scholarly journals Comparison of the Impact of Pre-Transplant Co-Morbidity Scores on Allogeneic Hematopoietic Stem Cell Transplant Outcomes

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4670-4670
Author(s):  
Mohammed A. Marei ◽  
Eshetu G Atenafu ◽  
Arjun Law ◽  
Wilson Lam ◽  
Rajat Kumar ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Post Transplant ◽  
Transplant Outcomes ◽  
C Statistic ◽  
Co Morbidity ◽  
The Impact

Abstract Introduction: Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for the treatment of various hematological diseases, in part due to the effect of conditioning chemotherapy, and in part due to graft-versus-malignancy effect. However, alloHCT is associated with significant morbidity and mortality. Multiple co-morbidity indices have been published in the literature for the purpose of pre-transplant risk assessment. The purpose of the presented study is to assess a number of these pre-transplant scores on a single-center transplant population and to determine the score with improved risk stratification ability using concordance statistics. Methods: We investigated the impact of the prospectively collected Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) on post-transplant outcomes for 243 recipients of allo-HCT performed between August 2014 and October 2016 at the Princess Margaret Cancer Center (Toronto, Canada), and compared this score to other pre-transplant scores including the age-adjusted HCT-CI, PAM score (Pre-transplant Assessment of Mortality Score) and the Disease Risk Index (DRI). Partitioning of the HCT-CI, HCT-CI/age and PAM scores into three groups was performed based on maximum significant differences on univariate analysis for overall survival (OS). Concordance statistics were used to compare the stratification power of the scores. Statistical analyses were performed using SAS version 9.4 (SAS Institute, Inc, Cary, NC). Results: The median age at transplant is 56 years, patients were transplanted for AML (53%), ALL (7.5%), MDS (13.5%), MPN (14%), NHL/CLL (8.5%) and (3.5%) AA. Donors were matched related in 37%, unrelated in 59% and haploidentical in 3% of the patients. Reduced intensity conditioning chemotherapy was used in 132 patients (54%), 153 patients (63%) received in-vivo T-cell depletion by using Campath or ATG, both donor and recipient were CMV negative in 48 (20%) of the patients. DRI was high in 67 (29%), intermediate in 145 (62%) and low in 22 (9%) of patients. HCT-CI was 0 in 90 (37%), 1 in 49(21%) and ≥2 in 103 (43%) of patients. HCT-CI/age was 0 in 22 (10%), 1 in 72 (30%) and ≥2 in 148 (62%). PAM score was 1-17 in 157(68%), 18-24 in 70 (30%) and 25-27 in 7 (3%) of patients. Median follow up of survivors was 28 months (range 17-44 months). OS of the entire cohort was 51% and 43% at 2 and 5 years post-transplant respectively. Cumulative incidence of relapse (CIR) was 19% at 2 years. For OS, as grouped above, the DRI did not demonstrate a significant difference between groups (p=0.77). For HCT-CI, p=0.034 (Figure 1), for HCT-CI/age p=0.02 and for the PAM score p=0.38. For OS, for the DRI, the C-statistic was 0.51 (se=0.03, 95%CI 0.45-0.57). For the PAM score, C-statistic was 0.51 (se=0.02,95%CI 0.45-0.56). For the HCT-CI age, C-statistic was 0.56 (se=0.024, 95%CI 0.51-0.61). For the HCT-CI, C-statistic was 0.56 (se 0.02, 95% CI 0.50-0.61). For CIR, the PAM score demonstrated a superior C-statistic of 0.56 (se=0.06, 95%CI 0.44-0.67) compared to the other scores. For NRM, the HCT-CI score (Figure 2, p=0.039) is superior with C-statistic 0.56 (se=0.04, 95%CI=0.49-0.63). Conclusion: Based on the above described analysis, the original HCT-CI score as described by Sorror et aldemonstrates superior prognostic stratification ability for OS and NRM in our patient cohort compared to other scores. Further investigation for the development of an optimal risk scoring system for allogeneic HCT is required. Figure 1. Figure 1. Disclosures Kim: Paladin: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Lipton:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

scholarly journals Expanded Comorbidity Definitions Improve Application of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) for Children and Young Adults with Non-Malignant Diseases Receiving Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Larisa Broglie ◽  
Brian D Friend ◽  
Brent Logan ◽  
Caitrin Fretham ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Young Adults ◽  
Renal Disease ◽  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Validation Cohort ◽  
Hematopoietic Cell ◽  
Malignant Diseases ◽  
Publicly Traded ◽  
C Statistic

