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

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

Blood ◽

10.1182/blood.v108.11.5245.5245 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5245-5245

Author(s):

Jerzy Wojnar ◽

Sebastian Giebel ◽

Miroslaw Markiewicz ◽

Malgorzata Krawczyk-Kulis ◽

Iwona Wylezol ◽

...

Keyword(s):

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Hematological Toxicity ◽

Haemorrhagic Cystitis ◽

Hematopoietic Disorders ◽

One Year ◽

Reduced Toxicity

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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Refined Disease Risk Index (DRI) and Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) Predict Survival after Haploidentical Stem Cell Transplantation: A Comparative Study with EBMT Risk Score in 220 Consecutive Patients

Blood ◽

10.1182/blood.v126.23.4400.4400 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4400-4400 ◽

Cited By ~ 1

Author(s):

Maria Teresa Lupo-Stanghellini ◽

Elisa Sala ◽

Simona Piemontese ◽

Mara Morelli ◽

Raffaella Greco ◽

...

Keyword(s):

Risk Assessment ◽

Stem Cell ◽

Cell Transplantation ◽

Risk Score ◽

Hematopoietic Cell Transplantation ◽

Disease Risk ◽

Risk Index ◽

Hematopoietic Cell ◽

Comorbidity Index ◽

Very High

Abstract Background Optimization of pre-transplant risk assessment is a crucial issue to improve the allo-HSCT decision making process. Actually 3 major algorithms are in use in clinical practice: the EBMT risk score, the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score and - more recently introduced - the refined Disease Risk Index (DRI). DRI was defined to calibrate HSCT outcome across studies and centers. It was developed as a tool to assign patients into risk groups based on disease type and status at the time of transplantation. The aim of the DRI is to provide a robust tool that can be used for prognostication, for the analysis and interpretation of retrospective data, whether conducted in single-center, multicenter, or registry settings, or within the context of the federally mandated center outcome reporting. The DRI can also be used for the stratification of patients entering prospective HCT clinical trials. DRI is not a fixed tool but instead it was conceived to be refined by the transplant community as new information becomes available. Here we are presenting the results of a retrospective study designed to evaluate the 3 aforementioned score in stratification and prognostication of transplant outcome after a haploidentical HSCT (haplo-HSCT). Patients and Methods We included 220 adult patients (pts - 138 male, 82 female) who underwent a haplo-HSCT for hematologic malignancies, between 2006 and 2014 and were reported to our Institutional database. Risk assessment score and outcome analysis included all consecutive pts receiving an haplo-HSCT as 1st allogeneic transplantation. Pts receiving haplo-HSCT as 2nd or 3rd HSCT were excluded from the present analysis. Median age was 49 years (range, 15-77). The cohort included a broad representation of diseases (138/220 acute leukemia, 30 Hodgkin lymphoma); 62 pts were in complete remission at transplant, 158 were presenting active disease. Conditioning regimens mostly rely upon the combination of treosulfan plus fludarabine (201/220) and total body irradiation (range 200 - 400 cGy) was utilized in 52 patients. GVHD prophylaxis consisted mostly of an mTor inhibitor (rapamycin) combined with mycophenolate mofetil. The majority of patients received peripheral blood stem cells from a family haploidentical donor as stem cell source, while only 4 patients received bone marrow transplant. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki. Results The median follow-up for survivors was 37 months (r 6-107). The overall survival (OS) at 2-y was 35% and the transplant related mortality at 100-days 23%. The 2y OS according to EBMT / HCT-CI / DRI risk score are reported in table 1.a and figure 1. The evaluation of the HCT-CI impact after DRI stratification was able to show a significant difference in outcome showing better survival for pts with low DRI score and low HCT-CI score as expected (table 1.b). Discussion Refined DRI score and HCT-CI score predict survival after haplo-HSCT. The integrated application of refined DRI and HCT-CI may improve the definition of transplant eligibility for pts candidate to allogeneic HSCT form alternative donors including family haploidentical source. Table 1a. EBMT score 0-3 % pts 4-5 %pts > 5 %pts p 51% 17 34% 51 27% 32 0.07 HCT-CI score 0-2 3-4 >/= 5 48% 59 36% 31 0% 10 0.0001 DRI score Low-Intermediate High Very-High 61% 32 27% 51 5% 17 0.0001 Table 1b. HCT-CI 0-4 HCT-CI >/=5 p DRILow-Intermediate 64% 0% 0.0001 DRIHigh-Very High 29% 0% Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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The Disease Risk Index Predicts Outcomes Including Relapse and Survival in CD34-Selected Allogeneic HCT for Acute Leukemia and Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v128.22.3498.3498 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3498-3498

Author(s):

Christina Cho ◽

Patrick Hilden ◽

Jonathan U. Peled ◽

Scott T. Avecilla ◽

Pere Barba ◽

...

