scholarly journals Biologic Assignment Trial of Reduced-Intensity Hematopoietic Cell Transplantation Based on Donor Availability in Patients 50-75 Years of Age With Advanced Myelodysplastic Syndrome

2021 ◽  
pp. JCO.20.03380
Author(s):  
Ryotaro Nakamura ◽  
Wael Saber ◽  
Michael J. Martens ◽  
Alyssa Ramirez ◽  
Bart Scott ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cell Transplantation ◽  
Older Patients ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Hematopoietic Cell ◽  
Absolute Difference ◽  
No Donor ◽  
Matched Donor ◽  
Reduced Intensity

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for myelodysplastic syndromes (MDS), although it is infrequently offered to older patients. The relative benefits of HCT over non-HCT therapy in older patients with higher-risk MDS have not been defined. METHODS We conducted a multicenter biologic assignment trial comparing reduced-intensity HCT to hypomethylating therapy or best supportive care in subjects 50-75 years of age with intermediate-2 or high-risk de novo MDS. The primary outcome was overall survival probability at 3 years. Between January 2014 and November 2018, we enrolled 384 subjects at 34 centers. Subjects were assigned to the Donor or No-Donor arms according to the availability of a matched donor within 90 days of study registration. RESULTS The median follow-up time for surviving subjects was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No-Donor arm. In an intention-to-treat analysis, the adjusted overall survival rate at 3 years in the Donor arm was 47.9% (95% CI, 41.3 to 54.1) compared with 26.6% (95% CI, 18.4 to 35.6) in the No-Donor arm ( P = .0001) with an absolute difference of 21.3% (95% CI, 10.2 to 31.8). Leukemia-free survival at 3 years was greater in the Donor arm (35.8%; 95% CI, 29.8 to 41.8) compared with the No-Donor arm (20.6%; 95% CI, 13.3 to 29.1; P = .003). The survival benefit was seen across all subgroups examined. CONCLUSION We observed a significant survival advantage in older subjects with higher-risk MDS who have a matched donor identified and underwent reduced-intensity HCT, when compared with those without a donor. HCT should be included as an integral part of MDS management plans in fit older adults with higher-risk MDS.

scholarly journals Effect of Age on Outcome of Reduced-Intensity Hematopoietic Cell Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission or With Myelodysplastic Syndrome

2010 ◽  
Vol 28 (11) ◽  
pp. 1878-1887 ◽  
Author(s):  
Brian L. McClune ◽  
Daniel J. Weisdorf ◽  
Tanya L. Pedersen ◽  
Gisela Tunes da Silva ◽  
Martin S. Tallman ◽  
...  
Keyword(s):  
Complete Remission ◽  
Myelodysplastic Syndrome ◽  
Cell Transplantation ◽  
Older Patients ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Myelogenous Leukemia ◽  
The Impact ◽  
First Complete Remission ◽  
Reduced Intensity

PurposeAcute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) primarily afflict older individuals. Hematopoietic cell transplantation (HCT) is generally not offered because of concerns of excess morbidity and mortality. Reduced-intensity conditioning (RIC) regimens allow increased use of allogeneic HCT for older patients. To define prognostic factors impacting long-term outcomes of RIC regimens in patients older than age 40 years with AML in first complete remission or MDS and to determine the impact of age, we analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR).Patients and MethodsWe reviewed data reported to the CIBMTR (1995 to 2005) on 1,080 patients undergoing RIC HCT. Outcomes analyzed included neutrophil recovery, incidence of acute or chronic graft-versus-host disease (GVHD), nonrelapse mortality (NRM), relapse, disease-free survival (DFS), and overall survival (OS).ResultsUnivariate analyses demonstrated no age group differences in NRM, grade 2 to 4 acute GVHD, chronic GVHD, or relapse. Patients age 40 to 54, 55 to 59, 60 to 64, and ≥ 65 years had 2-year survival rates as follows: 44% (95% CI, 37% to 52%), 50% (95% CI, 41% to 59%), 34% (95% CI, 25% to 43%), and 36% (95% CI, 24% to 49%), respectively, for patients with AML (P = .06); and 42% (95% CI, 35% to 49%), 35% (95% CI, 27% to 43%), 45% (95% CI, 36% to 54%), and 38% (95% CI, 25% to 51%), respectively, for patients with MDS (P = .37). Multivariate analysis revealed no significant impact of age on NRM, relapse, DFS, or OS (all P > .3). Greater HLA disparity adversely affected 2-year NRM, DFS, and OS. Unfavorable cytogenetics adversely impacted relapse, DFS, and OS. Better pre-HCT performance status predicted improved 2-year OS.ConclusionWith these similar outcomes observed in older patients, we conclude that older age alone should not be considered a contraindication to HCT.