Introduction: Allogeneic hematopoietic cell transplantation (HCT) can be employed as curative therapy for many non-malignant diseases but there is risk of transplant related complications. Pre-HCT, patient-specific factors can help inform risk using the HCT comorbidity index (HCT-CI); however, it can be difficult to apply in children and young adults, where assessment of organ function differs from those defined by the HCT-CI. We aimed to supplement the HCT-CI with pediatric-specific comorbidity definitions to broaden the use of the HCT-CI for pediatric & young adult patients with non-malignant diseases. Methods: Patients <40 years old (yo) who received first allogeneic HCT for non-malignant diseases from 2008-2017 were identified in the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Separate training and validation samples were created using a 2/3, 1/3 split. Adjustment to the definition of renal disease was made, supplementing with estimated glomerular filtration rate (eGFR) and defined as mild (60-89) or moderate/severe (<60ml)/min/1.73m2. Nutritional assessment was supplemented to include obesity (body mass index (BMI) >95th percentile for <18yo) and added assessment of underweight (BMI <5th percentile for <18yo, <18kg/m2 for ≥18yo) by CDC guidelines. History of mechanical ventilation was included as an additional marker of pulmonary disease. Multivariable Cox regression analyses assessed the effect of each comorbidity, and then the modified scores, on overall survival (OS), adjusting for age, primary disease, donor, performance status, recipient CMV status, and year of HCT. We propose 2 potential scores based on modifications for pediatric and young adult patients: 1) Expanding the HCT-CI with broader definitions that can be applied to younger patients, 2) Simplifying the HCT-CI to remove certain comorbidities with hazard ratio (HR) <1.2. C-statistic was used to compare the modified scores to the original HCT-CI. Results: 2,815 patients received allogeneic HCT for non-malignant diseases (25.8% aplastic anemia, 26.5% immune deficiency, 18.2% hemoglobinopathies, 29.5% other) at a median age of 6 (<1-39)yo. 84.3% were ≤18yo and 15.7% were 19-40y. Conditioning intensity was myeloablative in 48.5%, donors were primarily matched sibling (21.2%) or well-matched unrelated donors (25.6%), and bone marrow was primary graft source (54%). Using the original HCT-CI, patients were categorized with scores of 0 (59%), 1-2 (20.8%), and ≥3 (20%). In multivariable analysis, comorbidities with pediatric-specific definitions demonstrated increased hazards of death, including in underweight patients (HR 1.55, 95% confidence interval (CI) 1.18-2.04), those with history of mechanical ventilation (HR 1.85, 95%CI 1.39-2.48), mild renal disease by eGFR (HR 1.49, 95%CI 1.11-2.0), or moderate/severe renal disease by eGFR (HR 2.04, 95%CI 1.1-3.26). Therefore, comorbidities were expanded to include these definitions in the Expanded HCT-CI. Expanding the comorbidity definitions increased the number of patients identified as having pre-HCT comorbidities: 35% were categorized with scores of 0, 32% with scores of 1-2, and 33% with scores of ≥3. Figure 1 shows the expanded comorbidity definitions and effect on OS. Arrhythmia and Psychiatric diseases were noted to have HR <1.2 and were removed in the Pediatric Simplified score. Increasing scores had increasing risk of death in the Expanded HCT-CI [validation cohort HR 1.31, 95%CI 0.81-2.02 for scores (1-2), HR 2.03, 95%CI 1.34-3.07 for (≥3), compared to scores of 0] and the Pediatric Simplified score (validation cohort HR 1.34, 95%CI 0.89-2.02 (1-2), HR 1.97, 95%CI 1.82-2.93 (≥3), compared to scores of 0]. Modifications to the HCT-CI predicted outcomes similar to the original HCT-CI (validation cohort c-statistic at 2yr - HCT-CI 64.3, expanded HCT-CI 65.8, and pediatric simplified HCT-CI 65.8). Conclusion: Modifications to definitions in the HCT-CI can create a pre-HCT risk tool that more broadly classifies organ dysfunction for children & young adults. By expanding the comorbidity definitions, 24% more patients were re-categorized as having at least 1 comorbidity, allowing for better assessment of pre-HCT risk. This expanded HCT-CI performs as well as the HCT-CI but is more broadly applicable to children & young adults with non-malignant diseases and can aid physicians in pre-HCT counseling. Disclosures Schiller: Johnson & Johnson: Current equity holder in publicly-traded company; Karyopharm: Research Funding; Sangamo: Research Funding; AstraZeneca: Consultancy; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Gilead: Speakers Bureau; Stemline: Speakers Bureau; Onconova: Research Funding; Samus: Research Funding; Regimmune: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Deciphera: Research Funding; DeltaFly: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Forma: Research Funding; FujiFilm: Research Funding; Gamida: Research Funding; Genentech-Roche: Research Funding; Geron: Research Funding; Jazz Pharmaceuticals: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Celator: Research Funding; Constellation: Research Funding; Astellas Pharma: Honoraria, Research Funding; Ariad: Research Funding; Actinium: Research Funding; Abbvie: Research Funding. Stadtmauer:Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Novartis, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding. Thakar:Infectious Disease Research Institute: Consultancy. Sorror:Jazz Pharmaceutical: Other: Honorarium for Advisory role. .