Keyword(s):

Multivariate Analysis ◽

Cumulative Incidence ◽

Disease Risk ◽

Risk Index ◽

Chronic Gvhd ◽

Univariate Analysis ◽

Relapse Free Survival ◽

Free Survival ◽

Donor Type ◽

Very High

Abstract INTRODUCTION: T-cell depleted allogeneic peripheral blood stem cell transplant (TCD PBSCT) using CD34 selection achieves relapse rates comparable to those of unmodified grafts (Pasquini et al., JCO 2012), but disease-related predictors of outcome have not been fully characterized in the TCD setting. We evaluated the prognostic utility of the refined Disease Risk Index (DRI; Armand et al., Blood 2014) in TCD PBSCT. METHODS: This was a retrospective analysis of patients who underwent first allogeneic HCT with TCD PBSCT for AML, ALL, or MDS at a single center between 1/2000 and 12/2015. Overall survival (OS), relapse-free survival (RFS), and chronic GVHD/relapse-free survival (CRFS) were estimated by the Kaplan-Meier method. Cumulative incidence of relapse, non-relapse mortality (NRM), acute GVHD (aGVHD), and chronic GVHD (cGVHD) were estimated using the cumulative incidence method for competing risks. The univariate association between variables of interest and OS/RFS/CRFS was evaluated using the log-rank test; Cox regression models assessed the adjusted effect of significant covariates on OS and RFS. Given only 1 patient with very high DRI, the high/very high DRI groups were combined. Similarly, given few patients with low DRI, the low/intermediate groups were combined in multivariate analysis. RESULTS: The analysis comprised a total of 519 patients. Median age was 55 years (range 18-73). There were 302 patients (58%) transplanted for AML, 144 (28%) for MDS, and 73 (14%) for ALL. Seventeen patients had low DRI scores (3%), 431 intermediate (83%), and 71 high/very high (14%). Median follow-up among survivors was 53.1 months (range 4.6-171.0). Two-year estimates for outcomes of interest were OS 62.8% (95% CI 58.5, 66.9), RFS 58.1% (95% CI 53.7, 62.3), and CRFS 54.0% (95% CI 49.5, 58.2). The cumulative incidence of relapse at 2 years was 17.3% (95% CI 14.2, 20.7). There were 0 relapse events in patients with low DRI, whereas intermediate and high/very high DRI scores were associated with a significantly increased incidence of relapse (p < 0.001), with 2 year estimates 14.7% (95% CI 11.5, 18.3) and 37.1% (95% CI 25.8, 48.4), respectively. The cumulative incidence of NRM was 24.6% (95% CI 20.9, 28.4) at 2 years. The cumulative incidence of aGVHD at 100 days was 12.5% (95% CI 9.8, 15.5) for grade 2-4 and 2.5% for grade 3-4 (95% CI 1.4, 4.1); with a cumulative incidence of cGVHD of 4.7% (95% CI 3.1, 6.7) at 1 year. NRM, aGVHD, and cGVHD did not vary with DRI. In univariate analysis, DRI was associated with significant differences in OS, RFS, and CRFS (Table 1; Figure). Additional factors associated with poorer OS in univariate analysis were HCT-CI score > 0, KPS < 90, donor type (matched unrelated or mismatched vs. matched related donor), and age > the median of 55.3 years; HCT-CI and KPS also correlated with significant differences in RFS. On multivariate analysis (Table 2), high/very high DRI corresponded to significantly greater risk of death (HR 1.72 for OS, [95% CI 1.24, 2.40]) and relapse or death (HR 1.86 for RFS [95% CI 1.35, 2.55]), compared with low/intermediate DRI. Multivariate analysis also showed that KPS < 90 was associated with worse OS and RFS, as did a higher HCT-CI score. Neither age nor donor type was significantly associated with OS in multivariate analysis. CONCLUSION: In a large cohort of patients undergoing first TCD PBSCT at a single center for acute leukemia or MDS, DRI score significantly correlated with relapse incidence as well as OS, RFS, and CRFS. We have previously shown that the HCT-CI score, which incorporates patients' baseline comorbidities, is also predictive of outcomes after TCD PBSCT. Combining these prognostic tools will serve to better select appropriate patients for TCD PBSCT, a transplant approach currently under investigation in a multicenter phase 3 trial (BMT CTN 1301). Disclosures Koehne: Atara Biotherapeutics: Consultancy.

