the assessment of its predictive ability is overoptimistic and it has to be validated in an independent study. Disclosures: Finke: Fresenius Biotech GmbH: Honoraria, Research Funding. Bethge:Fresenius Biotech GmbH: Lecture remuneration Other. Bertz:Fresenius Biotech GmbH: Lecture remuneration Other.

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Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children

Blood ◽

10.1182/blood.v99.6.2002 ◽

2002 ◽

Vol 99 (6) ◽

pp. 2002-2008 ◽

Cited By ~ 92

Author(s):

Ann E. Woolfrey ◽

Claudio Anasetti ◽

Barry Storer ◽

Kristine Doney ◽

Laurie A. Milner ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Chronic Gvhd ◽

Marrow Transplant ◽

Unrelated Donor ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Conditioning Treatment ◽

Unrelated Donors ◽

Total Body

Abstract Acute lymphoblastic leukemia (ALL) is the most common indication for transplantation of marrow from unrelated donors in children. We analyzed results of this procedure in children with ALL treated according to a standard protocol to determine risk factors for outcome. From January 1987 to 1999, 88 consecutively seen patients with ALL who were younger than 18 years received a marrow transplant from an HLA-matched (n = 56) or partly matched (n = 32) unrelated donor during first complete remission (CR1; n = 10), second remission (CR2; n = 34), third remission (CR3; n = 10), or relapse (n = 34). Patients received cyclophosphamide and fractionated total-body irradiation as conditioning treatment and were given methotrexate and cyclosporine for graft-versus-host disease (GVHD) prophylaxis. Three-year rates of leukemia-free survival (LFS) according to phase of disease were 70% for CR1, 46% for CR2, 20% for CR3, and 9% for relapse (P < .0001). Three-year cumulative relapse rates were 10%, 33%, 20%, and 50%, respectively, and 3-year cumulative rates of death not due to relapse were 20%, 22%, 60%, and 41%, respectively, for patients with CR1, CR2, CR3, and relapse. Grades III to IV acute GVHD occurred in 43% of patients given HLA-matched transplants and in 59% given partly matched transplants (P = .10); clinical extensive chronic GVHD occurred in 32% and 38%, respectively (P = .23). LFS rates were lower in patients with advanced disease (P < .0001), age 10 years or older (P = .002), or short duration of CR1 (P = .007). Thus, in addition to phase of disease, age and duration of CR1 were predictors of outcome after unrelated-donor transplantation for treatment of ALL in children. Outcome was particularly favorable in younger patients with early phases of the disease.

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Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) for Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (ALL).

Blood ◽

10.1182/blood.v114.22.3377.3377 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3377-3377

Author(s):

Michael Burke ◽

Barb Trotz ◽

Qing Cao ◽

Brenda Weigel ◽

Ashish Kumar ◽

...

Keyword(s):

Hematopoietic Cell Transplantation ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Disease Free Survival ◽

Unrelated Donor ◽

University Of Minnesota ◽

Transplant Outcomes ◽

Significant Difference ◽

The Impact

Abstract Abstract 3377 Poster Board III-265 Introduction: Allo-HCT with best available donor for children with Philadelphia positive (Ph+) ALL has previously been considered standard practice. Since the introduction of imatinib into the treatment of this disease, the role of allo-HCT is more uncertain. Patients and Methods: We investigated the impact of remission status, graft source, and imatinib use on transplant outcomes for thirty-seven children with Ph+ ALL who received an allo-HCT at the University of Minnesota between 1990 and 2006. The median age at HCT was 7.47 (range; 1.4 -16.4) years. Thirteen patients received imatinib therapy pre and/or post-HCT (imatinib group) and 24 patients, received either no imatinib (n=23) or only after post-HCT relapse (n=1) (non-imatinib group). Results: There was no difference in disease-free survival (DFS) or relapse between the imatinib and non-imatinib groups at 3 years (62% / 15% vs. 53% / 26%; p=0.99; 0.81, respectively). There was no significant difference in transplant outcomes between matched related donor or unrelated donor (umbilical cord blood or matched unrelated marrow) recipients whereas patients receiving allo-HCT in first remission (CR1) had superior DFS and less relapse compared to patients transplanted in ≥CR2 (71% / 16% vs. 29% / 36%; p=0.01; p=0.05). Conclusions: Based on this retrospective analysis at a single institution, the use of imatinib either pre and/or post-transplant does not appear to significantly impact outcomes for children with Ph+ ALL and allo-HCT with the best available donor should be encouraged in CR1. Disclosures: No relevant conflicts of interest to declare.

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PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL

Blood Advances ◽

10.1182/bloodadvances.2018027748 ◽

2019 ◽

Vol 3 (3) ◽

pp. 360-369 ◽

Cited By ~ 27

Author(s):

Peter Dreger ◽

Anna Sureda ◽

Kwang Woo Ahn ◽

Mary Eapen ◽

Carlos Litovich ◽

...

Keyword(s):

Hematopoietic Cell Transplantation ◽

Performance Status ◽

Chronic Gvhd ◽

B Cell Lymphoma ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Gvhd Prophylaxis ◽

Matched Donor ◽

Reduced Intensity

Abstract This study retrospectively compared long-term outcomes of nonmyeloablative/reduced intensity conditioning (NMC/RIC) allogeneic hematopoietic cell transplantation (allo-HCT) from a haploidentical family donor (haplo-HCT) using posttransplant cyclophosphamide (PTCy) with those of matched sibling donor (MSD) and matched unrelated donor (MUD) with or without T-cell depletion (TCD+/TCD−) in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Adult patients with DLBCL who had undergone their first NMC/RIC allo-HCT between 2008 and 2015 were included. Recipients of haplo-HCT were limited to those receiving graft-versus-host disease (GVHD) prophylaxis with PTCy. GVHD prophylaxis in MSD was limited to calcineurin inhibitor (CNI)–based approaches without in vivo TCD, while MUD recipients received CNI-based prophylaxis with or without TCD. Outcome analyses for overall survival (OS) and progression-free survival (PFS), nonrelapse mortality (NRM), and disease relapse/progression were calculated. A total of 1438 patients (haplo, 132; MSD, 525; MUD TCD+, 403; and MUD TCD−, 378) were included. Patients with haplo donors were significantly older, had a better performance status and had more frequently received total body irradiation-based conditioning regimens and bone marrow grafts than MSD and MUD TCD+ or TCD−. 3-year OS, PFS, NRM and relapse/progression incidence after haplo-HCT was 46%, 38%, 22%, and 41%, respectively, and not significantly different from outcomes of matched donor transplants on multivariate analyses. Haplo-HCT was associated with a lower cumulative incidence of chronic GVHD compared with MSD, MUD TCD+/TCD−. NMC/RIC haplo-HCT with PTCy seems to be a valuable alternative for patients with DLBCL considered for allo-HCT but lacking a matched donor.

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Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide

Blood Advances ◽

10.1182/bloodadvances.2020002945 ◽

2020 ◽

Vol 4 (20) ◽

pp. 5078-5088

Author(s):

Jonathan A. Webster ◽

Leo Luznik ◽

Hua-Ling Tsai ◽

Philip H. Imus ◽

Amy E. DeZern ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Kinase Inhibitors ◽

De Novo ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Philadelphia Chromosome ◽

Allogeneic Transplantation ◽

Donor Type

Abstract Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.

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