Treosulfan-Based Reduced Toxicity Regimen Prior to Allogeneic Hematopoietic Cell Transplantation in Non-Malignant Disorders.

Abstract Graft rejection is a major cause of failure after alloHCT in non-malignant hematopoietic disorders including severe aplastic anemia (SAA) and paroxysmal nocturnal hemaoglobinuria (PNH). For patients with high risk of this complication we introduced a novel conditioning regimens, based on treosulfan - an alkylating agent possesing both immuno- and myeloablative properties. Between 2003–2006, eleven patients (age: 23(14–35) years) with SAA (n=6) or PNH (n=5) were treated in a single institution with alloHSCT from either HLA-identical sibling (n=3) or an unrelated volunteer (n=8). For patients with SAA conditioning regimen consisted of treosulfan 10 g/m2/d on days -7, -6, cyclophosphamide 40 mg/kg/d on d. -5, -4, -3, -2, and anti-thymocyte globulin (ATG) 2 mg/kg/d on d. -3, -2, -1. PNH patients received treosulfan 14 g/m2/d on days -6, -5, -4, fludarabine 30 g/m2 on d. -6, -5, -4, -3, -2, and (ATG) 2 mg/kg/d on d. -3, -2, -1. Bone marrow was used as a source of stem cells in 5 patients and peripheral blood - in 6 cases. Graft-vs.-host disease (GVHD) prophylaxis consisted of Cyclosporin A and short-course Methotrexate. All patients engrafted with the median time to neutrophil >0.5×10e9/L and platelet >50×10e9/L recovery of 16 (14–22) days and 21.5 (12–29) days, respectively. Complete donor chimerism was achieved on day +30 in all cases. None of the patients developed grade III-IV acute GVHD, two patients experienced grade II acute GVHD. At one year the cumulative incidence of extensive chronic GVHD equaled 22%. No severe organ toxicity was observed. With the median follow-up of 19 months, the disease-free survival at 2.5 years was 91%. A single PNH patient died of haemorrhagic cystitis. We conclude that treosulfan-based preparative regimens are well-tolerated and allow stable engraftment in SAA and PNH patients. The use of treosulfan allows intensification of the conditioning without providing an additional non-hematological toxicity.

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Fludarabine and Busulfan (FluBuP Regimen) as Myeloablative Conditioning Regimen for Allogeneic PBSCT in 71 Leukemic Patients (A Unicenteric Study).

Blood ◽

10.1182/blood.v104.11.5156.5156 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5156-5156

Author(s):

Masoud Iravani ◽

Maryam Tavakoli ◽

Ahmad Reza Shamshiri ◽

Mohammad Reza Evazi ◽

Asadollah Mousavi ◽

...

Keyword(s):

Acute Gvhd ◽

Hemorrhagic Cystitis ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Cmv Infection ◽

Platelet Recovery ◽

Low Incidence ◽

Reduced Toxicity

Abstract Following 3 other centers in USA, Canada and Germany, we are evaluating fludarabine (40 mg/m2 on days −6 to −2) and busulfan (4 mg/kg/day on days −5 to −2) as a new conditioning regimen for allogeneic peripheral blood stem cell transplantation in leukemic patients with matched related donors. Seventy one patients were enrolled, 18 with high and 53 with standard risk (18 ALL, 35 AML, 16 CML and 2 MDS; F=29 M=42). The median patient age was 23.7 years(range, 2.4– 46.7). Cyclosporine was used as a prophylactic agent for GVHD (3mg/kg IV till +4, 10 mg/kg oral from day +5). The median follow-up was 269 days (range, 50–459 days). 91.5% and 15.5% developed mucositis and hepatic toxicity respectively which resolved with conservative therapy. There was no cardiac toxicity (except one patient with mild pericardial effusion and another with tachycardia). The median of highest serum creatinin level during hospitalization were 1.6 mg/dl (range, 0.8–3.7; 24.3% with Cr>2) and serum cyclosporine level, at the same time, was 246 ng/ml (range, 9–814). 7% experienced hemorrhagic cystitis (infection was ruled out) and 36.6% experienced moderate to severe headache. 38% and 14.1% of the patients showed grade 1, 2 and grade 3 acute GVHD respectively. Grade 4 acute GVHD was found in one patient. 50% and 6% showed limited and extensive chronic GVHD. 27% of patients became CMV+ (min +17, max +69). The median time for neutrophil and platelet recovery were 10 (min 0, max +26) and 12 (min 0, max +30) days. In day +38, 86.7% of the patients had 90% or more, mononuclear chimerism (with STR-PCR technique; median, 97%; range, 25–100). 5 ALL and 8 AML patients relapsed (18.3% of all patients) and 6 (8.45%) died after relapse. Nonrelapse mortality was 13% (9 patients; acute GVHD grade IV=1, CMV infection and GVHD=2, CMV infection=2, pneumonia=2, infection=2). With a median follow up of 9 months (range, 1.6–15.3 months), the probability of overall survival and disease free survival were 79.68% and 81.26% respectively. It could be beneficial to use fludarabine versus cyclophosphamide in standard conditioning regimen for leukemic patients because of reduced toxicity, low incidence of acute GVHD and facilitated donor engraftment.