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Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria

Blood ◽

10.1182/blood-2010-08-302109 ◽

2011 ◽

Vol 117 (11) ◽

pp. 3214-3219 ◽

Cited By ~ 320

Author(s):

Mary E. D. Flowers ◽

Yoshihiro Inamoto ◽

Paul A. Carpenter ◽

Stephanie J. Lee ◽

Hans-Peter Kiem ◽

...

Keyword(s):

Risk Factors ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Human Leukocyte ◽

National Institutes Of Health ◽

Host Disease ◽

Graft Versus Host ◽

Acute Graft

Abstract Risk factors for grades 2-4 acute graft-versus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD.

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Post-transplant cyclophosphamide in matched and haploidentical transplant recipients receiving myeloablative timed sequential busulfan conditioning regimen: Results of a phase II study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.7007 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 7007-7007

Author(s):

Uday R. Popat ◽

Rohtesh S. Mehta ◽

Roland Bassett ◽

Amanda Leigh Olson ◽

Amin Majid Alousi ◽

...

Keyword(s):

Phase Ii ◽

Disease Risk ◽

Phase Ii Study ◽

Risk Index ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Area Under The Curve ◽

Pharmacokinetic Studies ◽

Target Area ◽

Post Transplant

7007 Background: Myeloablative stem cell transplants have a lower rate of relapse than reduced intensity regimens. Timed sequential busulfan (TSB) with fludarabine (Flu) is a promising myeloablative regimen for patients undergoing matched sibling (MSD) or unrelated (MUD) donor transplantation (HCT) with low non-relapse mortality (NRM) (Popat et al Lancet Haematology 2018), but was not tested in haploidentical (haplo). Also, whether this approach can be used with post-transplant cyclophosphamide (PTCy) in MSD, MUD and haplo HCT is unknown. To address these issues, we conducted a prospective phase II study. Methods: Patients with hematological malignancies with MSD, MUD or haplo donor were eligible. They received fixed doses of Busulfan(BU) 80mg/m2 either on day -13 and -12 (n=45) or on -20 and -13 (n=10). Then, Flu 40mg/m2 was given on day -6 to -2 followed by Bu dosed to achieve target area under the curve (AUC) of 20,000 umol/min for the whole course based on pharmacokinetic studies. Thiotepa 5mg/kg was given on day -7 to haplo group. GVHD prophylaxis was PTCy 50mg/kg on day 3 and 4 and tacrolimus. Haplo and later MUD recipients also received mycophenolate mofetil. Results: 55 patients with a median age of 47 (15-65) years were enrolled. 30 patients had AML or MDS, 9 CML or MPD, 5 lymphoma, 5 myeloma and 6 ALL. About half had haplo 26 (47%); others had MUD 18 (33%) or MSD 11(20%). Disease risk index was high in 18 (32%), intermediate in 32 (58%), and low in 5 (9%) patients. Comorbidity score was ≥3 in 22 (40%) patients. With a median follow up of 17 months (5-28), 1-year OS, PFS, NRM and relapse rates were 71% (60-84%), 63% (51-77%), 20% (9-31%), and 17% (7-27%), respectively [Table]. There were no graft failures. Day 100 grade II-IV and III-IV acute GVHD rates were 38% (25-51%) and 9% (95% CI 1-17%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 10% (2-28%) and 8% (0-15%), respectively. 1-year OS in MSD, MUD and haplo groups were 91% (75-100%), 72% (54-96%), and 62% (45-83%) respectively (P=0.11). Conclusions: Myeloablative TSB with PTCy is feasible in MSD, MUD and haplo HCT. It lowers the incidence of severe acute and chronic GVHD without apparent increase in relapse. Clinical trial information: NCT02861417. [Table: see text]

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Risk Factors and Outcomes of Klebsiella Pneumoniae Infection before and after Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2019-125320 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4502-4502

Author(s):

Eleni Gavriilaki ◽

Ioanna Sakellari ◽

Thomas Chatziconstantinou ◽

Despina Mallouri ◽

Ioannis Batsis ◽

...