Reduced Intensity or Non-Ablative Hematopoietic Cell Transplantation in Older Patients with Non-Hodgkin Lymphoma (NHL): Encouraging Survival for Patients ≥55 Years

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1015-1015
Author(s):  
Brian McClune ◽  
Tanya L. Pedersen ◽  
Kwang W Ahn ◽  
Erica D Warlick ◽  
Joseph Pidala ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Cell Transplantation ◽  
Older Patients ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Hematopoietic Cell ◽  
Age Cohorts ◽  
Conditioning Regimens ◽  
Reduced Intensity

Abstract Abstract 1015 Non-Hodgkin lymphomas (NHL) disproportionately affect older patients. Hematopoietic cell transplantation (HCT) with non-ablative conditioning regimens is increasingly used to treat this population. We analyzed data reported to the CIBMTR on 1248 patients receiving either non-myeloablative (NMA) or reduced-intensity conditioning (RIC) HCT from 2001–2007 for both aggressive (n=668) and indolent (n=580) NHL testing the association of age on transplant-related mortality (TRM), relapse, engraftment, acute and chronic graft-versus-host disease (GVHD), progression-free (PFS) and overall survival (OS). Patients were stratified into 3 age cohorts: 40–54, 55–64, and ≥65 years. Clinical characteristics were mostly well-matched across age cohorts, but more frequent aggressive NHL histologies occurred in the oldest age group [67% vs. 49% (age 40–54) and 57% (age 55–64); p=0.0008] and fewer patients ≥65 years had prior autografts (9% vs. 26% and 24% in the younger groups; p=0.002); 30% of those ≥65 had resistant disease at HCT (vs. 25% and 23% in younger cohorts; p=0.79). Univariate analysis demonstrated no statistically significant differences in the incidence of relapse, acute or chronic GVHD across age cohorts (Table 1). We observed lower 1 year TRM for the youngest group, but TRM was similar in the two older cohorts. PFS and OS were also inferior in the two older cohorts, but no differences between those aged 55–64 and ≥65 were noted. Multivariate analysis (Table 2) revealed no independently significant impact of age on the incidence of acute (p=0.91) or chronic GVHD (p=0.66), or on relapse (p=0.06). Older age ≥55 years, lower Karnofsky performance status (KPS), and human leukocyte antigen (HLA) match disparity adversely impacted TRM, PFS, and OS. Advanced disease status (CR1/2 vs. PR1/2, or resistant) at HCT also significantly worsened TRM, relapse (p<0.0001), PFS and OS. Histology (aggressive vs. indolent) did not impact any multivariate model of outcomes. Compared to NMA regimens RIC worsened acute (p=0.007) and chronic (p=0.002) GVHD and OS (p=0.03), but not TRM or PFS. We conclude that patients ≥55 receiving non-ablative HCT for NHL have only modestly worse outcomes with no further decrement in those ≥65 years. These results are, however, influenced by KPS and disease status at time of HCT, and by HLA donor/recipient mismatch. Despite higher risk characteristics, 3 year survival still approached 40% for even the oldest groups making HCT a worthwhile option for these patients. Future work should focus on refining techniques for patient selection and optimizing conditioning regimens to improve these already encouraging results.Table 1.Univariate probabilities of patients receiving HCT for NHLN40–54N55–64N≥ 65P61455282TRM, 1 year22 (19–26)%27 (23–31)%34 (24–44)%0.05Relapse, 3 years28 (24–32)%33 (29–37)%33 (23–44)%0.22PFS, 3 years44 (39–48)%32 (28–36)%27 (17–37)%<0.0001OS, 3 years54 (50–58)%40 (36–44)%39 (28–50)%<0.0001Follow-up, median (months)56 (3–111)47 (2–111)47 (2–96)Table 2.Factors affecting multivariate analysis in patients receiving HCT for NHLAgeTRMPFSOSHRPHRPHRP    40–541.01.01.0    55–641.52<0.00011.37<0.00011.47<0.0001    65+1.570.021.330.041.470.01KPS    ≥ 801.01.01.0    < 801.87<0.00011.63<0.00011.87<0.0001HLA match    Identical sib1.01.01.0    URD well matched1.36<0.011.130.151.300.004    URD partial match2.30<0.00011.390.0031.90<0.0001    URD mismatch2.9<0.00012.28<0.00012.210.0001Disease Status    CR1/CR21.01.01.0    PR1/PR21.270.061.45<0.00011.290.01    Resistant1.90<0.00012.28<0.00011.97<0.0001 Disclosures: No relevant conflicts of interest to declare.