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One Antigen HLA-Mismatched Related and 8/8 Allele Matched Unrelated Donors Are Associated with Similar Survival after Hematopoietic Cell Transplantation for Acute Leukemia.

Blood ◽

10.1182/blood.v112.11.965.965 ◽

2008 ◽

Vol 112 (11) ◽

pp. 965-965

Author(s):

David Valcarcel ◽

Fangyu Kan ◽

Tao Wang ◽

Stephanie J. Lee ◽

Stephen R Spellman ◽

...

Keyword(s):

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Unrelated Donor ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Unrelated Donors ◽

Related Donor ◽

Disease Free

Abstract Patients in need of an allogenetic hematopoietic cell transplant but who lack an HLA genotypically identical sibling donor, are faced with the decision to consider a single HLA antigen mismatched related donor, or a search for a suitable 8/8 matched unrelated donor. We compared the outcomes of adult patients (≥18 years old) receiving a transplant for the treatment of AML or ALL in first or second remission from either a one-antigen mismatched related donor (MMRD group, N=89) reported to the CIBMTR or an 8/8 HLA-A, B, C and DRB1 allele matched unrelated donor (UD group, N=700) facilitated by the NMDP between 1995–2005. MMRD group was typed by serological or DNA-based methods for HLA-A, -B and –DR with all results verified by lab report review. The UD group was retrospectively typed for HLA-A, B, C and DRB1 by high resolution typing methods. Most received myeloablative conditioning regimens (77%), calcineurin inhibitor-based GVHD prophylaxis (100%) and T cell replete grafts (100%). 13% received ATG with the conditioning regimen. Median follow-up was 54 and 38 months in the MMRD and UD groups, respectively. The MMRD group was younger (median age 35 vs 43, p=0.002), had more ALL patients with low-risk cytogenetics (43% vs 18%, p=0.005), had older donors (median age: 38 vs 34, p=0.047), were more likely to receive methotrexate for GVHD prophylaxis (89% vs 77%, p=0.014) and were more likely to be transplanted prior to 2001 (62% vs 24%; p<0.001). There were no differences in patient or donor gender, diagnosis, disease-status, cytogenetic-risk of AML, time from diagnosis to transplant, stem cell source, conditioning regimen, use of ATG and Karnofsky index. Univariate comparisons (MMRD vs. UD) showed: 3-year OS (42% vs 44%, p=0.647), 3-year DFS (41% vs 41%, p=0.931), 3-year TRM (39% vs 31%, p=0.136), 3-year incidence of relapse (20% vs 28%, p=0.094), grade III–IV acute GVHD by 100 days (22% vs. 15%, p=0.147), chronic GVHD by 1 year (35% vs 47%, p=0.029). All multivariate analyses were adjusted for patient and transplant characteristics and are shown in the table below. In summary, transplants utilizing one-antigen mismatched related and 8/8 allele-matched unrelated donors did not significantly differ in overall survival or disease free survival, but chronic GVHD was more frequent after UD transplantation. Outcome RR (MMRD vs. UD) 95% CI p-value Survival 0.99 0.73–1.34 0.94 Disease-free survival 1.06 0.80–1.41 0.69 Treatment related mortality 1.14 0.77–1.69 0.52 Relapse 0.81 0.50–1.30 0.38 Acute GVHD III–IV 1.53 0.91–2.57 0.11 Chronic GVHD 0.58 0.39–0.85 0.006

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Incidence, Risk Factors and Outcomes of Sclerotic Chronic Graft-Versus-Host Disease (GVHD) Phenotype After Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood.v118.21.322.322 ◽

2011 ◽

Vol 118 (21) ◽

pp. 322-322

Author(s):

Yoshihiro Inamoto ◽

Barry Storer ◽

Effie W. Petersdorf ◽

Paul A. Carpenter ◽

Stephanie J. Lee ◽

...

Keyword(s):

Risk Factors ◽

Malignant Disease ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Factors Associated ◽