Keyword(s):

Risk Factors ◽

Overall Survival ◽

Klebsiella Pneumoniae ◽

Cell Transplantation ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Secondary Prophylaxis ◽

Post Transplant ◽

Before And After

Introduction: Carbapenemase-producing (KPC) Klebsiella pneumoniae (Kp) infections have emerged as a major healthcare concern worldwide. Although infections are recognized as a major contributor of morbidity and mortality before and after allogeneic hematopoietic cell transplantation (HCT), the burden of Kp infections has not been extensively evaluated. Therefore, we aimed to determine risk factors and outcomes of these infections in HCT recipients. Methods: We retrospectively studied consecutive patients with Kp colonization and/or infection before and/or after HCT performed in 2008-2018. Patients were transplanted according to standard operating procedures of our JACIE-accredited center. Colonization was defined as the isolation of the microorganism from any non-sterile body site in the absence of clinical signs or symptoms of disease. Patients with colonization or infection pre-transplant received secondary prophylaxis pre and during transplant. Nurses, visitors and staff were carefully trained on infection control measures such as contact precautions and intensified hygienic measures in patients with pre-transplant isolation. Statistical analysis included the following factors: age, gender, disease phase at transplant (early, intermediate or advanced), donor, pre-transplant and post-transplant Kp infections and colonizations, KPC-Kp, severe acute and extensive chronic GVHD, relapse, treatment-related mortality (TRM) and overall survival (OS). Results: We studied 52 patients with a median age of 42 (range 17-42). Colonizations were detected in 9 patients pre-transplant (17%) and 29 post-transplant (56%); whereas infections in 23 pre- and 28 post-transplant (44% and 54%, respectively). KPC-Kp was isolated in 12 patients (29%). With a median follow-up of 23.5 months (range 1-99), cumulative incidence (CI) of severe acute GVHD was 44.5% and severe chronic GVHD 56.7%. Two-year CI of TRM was 14.3% and was independently predicted by the isolation of KPC-Kp (p=0.040, Figure 1A) and chronic GVHD (p<0.001). Among pre-transplant and transplant factors, acute GVHD was associated only with pre-transplant Kp infections (p=0.049). Pre-transplant infections were also associated with post-transplant infections (p=0.010), despite secondary prophylaxis. Overall survival was associated with disease phase at transplant (p=0.017), post-transplant infections (p=0.034) and acute GVHD (p=0.013). In the multivariate model, only post-transplant Kp infections independently predicted OS (beta=9.042, p=0.008, Figure 1B). Conclusions: Our study highlights the significant impact of Kp infections on TRM and OS of HCT recipients. In our population of patients with Kp colonization and/or infection, the burden of GVHD was high. Acute GVHD was linked with pre-transplant Kp infections, suggesting that disruption of intestinal microbiota may be an underlying predisposing condition. Secondary prophylaxis did not improve rates of post-transplant infections, but allowed the performance of HCT with an acceptable TRM rate. Our data suggest that additional interventions need to be further investigated to address the major problem of Kp infections in HCT. Figure 1 Disclosures No relevant conflicts of interest to declare.

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Allogeneic Hematopoietic Peripheral Blood Stem-Cell Transplantation From HLA-Identical Siblings Versus Allelic-Matched Unrelated Donors (10/10 high resolution) in Patients with Acute Myeloid Leukemia and Myelodyplasic Syndrome After Reduced Intensity Conditioning,

Blood ◽

10.1182/blood.v118.21.4132.4132 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4132-4132

Author(s):

Marie Robin ◽

Raphael Porcher ◽

Lionel Ades ◽

Emmanuel Raffoux ◽

Nicolas Boissel ◽

...

Keyword(s):

Cumulative Incidence ◽

Myeloid Leukemia ◽

Acute Gvhd ◽

Disease Risk ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Sibling Donor ◽