scholarly journals Functional Status Is Associated with Outcomes after Allogeneic Stem Cell Transplantation for Older Patients with Hematologic Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3599-3599 ◽  
Author(s):  
Li-Wen Huang ◽  
Chiung-Yu Huang ◽  
Charalambos Andreadis ◽  
Aaron C. Logan ◽  
Gabriel N. Mannis ◽  
...  
Keyword(s):  
Physical Health ◽  
Functional Status ◽  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Univariate Analysis ◽  
Health Score ◽  
Post Transplant ◽  
Transplant Outcomes ◽  
Physical Health Score

Abstract Introduction: Allogeneic hematopoietic cell transplantation (alloHCT) has historically been reserved for younger, fit patients with hematologic malignancies. With the introduction of non-myeloablative conditioning regimens and improved supportive care, alloHCT has been increasingly offered to older adults. Objectives: To determine the association between functional status as measured by a cancer-specific comprehensive geriatric assessment (CGA) and post-transplant outcomes in an older alloHCT patient population. Methods: We conducted a prospective cohort study of patients aged 50 or older who underwent alloHCT at the University of California San Francisco between October 2011 and September 2017. A cancer-specific CGA (1) was administered prior to alloHCT, which included measures of functional status such as Lawton Instrumental Activities of Daily Living (IADL), Medical Outcomes Study (MOS) Physical Health scale, and patient-reported Karnofsky Performance Status (KPS). Post-transplant outcomes included length of hospital stay (LOS), non-relapse mortality (NRM), progression-free survival (PFS), and overall survival (OS). Results: A total of 148 patients were included in the analysis. The median age at transplant was 62 (range 50-76). Disease types included acute myeloid leukemia (43%), myelodysplastic syndrome (26%), myeloproliferative neoplasm (12%), acute lymphoblastic leukemia (10%), non-Hodgkin lymphoma (5%), multiple myeloma (1%), and other (3%); 68% received non-myeloablative conditioning. Median follow-up was 16.3 months (range 0.9-72.7 months). Median PFS and OS were 22.9 months and 47.6 months, respectively. At baseline, 39% had at least one IADL deficit, and 88% had at least one MOS Physical Health scale deficit. The mean patient-KPS was 82.4 and mean provider-KPS was 91.6; these were weakly correlated (Spearman's r=0.39, p<0.001). In univariate analysis, the presence of any IADL deficit was associated with inferior PFS (HR 1.78, p=0.01) and OS (HR 1.68, p=0.04) (Figure). MOS Physical Health score was associated with increased NRM (HR 1.06 per 1-point change in 20-point scale, p=0.04), inferior OS (HR 1.05, p=0.04), increased LOS (difference 0.63 days, p=0.007), but not with PFS (HR 1.04, p=0.06). Neither patient- nor provider-KPS was associated with NRM, PFS, or OS, but lower patient-KPS was associated with increased LOS (difference 1.94 days, p=0.01). In this study, the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), disease risk by American Society for Blood and Marrow Transplantation (ASBMT) classification, and conditioning intensity were not associated with NRM, PFS, or OS. Notably, chronologic age was not associated with NRM, PFS, or OS (Figure). In addition, age was not associated with baseline IADL score (r=-0.02, p=0.26) or MOS Physical Health score (r=-0.13, p=0.06). Conclusion: IADL impairment was associated with inferior PFS and OS, supporting previous studies (2, 3) identifying IADL as an important predictor for alloHCT. In univariate analysis, IADL was a stronger predictor of post-transplant outcomes than traditional prognostication tools such as age, HCT-CI, and provider-KPS. MOS Physical Health score was associated with multiple poor outcomes including NRM and LOS, suggesting a primary impact on alloHCT toxicity. Multivariate analyses, as well as examination of other CGA variables, are ongoing. References:J Clin Oncol. 2011 Apr 1;29(10):1290-6.Haematologica. 2014 Aug;99(8):1373-9.Bone Marrow Transplant. 2018 May;53(5):565-575. Figure. Figure. Disclosures Andreadis: Genentech: Consultancy, Employment; Gilead: Consultancy; Juno: Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; Kite: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Astellas: Consultancy. Logan:Napajen: Consultancy; Adaptive Biotech: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Mannis:Agios: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; NKarta: Membership on an entity's Board of Directors or advisory committees. Smith:Astellas Pharma: Research Funding. Martin:Roche: Consultancy; Amgen: Research Funding; Sanofi: Research Funding. Damon:Novartis: Other: spouse's relationship with company; Boston Scientific: Other: spouse's relationship with company; Actelion: Other: spouse's relationship with company; Gilead Sciences Inc: Other: spouse's relationship with company. Olin:Synapse: Honoraria; Astellas: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding.