Increased Risk ◽

Unrelated Donors ◽

Recurrent Malignancy

Abstract Abstract 322 Background: A sclerotic GVHD phenotype represents one of the most severe late complications of allogeneic hematopoietic cell transplantation (HCT), sharing some clinical similarities with systemic sclerosis. The incidence and risk factors of sclerotic chronic GVHD and its association with major transplant outcomes are not well established. Patients and methods: We analyzed 986 consecutive patients who received systemic therapy for chronic GVHD after a first allogeneic HCT performed between 2000 – 2008 in Seattle for malignant and nonmalignant diseases. Chronic GVHD was diagnosed by the NIH consensus criteria. Sclerotic GVHD was defined when manifestations of cutaneous sclerosis, fasciitis or joint contracture were first documented in the medical record. Multivariate Cox regression analyses accounted for patient and donor age per decade, donor type, HLA matching, ABO matching, diagnosis and disease risk, stem cell source, patient gender, intensity of conditioning regimen, use of total body irradiation (TBI) or rabbit antithymocyte globulin in the conditioning regimen, and GVHD prophylaxis. Risk factors considered at the onset of chronic GVHD were prior acute GVHD, prior severe (stage 3 and 4) skin acute GVHD, eosinophilia, thrombocytopenia, progressive onset, extent of skin involvement, and bronchiolitis obliterans. Overall mortality (OM), nonrelapse mortality (NRM; malignant disease only) and recurrent malignancy (malignant disease only) were compared between patients with and without sclerotic features using time-dependent Cox models. Results: Of the 986 patients, median age was 47 (0–78) years, 776 (79%) were Caucasian, 950 (96%) had malignant diseases, 407 (41%) had HLA-matched related donors, 356 (36%) had HLA-matched unrelated donors, and 223 (23%) had HLA-mismatched related or unrelated donors. The median time from HCT to chronic GVHD was 5.3 (2.5–46) months; 73 patients (7%) presented with sclerotic features at initial diagnosis and 142 patients (14%) developed sclerosis after the onset of chronic GVHD. The cumulative incidence of sclerotic GVHD was 20% (95%CI, 18–23) at 36 months after onset of chronic GVHD, and median onset of sclerosis was 7.9 months after onset of chronic GVHD (Figure). In multivariate models (Table), factors associated with an increased risk of sclerotic GVHD were mobilized blood cell graft, female recipient, TBI >450cGy, and prior severe skin acute GVHD. Factors associated with a decreased risk of sclerotic GVHD were HLA-mismatched donors and ABO major mismatch. Risks of OM, NRM and recurrent malignancy in patients with sclerotic features did not differ statistically from patients without sclerotic features (hazard ratio (HR) 0.97, 95% CI 0.7–1.3, p=0.83; HR 0.94, 95% CI 0.6–1.4, p=0.78; HR 0.73, 95% CI 0.5–1.2, p=0.17, respectively). Conclusion: Sclerotic GVHD is an underestimated phenotype of chronic GVHD. Female predominance in sclerotic chronic GVHD is similar to that in systemic sclerosis. Risks of major transplant outcomes do not differ statistically between patients with and without sclerotic chronic GVHD phenotype. Mechanisms that account for the decreased risk of sclerosis associated with HLA and ABO mismatching and for the increased risk associated with prior severe skin acute GVHD warrant future investigation. Disclosures: No relevant conflicts of interest to declare.

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Adult Matched Sibling Blood Cell Transplants (BCT) after Myeloablative Conditioning Incorporating Daily Intravenous (IV) Busulfan (BU) and Low-Dose Antithymocyte Globulin (ATG): Outcomes with Particular Respect to Transplant-Related Mortality (TRM) in 140 Patients.

Blood ◽

10.1182/blood.v104.11.2313.2313 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2313-2313

Author(s):

James A. Russell ◽

Ahsan M. Chaudhy ◽

Oluyeme Jeje ◽

Diana Quinlan ◽

Douglas Stewart ◽

...

Keyword(s):

Acute Leukemia ◽

Low Dose ◽

Acute Gvhd ◽

Myocardial Infarct ◽

Chronic Gvhd ◽

Disease Free Survival ◽

Increase Risk ◽

Cell Transplants ◽

One Year ◽

Related Mortality

Abstract Intravenous BU allows more predictable exposure and is more convenient to administer once daily than the conventional four times daily regimen. Low-dose pretransplant ATG may reduce morbidity and mortality from graft-versus-host disease (GVHD). We have investigated a myeloablative regimen incorporating these agents in 140 adults aged 18–65 (median 47) receiving a first MRD SCT between 05/99 and 01/04. Conditioning comprised fludarabine (FLU) 50mg/m2on days −6 to −2 and IV BU (Busulfex, ESP Pharma) 3.2 mg/kg daily days −5 to −2 inclusive (FLUBUP) in 116 patients (pts) with additional TBI 200cGy x 2 in 24 (14 ALL, 8AML, 2 biphenotypic). Forty-three pts had standard-risk (SR) acute leukemia in CR1 (35 AML, 8 ALL), and 23 had active acute leukemia (HA) (18 AML±MDS, 3 ALL, 2 biphenotypic). A third group of 74 other (OTH) pts comprised 2 AML CR2, 2 ALL CR2, 2 CML (1 AP, 1CP2), 13 MDS, 11 MM, 24 NHL, 6 HD (2 with CLL), 8 CLL, 5 other. All pts were given cyclosporine A, “short course” methotrexate with folinic acid and Thymoglobulin (Genzyme) (ATG) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing D0. Followup of survivors is 6–61 months, median 26. Incidence of acute GVHD (aGVHD) grade II–IV was 19±4%, grade III–IV 6±2% and chronic GVHD (cGVHD) 66±5% (at 2 years). Projected TRM is 4±2% at 100 days, 10±3% at 1 year and 14±4% at 5 years. For acute leukemia pts projected TRM at one year is 5±5% vs 12±5% with (n = 24) and without (n = 47) TBI respectively (p = ns). Four non-relapse deaths occurred before day 100 one each from myocardial infarct (MI), acute GVHD, candidiasis and VOD. Ten deaths between days 102–569 were related to aGVHD in one and complications in pts with cGVHD in 9 (occurring in 1 pt after 2nd BCT for graft failure) including 1 VZV, 3 other infection, 1 PE, 1 MI. Of 11 follicular NHL pts 3 died of cGVHD and its complications after 1st BCT compared with 5 of 129 others (p = 0.02). Twelve of the transplant-related deaths were in 76 pts ≥ 46 years old compared with 2 in 64 younger pts (TRM = 23±6%, vs 4±3%, p = 0.01). Of 55 relapsed pts 17 are alive, 8 of these are in remission after more treatment and/or onset of GVHD. Projected 5-year disease-free survival and survival respectively is 46±5% and 57±5% for all pts, 62±8% and 76±7% for SR, 51±7% and 59±9% for OTH, and 9±6% and 16±8% for HA. This study indicates that: 1) regimen related mortality is low in MRD BCT recipients given this regimen 2) cGVHD is the main cause of TRM 3) pts with follicular NHL seem to be comparatively susceptible to death related to cGVHD 4) addition of 400cGy TBI does not increase risk of TRM and 5) older age remains a risk factor for TRM.

