scholarly journals Trends in Late Mortality and Life Expectancy after Autologous Blood or Marrow Transplantation (BMT) Performed over Three Decades - a BMT Survivor Study (BMTSS) Report

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 484-484
Author(s):  
Mukta Arora ◽  
Chen Dai ◽  
Wendy Landier ◽  
Lindsey Hageman ◽  
Jessica Wu ◽  
...  
Keyword(s):  
Life Expectancy ◽  
Pulmonary Disease ◽  
Research Funding ◽  
Malignant Neoplasms ◽  
Years Of Life Lost ◽  
Late Mortality ◽  
The Impact ◽  
Related Mortality ◽  
Privately Held

Abstract Background: Advances in therapeutic and supportive care strategies have led to increasing use of autologous BMT to ensure durable disease-free survival in patients with hematologic malignancies. However, autologous BMT recipients carry a high burden of morbidity. The cumulative effect of autologous BMT and the long-term morbidity on life expectancy remains unknown. Further, the impact of changes in transplant practice (older age at BMT, increasing proportion of patients undergoing autologous BMT for plasma cell dyscrasias [PCD], increasing use of peripheral blood stem cells [PBSCs] and decreasing use of total body irradiation [TBI]) on late mortality and life expectancy remains unknown. We determined trends in life expectancy and cause-specific late mortality after autologous BMT performed over a 33y period (1981-2014) using the resources offered by BMTSS - a multi-institutional collaborative designed to examine late morbidity and mortality after BMT. Methods: This retrospective cohort included 4,702 individuals who lived ≥2y after autologous BMT performed between 1981 and 2014 at three transplant centers. We examined trends in life expectancy and late mortality over four eras: 1981-1999; 2000-2005; 2006-2010; 2011-2014. Endpoints included all-cause, recurrence-related mortality (RRM) and non-recurrence-related mortality (NRM) and projected reduction in life expectancy. Information on vital status and cause of death was obtained from National Death Index (NDI) Plus program and Accurinct databases. End of follow-up was 04/19/2021. Results: Median age at BMT was 53y (range, 0-78); 58.7% were male, 67.8% non-Hispanic white. Median follow up after BMT was 9y (range, 2-36). PCD was the most common indication for autologous BMT (42.3%). PBSCs were used for 91.6% of the transplants and TBI was used for conditioning in 23.1% of the patients. Across the four eras, the median age at BMT increased (40y→58y), as did the proportion of patients receiving autologous BMT for PCD (13.7%→60.0%) and the proportion of patients receiving PBSCs as the stem cell source (66.6%→99.5%). There was a dramatic decline in the proportion of patients conditioned with TBI (56.4%→5.2%), and those transplanted for acute myeloid leukemia/ myelodysplastic syndrome (AML/MDS) (15.4%→0.2%). Conditional on surviving ≥2y after autologous BMT, patients experienced a 25.8% reduction in life expectancy, representing 7.0y of life lost. In an analysis adjusted for all relevant demographic and clinical predictors and restricted to 5y of follow-up, the years of life lost declined across the four eras from 5y to 1.6y (Fig 1) The adjusted hazard of all-cause mortality also declined over the four eras (reference: 1981-1999; hazard ratio [HR]2000-2005=0.77; 95%CI=0.7-0.9; HR 2006-2010=0.62; 95%CI=0.5-0.7; HR 2011-2014=0.5; 95%CI=0.4-0.6; P trend <0.0001) (Fig 2). Mediation analysis revealed that the reduction in late mortality was evident among those transplanted for Hodgkin lymphoma (HL) or PCD, and among those who did not receive TBI . The 30y cumulative incidence of NRM (29.2%) was higher than that RRM (23.8%) (Fig 3). The adjusted hazard of RRM declined over the four eras (reference: 1981-1999; HR 2011-2014=0.55; 95%CI=0.4-0.7, P trend: <0.0001). Cause-specific late mortality declined for mortality related to infection (P trend <0.0001), subsequent malignant neoplasms (P trend=0.01), cardiovascular disease (P trend=0.001), and renal disease (P trend=0.0002), but not for pulmonary disease (P trend=0.3). Conclusions and Relevance: Late mortality among autologous BMT recipients has declined over a 30y period, likely due to changes in transplant practice (reduction in use of TBI) and improvement in disease-specific therapeutic strategies (newer therapeutic options for PCD and reduction in dose/volume of radiation for HL). Continued efforts need to focus on mitigation strategies for disease recurrence, subsequent neoplasms, infections, and cardiovascular, renal and pulmonary disease in this population. Figure 1 Figure 1. Disclosures Arora: Kadmom: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding. Forman: Allogene: Consultancy; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company. Weisdorf: Incyte: Research Funding; Fate Therapeutics: Research Funding.