scholarly journals Validation of Different Prognostic Scores in Allogeneic Hematopoietic Cell Transplantation in the Post-Transplant Cyclophosphamide Era

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3925-3925
Author(s):  
Maria Queralt Salas ◽  
Luis Gerardo Rodríguez-Lobato ◽  
María Suárez-Lledó ◽  
Nuria Martínez-Cibrian ◽  
Teresa Solano ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Research Funding ◽  
Operating Characteristic ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Prognostic Scores ◽  
Predictive Capacity ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Abstract INTRODUCTION The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GvHD) prophylaxis has decreased the rates of this complication, resulting on an improvement of transplant-related toxicity and survival. Secondary to its efficacy, the use of PTCy has been almost universally integrated for allogeneic hematopoietic cell transplantation (alloHCT), independently of the selected donor source. Clinical decisions in alloHCT are supported by the use of prognostic scores for outcome prediction. However, capability of prediction by diverse scores can vary depending on their features and on the composition of the study cohort. Additionally, the continuous innovation on alloHCT techniques and practices leads to an ongoing need to update risk indices aimed at improving risk stratification of patients undergoing alloHCT. This study explores the predictive capacity of different prognostic scores routinely used in alloHCT, in a contemporaneous cohort of adults undergoing peripheral blood (PB) alloHCT using PTCy-based GvHD prophylaxis. METHODS Between 2014 and 2020, 230 consecutive adults with hematological malignancies underwent PB-alloHCT with PTCy-based GvHD prophylaxis at our Institution. Data related to Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), Karnosfky Performance Status (KPS), Disease Risk Index (DRI), European Bone Marrow Transplantation (EBMT) score, and Endothelial Activation and Stress Index (EASIX) were collected retrospectively. Complete information was available for 216 patients. Overall survival (OS) was considered the main outcome variable. Patients were grouped into two risk groups based on the optimal cut-off value for each score. In the case of EASIX, 1.578 was the most discriminating cut-off for OS. The score discrimination for OS was measured independently for each index using the receiver operating characteristic curve (AUC) calculated using receiver operating characteristic (ROC) curves, and determined at different time-points after alloHCT. RESULTS Of the 216 patients included, the median age was 52 years (range: 18-70), acute myeloid leukemia (36.1%) was the most prevalent baseline diagnosis, 42.1% of adults underwent reduced-intensity conditioning alloHCT, 69.4% received grafts from unrelated donors, and 23.0% from haploidentical donors. With a median follow-up of 22.6 months, 24.1% patients relapsed, and 2-y OS and non-relapse mortality were 67.3% and 19.9%. DRI, HCT-CI, KPS, and EASIX successfully grouped patients into higher and lower risk strata, supporting their use for risk classification. HCT-CI [(score&gt;3 (vs 0-3): HR 2.02, p&lt;0.01], DRI [High - Very High risk (vs Low - Int): HR 2.08, p&lt;0.01], and EASIX [&gt;1.578 (vs ≤ 1.578): HR 1.73, p&lt;0.02], maintained an optimal discrimination capacity during the entire post-transplant follow-up (median AUC ranges &gt; 55%). DRI was the most accurate prognostic index during the entire post-transplant period (median AUC ranges &gt; 60%). KPS score was found to be a useful predictor of mortality up to the first year after alloHCT and with the highest prognostic accuracy at 3 months (AUC 67.09%). HCT-CI score was found to present a better discrimination capacity once elapsed 6 months after alloHCT and with a peak of prediction capacity at 2 years (AUC 60.3%). EASIX, when measured at the pre-transplant evaluation, demonstrated to have acceptable predictive ability during the entire post-transplant period (median AUC &gt; 55%), and with a peak of prediction at 3 months (AUC 62.6%). The EBMT score had the lowest predictive capacity in our analysis (Figure 1). CONCLUSION: This study validates, for the first time, the risk stratification capacity for OS of DRI, HCT-CI, KPS, and EASIX in PB-alloHCT with PCTy-based prophylaxis. Interestingly, the prediction accuracy of the prognostic scores differed depending on the time-period. This result can be taken into consideration to enhance the applicability of these scores and refine the clinical decisions taken based on the information provided from their use in routine clinical practice. Figure 1 Figure 1. Disclosures Lozano: Terumo BCT: Honoraria, Research Funding; Macopharma: Research Funding; Grifols: Honoraria. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Esteve: Novartis: Consultancy, Research Funding; Astellas: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Novartis: Research Funding; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy.