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Risk Factors for the Development of Acute and National Institute of Health (NIH) Chronic Graft-Versus-Host Disease (GVHD).

Blood ◽

10.1182/blood.v114.22.345.345 ◽

2009 ◽

Vol 114 (22) ◽

pp. 345-345

Author(s):

Mary E.D. Flowers ◽

Barry E. Storer ◽

Stephanie J. Lee ◽

Paulo Vidal Campregher ◽

Afonso Celso Vigorito ◽

...

Keyword(s):

Risk Factors ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Study Cohort ◽

Consensus Development ◽

Donor Age ◽

Multivariate Models ◽

Unrelated Donors

Abstract Abstract 345 Background: In 2005, an NIH consensus development conference proposed new categories for manifestations of acute and chronic GVHD after allogeneic hematopoietic cell transplantation (HCT). A question not addressed by this NIH consensus development project was whether acute and chronic GVHD result from different pathogenic pathways or from a single pathogenic pathway. Purpose: To explore this question, we analyzed risk factors for grade 2-4 acute GVHD and for chronic GVHD according to NIH consensus criteria after allogeneic hematopoietic cell transplantation (HCT). Identification of different risk factors would support the hypothesis that acute and chronic GVHD result from different pathogenic pathways. Patients and Methods: The study cohort included 2941 recipients of a first related or unrelated allogeneic HCT with bone marrow or growth factor-mobilized blood cells after a myeloablative conditioning regimen for treatment of hematological malignancies between 07/01/1992 and 2005 in Seattle. Endpoints were grade 2-4 acute GVHD that was diagnosed at any time before or after day 100 and chronic GVHD that was diagnosed according to NIH criteria and required systemic treatment. Risks factors considered in multivariate Cox regression analyses were patient and donor age per decade, donor types, stem cell source, recipient/donor gender combination, use of rabbit antithymocyte globulin (ATG) in the conditioning regimen, prior infection of patient or donor with cytomegalovirus, chronic myeloid leukemia (CML) and myeloid malignancy. The multivariate models were also adjusted for year of transplant. The analysis was carried out as of 07/23/2009. Results: The median age of the study cohort was 40 (0.6-71) years. Of the 2941 patients, 1927 (66%) received bone marrow, 1284 (44%) had HLA-matched related donors, 957 (33%) had HLA-matched unrelated donors, and 700 (24%) had HLA-mismatched related or unrelated donors. The cumulative incidence of grade 2-4 acute GVHD was 80% at 6 months, and the cumulative incidence of NIH chronic GVHD at 2 years was 34%. 461 (16%) patients did not develop either grade 2-4 acute GVHD or NIH chronic GVHD. 922 patients (31.3%) had both grade 2-4 acute GVHD and NIH chronic GVHD. Among these 922 patients, 840 (91%) had acute GVHD before NIH chronic GVHD, 77 (8%) developed acute and NIH chronic GVHD at the same time, and 5 (0.5%) had acute GVHD after NIH chronic GVHD. The median time from HCT to onset of grade 2-4 acute GVHD was 20 days (3-711) days and the median time from HCT to onset of NIH chronic GVHD was 162 (66-2805) days. The two diseases had closely similar profiles of risk factors. In multivariate models, most factors showed concordant association with an increased (unrelated, HLA-mismatched donors, male recipients with female donors, mobilized blood cell graft, donor age) or decreased (ATG and CML) risk of acute GVHD and NIH chronic GVHD (figure), although the use of mobilized blood cells had a stronger association with chronic GVHD than with acute GVHD. Only one risk factor showed discordant association with grade 2-4 acute GVHD and NIH chronic GVHD. Older patient age was associated with a slightly increased risk of NIH chronic GVHD (HR 1.12 per decade; 95% CI 1.06-1.18; p < 0.0001) but with a slightly lower risk of acute GVHD (HR 0.96 per decade; 95% CI 0.93-0.99, p = 0.02). Conclusion: The close similarity of risk factor profiles for acute and chronic GVHD can not rule out the hypothesis that these diseases result from different pathogenic pathways. Disclosures: No relevant conflicts of interest to declare.

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Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation With Nonmyeloablative Conditioning

Journal of Clinical Oncology ◽

10.1200/jco.2005.08.136 ◽

2005 ◽

Vol 23 (9) ◽

pp. 1993-2003 ◽

Cited By ~ 254

Author(s):

Frédéric Baron ◽

Michael B. Maris ◽

Brenda M. Sandmaier ◽

Barry E. Storer ◽

Mohamed Sorror ◽

...