scholarly journals Chronic Health Conditions and Late Mortality Among Survivors of Childhood Acute Myeloid Leukemia: A Report from the Childhood Cancer Survivor Study (CCSS)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1315-1315
Author(s):  
Lucie M Turcotte ◽  
John A Whitton ◽  
Wendy M. Leisenring ◽  
Todd Gibson ◽  
Rebecca M Howell ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Health Conditions ◽  
Late Mortality ◽  
Treatment Groups ◽  
Childhood Acute Myeloid Leukemia ◽  
Health Related ◽  
Related Mortality

Introduction: Five-year survival following childhood acute myeloid leukemia (AML) has doubled over the last 4 decades due to advances in treatment and supportive care, including more widespread use of hematopoietic cell transplantation (HCT). The impact on long-term morbidity and mortality among survivors is unknown. Methods: Cumulative incidence and 95% confidence intervals (CI) for overall and cause-specific late (>5 years from diagnosis) mortality and CTCAE grades 3-5 chronic health conditions (CHC) were estimated among 5-year survivors of AML diagnosed <21 years of age between1970-99 in the CCSS. Comparisons were made by decade of diagnosis (1970s, 1980s, 1990s) and treatment (HCT vs. chemotherapy only [chemo-only]). Cox regression models estimated hazard ratios (HR) for health-related deaths and CHC based on treatment decade and HCT status. Results: Among 927 AML survivors (median age at diagnosis 7.1 years [range 1-21 years]; median age at last follow-up 29.4 years [range 8-60 years]; 16,069 person-years of follow-up; 37% treated with HCT [15% of 1970s survivors, 36% of 1980s survivors, 44% of 1990s survivors), the 20-year cumulative incidence of all-cause mortality was 6.7% (CI 4.2-9.2%) for chemo-only survivors and 13.5% (CI 9.2-17.8%) for HCT survivors. For chemo-only survivors, the highest incidence of health-related mortality were attributable to cardiac causes (1.5%, CI 0.5-2.6), relapse (0.9%, CI 0.1-1.8), and SMN (0.6%, CI 0.0-1.2), whereas for HCT survivors the highest health-related causes of death were relapse (6.5%, CI 3.7-9.2%), SMN (1.3%, CI 0-2.5%), and pulmonary causes (0.6%, CI 0-1.5%). When treatment groups were considered in multivariable Cox models, risk for late mortality was similar for chemo-only survivors from the 1990s compared to the 1970s (HR 0.4, CI 0.1-1.4), but risk was reduced for HCT survivors from the 1990s compared to the 1970s (HR 0.2, CI 0.1-0.4). The 20-year cumulative incidence of grade 3-5 CHCs among chemo-only survivors was 26.9% (CI 23.0-30.7%) compared to 46.8% (CI 40.9-52.7%) among HCT survivors, with the highest incidence occurring for cardiovascular CHC (chemo-only, 9.7%, CI 7.1-12.2%; HCT, 10.6%, CI 7.0-14.2%), pulmonary CHC (chemo-only, 1.0%, CI 0.1-1.9%; HCT, 2.9%, CI 1.0-4.8%) and SMN (chemo-only, 0.8%, CI 0.0-1.7%; HCT, 5.7%, CI 2.9-8.6%). Incidence of overall CHC decreased in more recent decades among HCT survivors (p=0.03, Figure); however, among chemo-only survivors, CHC incidence did not significantly change by decade (p=0.12). When treatment groups were considered in adjusted models, risk for CHC was similar for those treated in the 1990s compared to the 1970s among chemo-only survivors (HR 1.5, CI 1.0-2.3) and risk estimates among HCT survivors decreased over time but did not achieve statistical significance (HR 0.6, CI 0.3-1.1). Conclusions: AML survivors treated with HCT had a reduced risk of late mortality and serious CHC in more recent treatment eras. In contrast, treatment with chemo-only was not associated with differences in mortality and serious CHC risk over time. Five-year survivors treated with chemo-only had a significantly reduced risk of health-related mortality compared with HCT survivors across all treatment eras. While treatment intensification with HCT has improved the cure rates for AML in recent decades, there remains disparity in long-term outcomes among AML survivors treated with HCT vs. chemo-only. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Impact of Clonal Hematopoiesis of Indeterminate Potential on Survival in Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4359-4359
Author(s):  
Koji Sasaki ◽  
Rashmi Kanagal-Shamanna ◽  
Guillermo Montalban-Bravo ◽  
Rita Assi ◽  
Kiran Naqvi ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Next Generation ◽  
Risk Of Death ◽  
Genetics Research ◽  
The Impact ◽  
Generation Sequencing