Impact of New Anti-Leukemia Agents on Transplant Outcomes in Adults with Acute Lymphoblastic Leukemia (ALL) Undergoing Allogeneic Hematopoietic Cell Transplantation (HCT) in Second Complete Remission

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4676-4676 ◽  
Author(s):  
Sara Lozano Cerrada ◽  
David Marin ◽  
Gabriela Rondon ◽  
Celina Ledesma ◽  
Uday R. Popat ◽  
...  
Keyword(s):  
T Cell ◽  
Complete Remission ◽  
Cell Transplantation ◽  
Salvage Therapy ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Transplant Outcomes ◽  
Equity Ownership

Abstract Introduction: The number of available salvage agents for patients with relapsed ALL has significantly increased in the last 5 years. Furthermore, these recent therapies, such as antibody and T-cell therapy, have a distinct mechanism of action and toxicity profile compared to conventional multi-drug chemotherapy combinations which have been the mainstay of ALL treatment. We sought to investigate the potential efficacy and toxicity of these agents when used prior to allogeneic hematopoietic cell transplantation (HCT), and to compare overall transplant outcomes with these different types of therapies. Methods: 126 consecutive patients with ALL in second complete remission (CR2) underwent HCT at MD Anderson Cancer Center between January 2004 and December 2015. The patient and transplant characteristics are described in Table 1. The probabilities of outcomes were calculated with the Kaplan-Meyer method. Variables found to be significant at the p<0.1 level were included in a Cox regression multivariate model. All p values are two sided. Results: With a median follow-up of 38.4 months (range 6-125), the 3-year overall survival(OS), progression-free survival (PFS) and transplant-related mortality (TRM) rates were 34.6%, 29.5% and 33.2%, respectively, for the entire group. Patients receiving well-matched transplant donors fared better than those receiving mismatched donors (Figure 1). Second CR was attained in 104 patients with the first line of salvage therapy. Salvage therapy consisted of HyperCVAD-based chemotherapy alone in 57 patients, chemotherapy plus tyrosine kinase inhibitors (TKI) in 18, chemotherapy plus rituximab in 11, chemotherapy plus inotuzumab in 5, inotuzumab monotherapy in 12, and blinatumomab monotherapy in one patient. We found no statistical difference in OS, PFS or TRM following transplant based on these prior therapies. Furthermore, we found no difference in the expected probabilities of acute or chronic GVHD. In the 8 patients treated with blinatumomab monotherapy for first or subsequent salvage, all 8 progressed following transplant at a median of 4.5 months. Eight out of 126 (6.3%) patients developed VOD; 3 out of 26 (11.5%) patients treated with inotuzumab developed VOD, but this did not impact TRM post HCT compared with other treatment groups. Conclusions: Transplant outcomes were not different following antibody or T-cell salvage therapy as compared to conventional chemotherapy in this single center, retrospective study. Larger numbers of patients will need to be studied as we continue to incorporate these newer therapies into our treatment regimens. Disclosures Ciurea: Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board. Jabbour:BMS: Consultancy; ARIAD: Consultancy; Pfizer: Research Funding; Pfizer: Consultancy; Novartis: Research Funding; ARIAD: Research Funding. Kantarjian:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Champlin:Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.