Keyword(s):

Multivariate Analysis ◽

Cell Transplantation ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematopoietic Cell ◽

High Dose ◽

Increased Risk ◽

Risk Of Relapse

Purpose We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) with or without fludarabine (30 mg/m2/d for 3 days) for related and unrelated hematopoietic cell transplantation (HCT) in patients with hematologic malignancies who were not candidates for conventional HCT because of age, medical comorbidities, or preceding high-dose HCT. This approach relied on graft-versus-tumor (GVT) effects for control of malignancy. Patients and Methods We analyzed GVT effects in 322 patients given grafts from HLA-matched related (n = 192) or unrelated donors (n = 130). Results Of the 221 patients with measurable disease at HCT, 126 (57%) achieved complete (n = 98) or partial (n = 28) remissions. In multivariate analysis, there was a higher probability trend of achieving complete remissions in patients with chronic extensive graft-versus-host disease (GVHD; P = .07). One hundred eight patients (34%) relapsed or progressed. In multivariate analysis, achievement of full donor chimerism was associated with a decreased risk of relapse or progression (P = .002). Grade 2 to 4 acute GVHD had no significant impact on the risk of relapse or progression but was associated with increased risk of nonrelapse mortality and decreased probability of progression-free survival (PFS). Conversely, extensive chronic GVHD was associated with decreased risk of relapse or progression (P = .006) and increased probability of PFS (P = .003). Conclusion New approaches aimed at reducing the incidence of grade 2 to 4 acute GVHD might improve survival after allogeneic HCT after nonmyeloablative conditioning.

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Risk Factors for Adverse Outcomes Following Haploidentical Hematopoietic Cell Transplantation with Posttransplant Cyclophosphamide: A Two-Center Analysis

Blood ◽

10.1182/blood-2021-153961 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4889-4889

Author(s):

Viviane De Jesus Torres Lima ◽

Anderson Felipe Felipe Da Silva ◽

Andreza Alice Feitosa Ribeiro ◽

Mariana Nassif Kerbauy ◽

Lucila Kerbauy ◽

...

Keyword(s):

Risk Factors ◽

Risk Factor ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Disease Risk ◽

Risk Index ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Adverse Outcomes ◽

Very High

Abstract Introduction Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for several malignant hematologic diseases. As only 30% of patients will have a matched related donor, alternative donors play a significant role in HCT. Luznik et al pioneered the use of posttransplant cyclophosphamide (PTCy) based GVHD prophylaxis in haploidentical transplantation (haplo-HCT), which greatly expanded the pool of donors and nearly revolutionized the field. Despite the increasing use of haplo-HCT with PTCy, some questions remain, namely the selection of the best donor, graft source and conditioning regimen, and risk factors for adverse outcomes. Methods Retrospective study conducted at two Brazilian centers. All patients with hematologic malignancies who underwent first HCT between 2010 and 2021, haploidentical with posttransplant cyclophosphamide, were included. The objective was to identify risk factors for adverse outcomes following haploidentical HCT with PTCy. Independent variables are detailed in table 1. Acute GVHD was graded according to the MAGIC criteria and chronic GVHD was diagnosed according to the NIH consensus criteria. Survival and cumulative incidence curves were built with the Kaplan-Meier and Gray methods, and compared with the logrank and Gray tests, respectively. Multivariate analyses were carried out with Cox models. GVHD, as an independent variable, was included as a time-dependent covariate. Results A total of 103 patients were included (table 1). In brief, median age was 39 y/o and most patients were male (58%); 71 patients had low or intermediate disease risk index, while 29 had high or very high-risk disease. Bone marrow was the preferred stem-cell (72%, followed by peripheral blood stem-cells - 28%) and reduced-intensity, the most frequent conditioning regimen (43%). Median follow-up for the whole cohort was 2.6 years. Overall survival at 2 years was 51.7% (95CI 42.4-63.0%, figure 1). Multivariable analyses are in table 2. Risk factors for death were age at transplant (HR = 1.03 for each year; 95CI 1.01-1.05; p = 0.002), high or very high disease risk index (HR = 2.73; 95CI 1.52-4.90; p = 0.0008), and compared with low or intermediate, and mother as the donor (HR = 3.50; 95CI 1.44-8.47; p = 0.006). Progression-free survival at 2 years was 45.8% (95CI 36.6-57.2%). In multivariate analysis (table 2), progression-free survival was significantly poorer for older patients (HR = 1.02; 95CI 1.01-1.04; p = 0.009), high or very high disease risk index (HR = 2.29; 95CI 1.30-4.04; p = 0.004), compared with low or intermediate, and mother as a donor (HR = 3.15; 95CI 1.37-7.22; p = 0.007; figure 2). Two-year relapse rate was 22.2% (95CI 15.2-32.5%). Risk factors for relapse (table 2) were high or very high disease risk index (HR = 3.55; 95CI 1.44-8.74; p = 0.006), compared with low or intermediate, and mother as the donor (HR = 2.85; 95CI 1.12-7.25; p = 0.007). Two-year non-relapse mortality was 32.0% (23.9-42.9%). The only risk factor we found was age at transplantation (HR = 1.03 for each year; 95CI 1.01-1.05; p = 0.02; table 2). We found no effect of GVHD, acute or chronic, on relapse, nor on non-relapse mortality. Rates of grades II-IV and III-IV acute GVHD and 2y-chronic GVHD were 30.4% (95CI 22.7-40.8%), 6.9% (95CI 3.4-14.1%) and 19.8% (95CI 13.2-29.7%), respectively. The only risk factor (table 2) identified for grades II-IV acute GVHD was tacrolimus (HR = 0.36; 95CI 0.14-0.95; p = 0.04) compared with cyclosporine. We have not carried out multivariate analysis for grades III-IV acute GVHD due to the low number of events (only 7). In multivariable analysis (table 2), peripheral blood graft was a risk factor for chronic GVHD (HR = 3.72; 95CI 1.53-9.01; p = 0.004; figure 3), compared with bone marrow, while tacrolimus was protective (HR = 0.27; 95CI 0.11-0.68; p = 0.005), compared with cyclosporine. Conclusion Our results show that mother as the donor was an important risk factor for poorer OS, PFS and relapse, and mothers might not the best choice of donor. Tacrolimus was protective for both grades II-IV aGVHD and for cGVHD, suggesting that tacrolimus may be more effective than cyclosporine in preventing GVHD. PBSC was a risk factor for cGVHD without any impact on relapse, and this result does not support the systematic use of PBSC in detriment of BM. As expected, age at transplant negatively impacted OS, PFS and NRM as well as high/very high DRI led to poorer OS, PFS and relapse. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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HLA-Identical Sibling-Matched, CD34+ Selected, T Cell Depleted Peripheral Blood Stem Cells Following Myeloablative Conditioning for First or Second Remission Acute Myeloid Leukemia (AML): Results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303.