Residual Disease Detection by Flow Cytometry Predicts Risk of Relapse and Overall Survival in Patients with Acute Myeloid Leukemia Following Reduced Intensity- and Myeloablative- Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4098-4098
Author(s):  
Charlotte Ann Bradbury ◽  
Janice Ward ◽  
Paresh Vyas ◽  
Nigel H. Russell ◽  
Grimwade David ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Overall Survival ◽  
Cell Transplantation ◽  
Disease Burden ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Hematopoietic Cell ◽  
Post Transplant ◽  
Reduced Intensity ◽  
Acute Myeloid

Abstract Abstract 4098 Relapse after allogeneic hematopoietic cell transplantation (HCT) is usually incurable for acute myeloid leukemic (AML) patients. Residual disease (MRD) monitoring pre- and post-HCT may improve relapse prediction, allowing the targeted implementation of post-HCT interventions to at risk patients when disease burden is sufficiently low for these to be effective. Previous studies have shown that MRD detection by multiparameter flow cytometry (MRD MFC) at either pre- (Leung et al 2012, Walter et al 2011) or post- transplant (Yan et al 2012) timepoints is prognostic for myeloablative HCT outcome in AML. Quantification of hematopoietic populations enriched for leukemic stem cells such as CD34+CD38low or lymphoid-primed multi-potential progenitor-like (LMPP-like) (Lin-CD34+CD38lowCD90-CD45RA+) (Goardon et al 2011) may improve the specificity of MFC MRD assays. In this study we retrospectively evaluated the predictive value of MRD MFC at both pre- and post- HCT timepoints in a cohort of unselected AML/high risk myelodysplasia (MDS) patients (n=44) who underwent reduced intensity conditioning (RI n= 32, median age 59, range 34–70) or myeloablative (MA n=12, median age 28, range 19–47) HCT between June 2010 and November 2011 (Table 1). MFC MRD was assessed both by detection of standard leukemic- aberrant-immunophenotypes (LAIPs) (identified at presentation and/or relapse) and quantification of CD34+CD38low and LMPP-like progenitors (LSC-enriched progenitors, LSC-EP). Pre HCT, 37 patients (MA = 11, RI = 26) were assessable for MFC MRD. 15 (41%) were MRD positive (LAIP MRD+) and 47% (7/15) (MA = 37.5%, 3/8; RI = 57%, 4/7) of these relapsed post HCT compared to 8% (MA = 0%, RI = 9%) of MRD negative patients (LAIP-MRD-), (Fig 1 p 0.03). Post HCT, 34 patients (MA = 9, RI =25) were assessable for MFC MRD. 10 (37%) had detectable LAIP MRD positivity between 2 and 9 months post HCT. 80% of these relapsed (MA = 60%; RI = 100%) with a median disease free survival (DFS) post HCT of 5 months (MA = 4 months; RI = 5 months); there were no relapses in the 17 patients who remained LAIP MRD- at a median follow-up of 20 months (range 9–26). (p=0.0006, Figure 2a). Presence of MRD post-transplant was associated with significantly poorer overall survival (p=0.005). Although 1 patient with high MRD (in CR, LAIP >1%, LSC-EP +) pre HCT relapsed <3 months post HCT, in 8 of 9 other relapses MRD positivity detected at ≥ 2 months post HCT preceded clinical relapse by >1 month (median time to relapse from MRD detection of 1.5 months, range 1–6; OS, median 4 months, range 1 - not reached). CD34+CD38low progenitors (34+38low) were < 0.03% of bone marrow nucleated cells in the majority of patients. Detectable 34+38low were mainly CD45RA+ so in most cases correlated with LMPP-like quantitation. Pre HCT, 34+38low were detectable in 40% of patients who went on to relapse and in only 9% of those who have not yet relapsed. Post HCT, 34+38lowpositivity preceded frank relapse by ≥1 month in 60% of patients who relapsed. Only 6% of patients who have not yet relapsed had detectable 34+38low. LSC-LEP positivity appears prognostic for DFS and OS (Figure 2b) but for a lower frequency of relapses compared to LAIP MRD positivity (60% v 80%). Conclusions: These data suggest that post HCT MFC detection of LAIP MRD is predictive of relapse in RI as well as MA HCT. LSC-LEP quantitation may be prognostic in a subset of patients. Pre HCT MRD might be more predictive of relapse in RI than MA HCT. However, post HCT MRD positivity precedes most clinical relapses by a time window which may be sufficient for interventions such as azacytidine or donor lymphocyte infusion (DLI) when disease burden is still low. These results provide a basis for the use of MFC residual disease detection pre and post HCT to inform treatment decisions in reduced intensity as well as myeloablative HCT. Disclosures: No relevant conflicts of interest to declare.