Impact of Mutations in the Spliceosome Machinery and Ring Sideroblasts in Patients with Myeloid Malignancies Who Received Conventional Chemotherapy or Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1973-1973
Author(s):  
Betty K. Hamilton ◽  
Ali Tabarroki ◽  
Valeria Visconte ◽  
Edy Hasrouni ◽  
Hideki Makishima ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Statistical Significance ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Conventional Chemotherapy ◽  
Myeloid Malignancies ◽  
Ring Sideroblasts ◽  
The Impact

Abstract Abstract 1973 Mutations in the spliceosome machinery have recently been identified in myeloid neoplasms including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and MDS/MPN overlap syndromes. Somatic alterations in SF3B1, U2AF1 and SRSF2 are the most frequently affected spliceosome genes in myeloid malignancies with the frequencies of any of the 3 genes being 39% in low risk MDS, 11% in high risk MDS/AML (primarily U2AF1), and 24% in MDS/MPN, (primarily SRSF2). While SF3B1 mutations as well as ring sideroblasts (RS) appear to be associated with improved survival and lower risk of leukemic evolution, mutations of U2AF1 and SRSF2 appear to be associated with poorer outcomes. Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for many myeloid malignancies, however, the prognostic role of SF3B1, U2AF1 or SRSF2 mutations in patients (pts) undergoing high intensity chemotherapy (HIC) and HCT has yet to be investigated. We evaluated 404 pts with the diagnosis of AML (n=96), MDS and MDS/MPN (n=294), MPN (n=13), and congenital sideroblastic anemia (n=1). 35 pts received HIC defined as treatment with 7+3, high dose cytarabine, clofarabine, or other comparable chemotherapy in the context of a clinical trial. 97 pts underwent a myeloablative (n=69) or reduced intensity (n=28) allogeneic HCT from an HLA matched related (n=39), unrelated (n=50) or cord blood (n=8) donor from April 2003 until August 2011. Median age of the whole cohort was 69 and those who underwent BMT at time of transplant was 52 (range 19–70). We performed direct sequencing for the three most commonly mutated spliceosome genes, SF3B1 (exon 13–16), SRSF2 (exon 1 and 2) and U2AF1 (exon 2–6). Given the close association between SF3B1 mutations and RS, we analyzed the impact of the presence or absence of RS on the outcomes associated with the type of therapy received. We found a total of 24 SF3B1 mutations in MDS and MDS/MPN (primarily in pts with RS), 37 SRSF2 mutations in MDS and MDS/MPN (primarily CMML), and 13 U2AF1 mutations in MDS, MDS/MPN and secondary AML. Among pts with MDS and MDS/MPN, significant overall survival (OS) differences were found between SF3B1 mutant and wild type (WT), (83 vs. 31 months, p=0.001) and U2AF1 or SRSF2 mutant (18 vs. 37 months, p=0.007). The U2AF1 mutation by itself was more strongly associated with poor outcome (8 vs. 37 months, p<0.0001), compared to an SRSF2 mutation (26 vs. 36 months, p=0.16). Analysis of survival according to treatment type revealed that no pts who underwent HIC or HCT carried an SF3B1 mutation. The presence of RS was also associated with improved survival (38 vs. 25 months, p=0.04), and this benefit remained if pts received HIC (18 vs. 9 months, p=0.04). However, this benefit became non-significant if pts underwent HCT. There were 19 pts who had either an U2AF1 or SRSF2 mutation that underwent HIC. Although it appeared that having either mutation was associated with worse survival, (9 vs. 21 months), it did not reach statistical significance (p=0.46). Among pts who underwent HCT, there were 10 pts who carried either an U2AF1 or SRSF2 mutation. Those pts with mutations appeared to have superior survival with HCT compared to WT, (53 vs. 34 months), but this did not reach statistical significance (p=0.54). Among pts with either an U2AF1 or SRSF2 mutation, those who underwent HCT had a superior survival (53 vs. 17 months, p=0.05) compared to those who received conventional chemotherapy, defined as HIC or low intensity chemotherapy (LIC), such as hypomethylating agents. There was no difference in survival between receiving HCT or conventional chemotherapy in pts who were WT for U2AF1 or SRSF2 (34 vs. 31 months, p=0.08). Consistent with previous findings of improved survival and loss of SF3B1 with leukemic progression in MDS and MDS/MPN pts, we found no SF3B1 mutations in our cohort of pts receiving HIC or HCT. In contrast, we found poorer outcomes with SRSF2 or U2AF1 mutations. Although the incidence of these mutations was rare in our cohort of pts, we found statistically significant survival benefit for pts with these mutations if they underwent HCT compared to conventional chemotherapy. This is the first study evaluating the impact of spliceosomal mutations on the survival outcomes of pts undergoing HCT. Our preliminary findings of improved survival with HCT in poorer-risk spliceosome mutations is provoking and further molecular analysis is ongoing. Disclosures: Maciejewski: NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding.