Blood ◽

10.1182/blood.v114.22.655.655 ◽

2009 ◽

Vol 114 (22) ◽

pp. 655-655 ◽

Cited By ~ 1

Author(s):

Steven M. Devine ◽

Robert J Soiffer ◽

Marcelo C. Pasquini ◽

Shelly Carter ◽

Parameswaran N Hari ◽

...

Keyword(s):

T Cell ◽

Hematopoietic Cell Transplantation ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Unrelated Donor ◽

Post Transplant ◽

Gvhd Prophylaxis

Abstract Abstract 655 Allogeneic hematopoietic cell transplantation (HCT) is the most effective means to prevent relapse in patients (pts) with AML in complete remission (CR). However, quality of life and overall survival (OS) are often affected by both acute and chronic graft versus host disease (GVHD). GVHD is most effectively prevented by ex vivo T cell depletion (TCD) of the allograft, but has been limited in its use by logistical difficulties, lack of an FDA-approved method, and concerns regarding potential risk of graft rejection, post transplant infections, and leukemic relapse. Most reported TCD studies represent single centers, multiple disease types and processing methods with varying degrees of TCD, all of which affect outcome. Therefore we designed a trial using a single processing method providing extensive TCD that did not require post transplant GVHD prophylaxis involving adult pts with AML in first or second CR. We hypothesized that the undesired side effects of TCD HCT would be reduced if combined with a conditioning regimen that was highly immunosuppressive and anti-leukemic. The primary objective was to achieve a disease-free survival (DFS) rate at 6 months (mos) post transplant that exceeded 75%. Secondary objectives included assessments of engraftment, transplant related mortality (TRM), GVHD, relapse, and performance of a single TCD method (CD34+ cell selection using the Miltenyi CliniMACS device) at participating centers. From 10/2005 to 12/2008, 47 pts were enrolled and 44 transplanted at 8 different centers. Median age was 48.5 years (range 21-59) with 28 female and 16 male pts. Of 37 AML CR1 pts, 49% had an unfavorable cytogenetic or molecular risk profile. The conditioning regimen consisted of hyperfractionated total body irradiation (1375cGy in 11 fractions) with partial lung shielding, thiotepa (10mg/kg), cyclophosphamide (120mg/kg), and rabbit antithymocyte globulin (2.5mg/kg). The donors, all HLA-identical siblings, were given G-CSF for mobilization and scheduled to undergo at least 2 leukapheresis procedures to ensure a graft with a high CD34+ cell content. All allografts were CD34-enriched and were targeted to contain ≥ 5×10e6 CD34+ cells/kg and < 1.0×10e5 CD3+ cells/kg. The median CD34+ and CD3+ doses achieved were 8.1 × 10e6/kg (range 2.4-46.2) and 0.07 × 10e5/kg (range 0.01-0.85), respectively. The majority (81%) of pts received the targeted CD34+ cell dose and no pt received > 1.0×10e5 CD3+ cells/kg. No pharmacological GVHD prophylaxis was given post transplant. There were no significant toxicities related to infusion of the CD34 enriched allografts. The most common grade 3-5 regimen-related toxicities included grades 3 or 4 mucositis (39%) and grades 3-5 pulmonary abnormalities (11%). Only 1 pt experienced hepatic veno-occlusive disease. All pts engrafted rapidly with a median time to neutrophil recovery (ANC > 500/ul) of 11 days (range 9-19). There was 1 secondary graft failure. The assessed outcomes are shown below.Estimate (95% Confidence Interval)Outcome100 Days6 Months12 MonthsAcute GVHD II-IV20.5% (8.7 – 23.3%)Acute GVHD III-IV4.5% (0 – 10.6%)Chronic GVHD17.7% (5.8-29.6%)Extensive Chronic GVHD7.6% (0-15.7%)TRM17.8% (5.8-29.8%)Overall Relapse18.2% (5.9-30.5%)Relapse 1st CR9.6% (0- 19.8%%)Relapse 2nd CR64.3% (27.5-100%)DFS81.3% (66.1-90.2%)64.0% (46.5-77.1%)DFS 1st CR89.2% (73.7-95.8%)72.1% (53.0-84.6%)OS74.3% (57.3-85.4%) The absolute peripheral CD4+ cell count remained on average below 200/ul until day +365. Donor cell chimerism increased in the CD3+ cell compartment through day +365. There were 14 deaths. The most common causes of death were relapse (N=5) and pulmonary toxicity (N=4). The median follow-up of survivors is 489 days (range 96-776). There was no difference in OS or DFS for pts above or below the median age of 48.5 years. We conclude that TCD HCT following myeloablative chemoradiotherapy can be performed in a multi-center setting using a single TCD method without additional post transplant prophylaxis with excellent DFS and OS, consistent engraftment, low TRM, and low incidence of relapse even in pts with unfavorable risk AML in CR1. The low incidences of acute and chronic GVHD in the absence of post transplant prophylaxis were particularly encouraging. A follow-up study of TCD HCT in AML recipients of unrelated donor allografts is being planned by the BMT CTN Disclosures: No relevant conflicts of interest to declare.