Abstract Introduction: Clearance of detected somatic mutations at complete response by next-generation sequencing is a prognostic marker for survival in patients with acute myeloid leukemia (AML). However, the impact of allelic burden and persistence of clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations on survival remains unclear. The aim of this study is to evaluate the prognostic impact of allelic burden of CHIP mutations at diagnosis, and their persistence within 6 months of therapy. Methods: From February 1, 2012 to May 26, 2016, we reviewed 562 patients with newly diagnosed AML. Next-generation sequencing was performed on the bone marrow samples to detect the presence of CHIP-associated mutations defined as DNMT3A, TET2, ASXL1, JAK2 and TP53. Overall survival (OS) was defined as time period from the diagnosis of AML to the date of last follow-up or death. Univariate (UVA) and multivariate Cox proportional hazard regression (MVA) were performed to identify prognostic factors for OS with p value cutoff of 0.020 for the selection of variables for MVA. Landmark analysis at 6 months was performed for the evaluation of the impact of clearance of CHIP, FLT3-ITD, FLT3D835, and NPM1 mutations. Results: We identified 378 patients (74%) with AML with CHIP mutations; 134 patients (26%) with AML without CHIP mutations. The overall median follow-up of 23 months (range, 0.1-49.0). The median age at diagnosis was 70 years (range, 17-92) and 66 years (range, 20-87) in CHIP AML and non-CHIP AML, respectively (p =0.001). Of 371 patients and 127 patients evaluable for cytogenetic in CHIP AML and non-CHIP AML, 124 (33%) and 25 patients (20%) had complex karyotype, respectively (p= 0.004). Of 378 patients with CHIP AML, 183 patients (48%) had TET2 mutations; 113 (30%), TP53; 110 (29%), ASXL1; 109 (29%), DNMT3A; JAK2, 46 (12%). Of 378 patients, single CHIP mutations was observed in 225 patients (60%); double, 33 (9%); triple, 28 (7%); quadruple, 1 (0%). Concurrent FLT3-ITD mutations was detected in 47 patients (13%) and 12 patients (9%) in CHIP AML and non-CHIP AML, respectively (p= 0.287); FLT3-D835, 22 (6%) and 8 (6%), respectively (p= 0.932); NPM1 mutations, 62 (17%) and 13 (10%), respectively (p= 0.057). Of 183 patients with TET2-mutated AML, the median TET2 variant allele frequency (VAF) was 42.9% (range, 2.26-95.32); of 113 with TP53-mutated AML, the median TP53 VAF, 45.9% (range, 1.15-93.74); of 109 with ASXL1-mutated AML, the median ASXL1 VAF was 34.5% (range, 1.17-58.62); of 109 with DNMT3A-mutated AML, the median DNMT3A VAF was 41.8% (range, 1.02-91.66); of 46 with JAK2-mutated AML, the median JAK2 VAF was 54.4% (range, 1.49-98.52). Overall, the median OS was 12 months and 11 months in CHIP AML and non-CHIP AML, respectively (p= 0.564); 16 months and 5 months in TET2-mutated AML and non-TET2-mutated AML, respectively (p <0.001); 4 months and 13 months in TP53-mutated and non-TP53-mutated AML, respectively (p< 0.001); 17 months and 11 months in DNMT3A-mutated and non-DNMT3A-mutated AML, respectively (p= 0.072); 16 months and 11 months in ASXL1-mutated AML and non-ASXL1-mutated AML, respectively (p= 0.067); 11 months and 12 months in JAK2-murated and non-JAK2-mutated AML, respectively (p= 0.123). The presence and number of CHIP mutations were not a prognostic factor for OS by univariate analysis (p=0.565; hazard ratio [HR], 0.929; 95% confidence interval [CI], 0.722-1.194: p= 0.408; hazard ratio, 1.058; 95% confidence interval, 0.926-1.208, respectively). MVA Cox regression identified age (p< 0.001; HR, 1.036; 95% CI, 1.024-1.048), TP53 VAF (p= 0.007; HR, 1.009; 95% CI, 1.002-1.016), NPM1 VAF (p=0.006; HR, 0.980; 95% CI, 0.967-0.994), and complex karyotype (p<0.001; HR, 1.869; 95% CI, 1.332-2.622) as independent prognostic factors for OS. Of 33 patients with CHIP AML who were evaluated for the clearance of VAF by next generation sequencing , landmark analysis at 6 months showed median OS of not reached and 20.3 months in patients with and without CHIP-mutation clearance, respectively (p=0.310). Conclusion: The VAF of TP53 and NPM1 mutations by next generation sequencing can further stratify patients with newly diagnosed AML. Approximately, each increment of TP53 and NPM1 VAF by 1% is independently associated with 1% higher risk of death, and 2% lower risk of death, respectively. The presence of CHIP mutations except TP53 does not affect outcome. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Short:Takeda Oncology: Consultancy. Ravandi:Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Sunesis: Honoraria; Xencor: Research Funding; Jazz: Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria. Kadia:BMS: Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Celgene: Research Funding. DiNardo:Karyopharm: Honoraria; Agios: Consultancy; Celgene: Honoraria; Medimmune: Honoraria; Bayer: Honoraria; Abbvie: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