scholarly journals Increased Early Mortality After Fludarabine and Melphalan Conditioning with Peripheral Blood Grafts in Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide

2021 ◽  
Author(s):  
Luke Eastburg ◽  
David Russler-Germain ◽  
John DiPersio ◽  
Thomas Fountaine ◽  
Jeffrey Andolina ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Peripheral Blood ◽  
Hematopoietic Cell Transplantation ◽  
Disease Free Survival ◽  
Hematopoietic Cell ◽  
High Rate ◽  
Cell Transplant ◽  
Post Transplant ◽  
Conditioning Regimens ◽  
Haploidentical Hematopoietic Cell Transplantation

Abstract Due to the evolving use of haploidentical donor grafts in hematopoietic cell transplantation, there is increased need to better understand the risks and benefits of using bone marrow versus peripheral blood grafts, as well as how specific pre-transplantation conditioning regimens impact patient safety and treatment outcomes. We performed a retrospective analysis of 38 patients at two centers who specifically underwent haploidentical hematopoietic cell transplantation using fludarabine plus melphalan-based conditioning regimens with post-transplant cyclophosphamide and peripheral blood donor grafts. We observed an unexpectedly high rate of early non-relapse mortality of 21% at 100 days and 34% at 1-year. In addition, 40% of all patients suffered from severe cytokine release syndrome and 45% of all patients suffered from kidney injury, often necessitating renal replacement therapy. The poor outcomes with 1-year overall survival of 34%, disease-free survival of 29%, and non-relapse mortality of 34% motivate us to reconsider the appropriateness of the combination of fludarabine and melphalan conditioning with T-cell replete peripheral blood grafts in the setting of haploidentical hematopoietic cell transplant with post-transplant cyclophosphamide.

scholarly journals Burden and Impact of Geriatric Syndromes Associated with Allogeneic Hematopoietic Cell Transplantation in Older Adults

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3370-3370
Author(s):  
Richard J Lin ◽  
Theresa A Elko ◽  
Patrick Hilden ◽  
Parastoo B. Dahi ◽  
Ann A. Jakubowski ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Older Patients ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Geriatric Syndromes ◽  
The Impact

Abstract While there has been significant increase in the number of older patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT), the prevalence and the impact of geriatric syndromes associated with allo-HCT remains unknown. Using an institutional database and the electronic medical record, we retrospectively examined the incidence, predictive factors, and the impact of common geriatric syndromes of delirium, urinary incontinence, pressure ulcer, and mechanical fall among 527 patients age 60 and above (range 60-78.7) who underwent first allo-HCT for hematological malignancies at our institution from 2001 to 2016. We hypothesize that allo-HCT-associated geriatric syndromes negatively impact non-relapse mortality and overall survival. We identified all relevant geriatric events from the start of the conditioning regimen to 100 days post stem cell infusion. Among common geriatric syndromes, we found that delirium had the highest 100-day cumulative incidence at 21% (95% CI 18-25), followed by falls at 7% (95% CI 5-9) (Figure 1). There were only 11 incidences of new urinary incontinence and 3 incidences of new pressure ulcers. With a median follow-up of 46 months for survivors, the 3-year probability of overall survival and progression-free survival is 47% (95% CI 42-51) and 40% (95% CI 36-44), respectively (Figure 1). The 2-year cumulative incidence of non-relapse mortality is 28% (95% CI 24-32). We assessed the association of standard, pre-transplant patient demographic, clinical, geriatric, and laboratory characteristics with the cumulative incidence of delirium and fall. We found that prior fall within last year, potentially inappropriate medications use prior to transplant admission (defined by 2015 American Geriatric Society updated Beers criteria), platelet count <50 k/µl, creatinine clearance <60 ml/min predicted delirium in the multivariate analysis. Age over 70 and impaired activities of daily living (ADL) predicted fall in the multivariate analysis with prior fall within last year close to be a significant variable (Table 1). We next investigated the impact of delirium and fall on transplant outcomes. Delirium, but not fall, is independently associated with significantly increased risk of death at 100 days adjusted for standard transplant variables (OR 6.3, 95% CI 3-13.4, p<0.001). In addition, patients who experienced delirium and fall during their initial transplant admission had significantly increased length of stay (11 and 15 days longer, respectively, both p<0.001). In a landmark analysis of 100-day post-transplant survivors, both delirium and fall are associated with significantly increased long-term non-relapse mortality, with hematopoietic cell transplantation comorbidity index (HCT-CI) as an additional significant predictor (Table 2). While limited by the retrospective design and likely under-reporting, our findings establish for the first time the baseline incidence and predictors of common geriatric syndromes associated with allo-HCT. Importantly, we have demonstrated significant negative impact of delirium and fall on the short- and long-term transplant-associated mortality and morbidities. The temporal pattern and impact of geriatric delirium and fall warrants preemptive, targeted, longitudinal, and multidisciplinary interventions to improve transplant outcomes and to expedite functional recovery after allo-HCT for older patients. Disclosures Perales: Takeda: Other: Personal fees; Novartis: Other: Personal fees; Abbvie: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy.