Matched Sibling

Abstract Abstract 4132 Introduction: Although precise matching of the donor/recipient pairs has been made easier by HLA typing at the allelic level, several issues with respect to unrelated transplantation remain to be addressed. In particular, the impacts of allelic HLA matching in patients with Acute Myeloid Leukemia (AML) and myelodysplasic syndrome (MDS) who receive allogeneic Peripheral Blood Stem cells (PBSC) after a reduced intensity conditioning (RIC) regimen is still unclear. In the present study, we aim to compare the impact of the donor type in this setting: HLA identical sibling versus HLA matched 10/10 (high resolution) unrelated donor (MUD). Method and transplantation characteristics: From 01/2001 to 12/2010, 108 consecutive patients with AML (n=63) and MDS (n=45) received PBSC after RIC in our center, either from HLA identical sibling (n=69) or MUD (n=39). Conditioning regimen was fludarabine based in 95% of patients and GvHD prophylaxis consisted in cyclosporine plus mycophenolate in 79% of patients. Engraftment, acute and chronic graft-versus-host disease (GvHD), transplantation-related mortality (TRM), relapse rate and overall survival (OS) at 3 years were compared according to type of donor: HLA identical sibling donor and MUD. Disease characteristics: WHO classification for MDS at time of hematopoietic stem cell transplantation (HSCT) was RAEB1 (24%), RAEB2 (36%), MDS transformed into secondary AML (20%), CMML2 (9%), RA (4%), or other (7%). Disease risk was assumed by cytogenetic (MRC for AML, IPSS for MDS) and EBMT score (good risk: CR1 for AML or MDS or untreated MDS, intermediate risk: CR2 for AML, CR2 or partial remission for MDS, poor risk: all other status). Cytogenetic (no missing data) was poor, intermediate or good for 21, 74 and 5% of AML and 24, 36 and 40% of MDS, respectively. EBMT score at time of HSCT was poor, intermediate or good for 29, 7, 64% of MDS and 11, 21, 68% of AML, respectively. Results of the comparison: Patients characteristics according to type of donor were similar for age (median 57 years), gender and disease distribution. Particularly, disease risks were comparable in 2 groups. Conversely, conditioning regimen (more ATG in MUD: 69 vs. 43%, p=0.016), donor age (younger for MUD: 30 vs. 52 years, p<0.0001) and number of CD34+ cells infused (higher in MUD: 7 vs. 6.5 × 106/kg, p=0.022) were different. The median follow-up was 36 months (range 2 to 72). All patients engrafted. The cumulative incidence of acute GvHD was 40% with HLA matched sibling donor and 44% for MUD (p=0.58). The cumulative incidence of chronic GvHD at 3 years was 49% with HLA matched sibling donor and 45% with MUD (p=0.66). No risk factor was associated with acute GvHD but chronic GvHD was less frequent in patients with AML vs. MDS (41% vs. 59%, p=0.077) and in those patients who received ATG in conditioning regimen (54% vs. 43%, p=0.067). During follow-up, 47 patients died. The 3-year cumulative incidence of TRM was 17% and 22% with HLA matched sibling donor and MUD, respectively (p=0.55). Adjusting for age, MDS was the only factor increasing TRM (HR 3.4; 95% CI 1.2 to 9.5; p=0.02). The 3-year cumulative incidence of relapse was 46% with HLA matched sibling donor and 30% with MUD (p=0.28) knowing that there was no difference between both groups regarding disease risk (cytogenetic and EBMT score). The 3-year OS was 44% with HLA matched sibling donor (95%CI: 33–61) and 50% with MUD (95%CI: 35–71) (Figure 1). Disclosures: Fenaux: Celgene: Honoraria, Research Funding. Peffault de Latour:Alexion: Consultancy, Research Funding.

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A Phase I Dose Escalation Study of Lenalidomide Following Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood.v124.21.3954.3954 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3954-3954 ◽

Cited By ~ 1

Author(s):

Leslie A. Andritsos ◽

William Blum ◽

Rebecca B. Klisovic ◽

Sumithira Vasu ◽

Sam Penza ◽

...

Keyword(s):