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Post-Transplantation Cyclophosphamide for Gvhd Prophylaxis in Related and Unrelated Allogeneic Hematopoietic Cell Transplantation: Study from the SFGM-TC Registry

Blood ◽

10.1182/blood-2021-151989 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2883-2883

Author(s):

Mauricette Michallet ◽

Tereza Coman ◽

Stephane Morisset ◽

Mohamad Sobh ◽

Raynier Devillier ◽

...

Keyword(s):

Cell Transplantation ◽

Lower Incidence ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Gvhd Prophylaxis ◽

Significant Difference

Abstract Rational: The significant increase in haplo-identical allogeneic cell transplantation (Allo-HCT) has led to the more frequent use of cyclophosphamide (Cy) after transplantation for graft-versus-host disease (GVHD) prophylaxis (PT-Cy). This strategy has subsequently been used in related and unrelated allogeneic HCT settings as well with some controversial results. Patients and Methods: We analyzed all consecutive Allo-HCTs from matched related (MR) and unrelated donors (HLA matched and mismatched: MUD and MMUD) reported to the SFGM-TC registry from January 2014 to December 2019 and who have received PT-Cy alone or in combination with other immunosuppressive molecules (IS). We therefore performed a pair-matched analysis (1/2) with transplantations using classic GVHD prophylaxis with (w) or without (wo) anti-thymocyte globulins (ATG). The primary objective was to evaluate the incidence and severity of acute and chronic GVHD in PT-Cy compared to other strategies. Secondary objectives included: modalities of PT-Cy and IS, cumulative incidence of relapse (CIR), non-relapse mortality (NRM), overall survival (OS), GVHD and relapse free-survival (GRFS), infection rates. Results: We analyzed a total of 1190 patients (pts), 386 (32%) received PT-Cy and matched with 804 (68%) pts who received classic GVHD prophylaxis (no PT-Cy). Among PT-Cy patients, 59% were males with a median age of 55.3 years (3.4-75.5), 49% were AML, 14% ALL, 20% MDS and MPS, 12.5% NHL and HL, and 4.5% Multiple Myeloma. Before transplantation, 61% of pts were in complete remission (CR), 34% not in CR, 2% in stable disease and 3% were not treated. Conditioning regimen was myeloablative in 35% of patients, 86% received peripheral blood stem cells, 31% were CMV negative pairs, 58% were sex-matched and 51% were ABO compatible. There was no significant difference between the PT-Cy and no PT-Cy groups regarding all the variables. We identified four groups: group 1: PT-Cy + IS (n=259), group 2: PT-Cy + ATG + IS (n=120), group 3: ATG w or wo IS (n=651) and group 4: other IS (n=160). We observed significant differences between the 4 groups for age (p<0.001), type of disease (p<0.001), disease status (p=0.016), conditioning intensity (p=0.002), HC source (p<0.001), HLA matching (p<0.001) and ABO compatibility (p<0.001). The cumulative incidence of acute GVHD grades II, III/IV, chronic GVHD, relapse and NRM, the probability of OS and GRFS are shown in Table 1. The results of multivariate analysis (Table 2) showed a significant lower incidence of acute GVHD gr II, III, IV and chronic GVHD after PT-Cy + IS and a significant higher TRM after ATG ± IS. In addition, other well-known parameters were found to have a significant impact as age on OS and GRFS, use of unrelated donor on OS and CIR and PBSC on chronic GVHD. Regarding severe infections after HCT, there was no difference between PT-cy and pair-matched patients except for pneumonia (12.5% vs. 8% respectively, p=0.08) and septicemia (12% vs. 1.7% respectively, p<0.001). In conclusion, there was a significant lower incidence and severity of acute and chronic GVHD in the PT-Cy group after related, HLA matched and mismatched unrelated Allo-HCT compared to matched patients with other GVHD prophylaxis with a higher NRM when patients received ATG. We did not observe significant translation into GRFS improvement probably due to the higher toxicity of PT-Cy. Figure 1 Figure 1. Disclosures Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Forcade: Novartis: Other: travel grant. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huynh: Jazz Pharmaceuticals: Honoraria. Dulery: Novartis: Honoraria; Takeda: Consultancy; Gilead: Other: Travel support and registration fees for scientific meetings .