Does Allogeneic Hematopoietic Cell Transplantation Benefit Older (≥ 60) AML/MDS Patients With Monosomal Karyotype?

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3399-3399
Author(s):  
James L Slack ◽  
Nandita Khera ◽  
Veena Fauble ◽  
Jose F Leis ◽  
Lisa Sproat ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Progression Free Survival ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Structural Abnormality ◽  
Free Survival ◽  
The Impact ◽  
Monosomal Karyotype

Abstract Background The prognosis for AML or MDS patients (pts) with monosomal karyotype (MK) is dismal. Although a benefit for allogeneic hematopoietic cell transplantation (allo-HCT) compared to chemotherapy or autologous HCT has been demonstrated in young (≤ 60) pts (Cornelissen, 2012), the curative potential of allo-HCT in older (≥ 60) pts with monosomal karyotype AML/MDS is not known. Patients and methods In this retrospective review, we analyzed outcomes for 69 AML (n = 49) or MDS (n = 20) pts ≥ 60 who underwent allo-HCT at Mayo Clinic Arizona between 2005 and 2013, based on cytogenetic grouping as follows: cytogenetically normal (CN, n = 23), cytogenetically abnormal but not MK (CA, n = 32), and MK (n = 14). Monosomal karyotype was defined (Breems, 2008) as a karyotype with at least two autosomal monosomies or a single autosomal monosomy in combination with at least one structural abnormality. Univariate and multivariate statistical analyses were performed to evaluate the impact of these 3 cytogenetic groupings on outcome (primary endpoint progression-free survival). The median age for all pts was 66 (60-76), and median follow-up for surviving pts was 22 months (range 70 days – 7.1 years). Thirty-seven pts had high-risk disease (MDS > 5% blasts or AML not in CR), while 32 were considered standard risk (MDS <5% blasts or AML in CR). The majority of pts had good performance status (KPS ≥ 90% in 66), but 34 pts (49%) had an HCT-CI score of ≥ 3. Conditioning was myeloablative (Bu-Cy) in 4, reduced toxicity FBM (Fludarabine, BCNU, Melphalan) in 36, and RIC/NMA in 29. Donors were matched related in 18, matched unrelated in 36, and mismatched unrelated in 15. GVHD prophylaxis included tacrolimus in all pts combined with mycophenolate mofetil (37) or methotrexate (32); 49 pts received in-vivo T-cell depletion with rabbit anti-thymocyte globulin (rATG, Thymoglobulin, Genzyme, Cambridge, MA). Results The Kaplan-Meier estimate of progression-free survival (PFS) at 2 yrs was 59% (CN), 39% (CA), and 1.5% (MK); P = 0.004 (Fig. 1). The cumulative incidence of relapse at 2 yrs (with death without relapse as a competing risk) was 34% (CN), 25% (CA), and 94% (MK); P= 0.009). In a Cox proportional hazards analysis adjusted for age (≤ 66 vs. > 66), risk status (standard vs. high), conditioning (myeloablative [Bu-Cy + FBM] vs. RIC/NMA), use of ATG (yes/no), donor type (unrelated vs. related), and HCT-CI (0-2 vs. ≥ 3), the only factor predictive for inferior PFS was cytogenetic status (MK vs. CN, HR 4.64 [95% CI, 1.7 – 13]; P = 0.003); (MK vs. CA, HR 2.4 [95% CI 0.97 – 5.9]; P = .057). Conclusions Standard allo-HCT in AML or MDS pts ≥ 60 with a monosomal karyotype appears to have limited curative potential. Although larger studies will be required to confirm our results, novel transplant approaches or post-transplant strategies to prevent relapse should be a focus of future studies in this incurable pt population. Disclosures: Reeder: Novartis: Research Funding; Celgene: Research Funding; Millennium: Research Funding.

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