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.

Hematopoietic Cell Transplantation-Specific Comorbidity Index To Predict Non-Relapse Mortality and Survival after Allografting.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2731-2731 ◽  
Author(s):  
Ruri Kato ◽  
Takahiro Fukuda ◽  
Eiji Usui ◽  
Satoshi Yamasaki ◽  
Dai Maruyama ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematologic Malignancies ◽  
Hematopoietic Cell ◽  
Organ Systems ◽  
Increased Risk ◽  
Comorbidity Index ◽  
Reduced Intensity

Abstract Pre-transplant comorbidity can affect the outcome of allogeneic hematopoietic cell transplantation (HCT). The Seattle group recently proposed a new HCT-specific comorbidity index (HCT-CI) which was based on the Charlson Comorbidity Index (Blood, prepublished online, June 30, 2005). To validate this scoring system, we retrospectively reviewed the medical records of 315 patients with hematologic malignancies who underwent allogeneic HCT after fludarabine-based reduced-intensity (n=160) or conventional (n=155) conditioning at our center between 2000 and 2004. The median age of the patients was 46 (range, 1–68) years. The diagnoses included acute myeloid leukemia or myelodysplastic syndrome (n=153), chronic myelogeneous leukemia (n=30), acute lymphoblastic leukemia (n=36), lymphoma (n=90), and other hematologic malignancies (n=6). Donors included HLA-matched (n=120) or mismatched (n=53) relatives and unrelated volunteers (n=142). Stem cell source was G-CSF-mobilized peripheral blood stem cell (n=169), bone marrow (n=117), or cord blood (n=29). We did not include the pulmonary function test results due to our inconsistency with the test. The HCT-CI captured 45% of patients with scores >0 (score 1, n=71; score 2, n=22; score 3, n=27; score 4, n=15; score >4, n=6). The capture rate of HCT-CI in patients who received reduced-intensity conditioning was higher than that in those who received conventional conditioning (51% vs 38%). The involved organ systems included hepatic (n=68), recent infection (n=38), prior malignancies (n=17), cardiac (n=16), renal (n=11), metabolic (n=11), psychiatric (n=11), pulmonary (n=8), and gastrointestinal (n=4) abnormalities. The Kaplan-Meier estimate of overall survival was significantly different among risk groups stratified according to HCT-CI (Figure 1, p<0.0001). In Cox proportional hazard models, a higher HCT-CI score, disease risk, and transplant from donors other than HLA-matched relatives were associated with poor overall survival. A higher HCT-CI score, greater patient age, and transplant from donors other than HLA-matched relatives were associated with a significantly increased risk for non-relapse mortality. In conclusion, the new HCT-CI using pre-transplant variables was the most significant predictor of non-relapse mortality and survival after allografting. Our validation study suggests that this index will be a useful tool for future use in clinical trials and standard practice. Overall Survival according to HCT-specific Comorbidity Index Overall Survival according to HCT-specific Comorbidity Index

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