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Primed-GCSF BMT Following Reduced Intensity Conditioning Regimen (RIC) for Patients (pts) with Poor-Prognosis, Heavily Pre-Treated, Hodgkin's Disease (HD).

Blood ◽

10.1182/blood.v116.21.1312.1312 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1312-1312

Author(s):

Rodolfo Calixto ◽

Mauricio Ostronoff ◽

Fabiana Ostronoff ◽

Djenane Manso ◽

ANA Patricia Souto Maior ◽

...

Keyword(s):

Poor Prognosis ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Refractory Disease ◽

Bulky Disease ◽

Free Survival ◽

Disease Free ◽

Neutrophil Engraftment

Abstract Abstract 1312 Poor prognosis factors in HD include chemotherapy refractoriness, early relapse (especially in areas that has been previously irradiated), bulky disease and bone marrow or visceral involvement. Pts with poor prognosis resistant disease have been treated with RIC allo-SCT or tandem auto-SCT followed by RIC allo-SCT. Primed-GCSF BMT has shown to accelerate the neutrophil recovery and decrease the incidence of chronic GVHD in comparison to PBSCT without affecting the graft-versus-lymphoma (GVL) effect. From December 2004 to January 2010 we treated 18 pts with chemo and radiotherapy resistant HD with G-CSF-primed allo-BMT. Initial staging was II-B in 6 pts and III-B 7 pts, IV-B 5 pts. The median time between diagnosis of HD and the transplant was 19 months (9 – 38 mo). Ten out of the 18 pts had chemotherapy-refractory disease, 6 had early relapses (< 12 mo) in previously irradiated areas and 2 had visceral relapse (pulmonary). Prior to transplant, 39% of the pts had been treated with 2 chemotherapy regimens prior to respond and 61% had been treated with 3 or more. Ten pts had received prior radiation therapy and all patients with bulky disease were previously irradiated. Thirteen pts received one auto-SCT prior to the allo-SCT for cytoreduction (6 chemo sensitive and 07 chemo resistant). The toxicity for tandem transplant, auto-SCT followed by RIC allo-BMT, for the remaining 5 refractory pts was thought to be excessively high and therefore they went straight to allo-BMT. The protocol was approved by our institutional review board and informed consent was obtained from each pt and donor and or their guardians. Conditioning regimen for the auto-SCT consisted of Cyclophosphamide 1500 mg/m2 (D-6 to D-3), Etoposide 400 mg/m2 (D-6 to D-3) and Carmustin 150 mg/m2 (D-6 to D-4). This regimen was well tolerated by all pts undergoing tandem-SCT. RIC regimen for the allogeneic G-CSF-primed BMT consisted of Busulfan 4mg/kg/day (D-5 and D-4) and fludarabine 30 mg/m2/day (D-7 to D-2) and Cyclophophamide 350mg/m2/day (D-4 to D-2). GVHD prophylaxis consisted of CSA 5mg/kg/day orally from day -1 to day +90 and MMF 45mg/kg/day orally until day +30. The donors received G-CSF 5 μg/kg/d subcutaneously for five days (D–4 to D0) prior to harvest the bone marrow. The median CD34+, CD3+ and CD8+ cell count infused were respectively 3.1 × 106 cells/kg (1.9 - 8.5 × 106/kg), 42 × 106 (28 – 59 × 106 cells/kg) and 11 × 106 cells/kg (6 - 31 × 106). All pts received G-CSF 10 micrograms/kg/day SC from D0 until neutrophil engraftment. The median time for neutrophil and platelet to recover was respectively 5 days (3 – 12 d) and 6 days (4 – 13 d). All pts had complete chimerism on day +30 and there were no graft rejections. One pt had CMV reactivation which was treated with gancyclovir. Treatment related mortality at D+365 after the allo-BMT was 22% (4 out of 18 pts); three pts died of acute GVHD on D+49, D+88, D+110 and one pt died of chronic GVHD of the lung on D+198. Grade ≥ II acute GVHD occurred in 9/18 pts (50%) and grade III-IV in 3/18 (17%). Extensive chronic GVHD occurred in 2/18 pts (11%). There were 9 deaths (50%); causes of death included acute GVHD in 3 pts, pulmonary GVHD in one pt and relapse in 4 pts at 2, 6, 9 and 17 months after the allo-BMT. The overall survival and disease free survival were respectively 50% and 45% with a median follow up of 27 months (range, 8 – 48 months). One patient relapsed on day+220; this pt maintained full donor chimerism and had no evidence of chronic GVHD. DLI was attempted without success. Disease free survival for pts with refractory disease (10 pts) was 40% (8, 13, 27, 31 months). Primed-BMT after RIC for patients with poor prognosis HD resistant to chemo and/ or radiotherapy may be potential treatment, offering lower toxicity, rapid neutrophil engraftment and low incidence of chronic GVHD without affecting the GVL effect. Disclosures: No relevant conflicts of interest to declare.

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