Skin Rash ◽

Dose Escalation ◽

Acute Gvhd ◽

Disease Risk ◽

Risk Index ◽

Reduced Intensity Conditioning ◽

Dose Escalation Study ◽

Elevated Creatinine ◽

Very High ◽

Reduced Intensity

Abstract Lenalidomide is an immunomodulatory drug that is FDA approved for treatment of 5q- myelodysplastic syndrome (MDS) and myeloma. It has also been tested as a salvage therapy of refractory/relapsed AML with encouraging activity, especially in patients (pts) who relapsed post allogeneic transplant (alloSCT). In this setting, it has been postulated that lenalidomide may re-activate donor immune system and enhance a graft-versus-leukemia effect. This hypothesis is also supported by evidence of increase graft-versus-disease (GVHD) observed in pts treated with lenalidomide post-alloSCT. Therefore, in order to prospectively study the safety, feasibility, and early impact on risk of disease relapse we performed a phase 1 dose escalation study of lenalidomide administered orally daily following reduced intensity conditioning (RIC) alloSCT in pts with leukemia and lymphoma eligible for transplant. Methods: Pts were enrolled on a two-step process, with initial enrollment prior to transplant followed by a re-registration evaluation post-transplant at day +60 (+/- 7 days) to ensure eligibility. At this screening, pts were required to demonstrate engraftment with ANC >1000/uL, platelet count ³50,000/uL, and T-cell chimerism ³40% by day +30. Pts were required to have a creatinine clearance ³50 mL/min, AST ²3 x ULN, and ECOG PS of 0-2. Grades 1 or 2 acute GVHD (aGVHD) were allowed if controlled on ² 20 mg of prednisone daily; pts with a history of grades 3 or 4 aGVHD were excluded. Lenalidomide was given orally daily for 28 days/cycle. Dosing escalation was performed using a standard 3 x 3 design, with dose level (DL) 1 = 5 mg , DL 2 = 10 mg, and DL 3 = 15 mg. Results: From 6/2011 to 10/2012, 17 pts with AML (n=13), CLL (n=1), and DLBCL (n=3) were enrolled (Table 1) and underwent RIC alloSCT. The majority of patients had a Disease Risk Index (Armand et al. Blood, 2014) of high or very high. Of enrolled pts, only 3 received lenalidomide. Of the pts who did not proceed to treatment at re-registration, 4 were ineligible due to relapse, 3 were ineligible due to elevated creatinine, 3 were ineligible due to GVHD, 2 declined, and 2 were not treated due to study closure. All pts who received lenalidomide were treated at DL 1. The first pt treated (00-06) received cycle 1 without toxicity. On cycle 2 day 9 he developed a skin rash consistent with acute GVHD and discontinued therapy. The second pt treated (00-11) developed skin rash and diarrhea on cycle 1 day 3 and was diagnosed with steroid refractory aGVHD of the GI tract. He expired from complications of treatment. The third pt treated (00-12) developed a skin rash and diarrhea on cycle 1 day 6. Lenalidomide was discontinued. Based on these outcomes, the study was closed due to concerns regarding the risk of severe aGVHD caused by lenalidomide. However, patients 00-06 and 00-12 remain alive and in CR days 958 and 751 post transplant, respectively. In the entire cohort, the median PFS was 103 days (range = 15-992) with median OS 103 days (range = 30-1085). Conclusion: Early administration of low-dose lenalidomide following alloSCT is not feasible due to potential increased risk of severe aGVHD and likelihood of elevated creatinine at this time point. However, 2 of 3 pts who received lenalidomide and responded to treatment for aGVHD remain in CR from their high-risk AML. Thus, an amended approach with lower/fewer dose of lenalidomide/cycle or alternatively, use in transplants that do not utilize calcineurin phosphatase inhibitors (such as T-cell depletion based approaches) warrants additional consideration. Abstract 3954. Table 1 PT Age Sex Diagnosis Disease Risk Index Comorbidity Index Lena Treatment Progression free survival (days) Overall survival (days) Cause of death 01 64 F AML High 3 Ineligible1 592 979 Relapse 02 64 M AML Very high 1 Ineligible1 140 229 Relapse 03 26 F AML High 6 Ineligible2 35 121 Relapse 04 39 M DLBCL Intermediate 0 Declined 789 1085 05 64 M DLBCL Intermediate 1 Declined 108 121 Relapse 06 36 M AML High 3 Yes 958 958 07 60 M AML High 3 Ineligible3 992 992 08 61 M CLL Low 0 Ineligible3 101 101 Acute GVHD 09 71 M AML High 1 Ineligible1 957 957 10 57 M AML High 5 Ineligible2 30 30 Regimen Related Toxicity 11 32 M AML Very High 2 Yes 103 103 Acute GVHD 12 50 F AML Very High 4 Yes 751 751 13 61 F AML Very High 4 Ineligible2 42 242 Relapse 14 60 M AML Very High 0 Ineligible2 15 160 Relapse 15 63 F AML High 3 Ineligible3 61 61 Acute GVHD 16 66 M AML High 3 Study closure 706 706 17 68 M DLBCL High 5 Study closure 72 72 Pneumonia 1 = elevated creatinine 2 = relapse 3 = GVHD Disclosures Off Label Use: Lenalidomide administration following allogeneic transplantation.. Blum:Celgene: Consultancy.

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