Abstract 14499: Impact of Pre-existing and New Incident Atrial Fibrillation on Outcomes of Patients With Acute Pulmonary Embolism: Findings From an International Registry

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Behnood Bikdeli ◽  
David Jimenez ◽  
Jorg Del Toro ◽  
Gregory Piazza ◽  
Augussina Rivas ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Pulmonary Embolism ◽  
Ischemic Stroke ◽  
Acute Pulmonary Embolism ◽  
Adverse Outcomes ◽  
Risk Of Mortality ◽  
Patient Groups ◽  
The Impact ◽  
Related Mortality

Background: Atrial fibrillation (AF) may occur prior to or early in the course of acute pulmonary embolism (PE). The impact of AF on outcomes of patients with PE remains uncertain. Methods: Using the data from a large prospective multicenter registry of patients with objectively-confirmed PE (04/2014 to 01/2020), we identified three patient groups: 1) those with pre-existing AF 2) patients with newly identified AF within 2 days from the index PE (incident AF) and 3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, in unadjusted and multivariable adjusted models considering those without AF as referent. Results: Among 16,497 patients with PE, 792 had pre-existing AF. Compared with those without AF, patients with pre-existing AF, had increased odds of 90-day all-cause (Odds ratio [OR]: 2.81 (95% confidence interval [CI]: 2.33-3.38) and PE-related mortality (OR: 2.38, 95% CI: 1.37-4.14). After multivariable adjustment, pre-existing AF significantly increased the odds of all-cause mortality (OR: 1.91, 95% CI: 1.57-2.32) but not PE-related mortality (OR: 1.50; 95% CI: 0.85-2.66). Pre-existing AF was associated with increased hazard for ischemic stroke at 1-year follow-up (hazard ratio [HR]: 5.48; 95% CI: 3.10-9.69). Among 16,497 patients with PE, 445 developed incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR: 2.28; 95% CI: 1.75-2.97) and PE-related (OR: 3.64; 95% CI: 2.01-6.59) mortality. Findings were similar in multivariable analyses and at 1-year follow-up (Figure). No patients with incident AF developed ischemic stroke. Conclusion: In patients with acute symptomatic PE, both pre-existing AF and incident AF predict an adverse clinical course, although the type of adverse outcomes may be different depending on the timing of AF onset.

scholarly journals Failure to reach uric acid target of <0.36 mmol/L in hyperuricaemia of gout is associated with elevated total and cardiovascular mortality

RMD Open ◽  
2019 ◽  
Vol 5 (2) ◽  
pp. e001015 ◽  
Author(s):  
Fernando Pérez Ruiz ◽  
Pascal Richette ◽  
Austin G Stack ◽  
Ravichandra Karra Gurunath ◽  
Ma Jesus García de Yébenes ◽  
...  
Keyword(s):  
Uric Acid ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
First Year ◽  
Cox Proportional Hazards Models ◽  
Crude Mortality ◽  
Risk Patients ◽  
The Impact ◽  
Related Mortality

ObjectiveTo determine the impact of achieving serum uric acid (sUA) of <0.36 mmol/L on overall and cardiovascular (CV) mortality in patients with gout.MethodsProspective cohort of patients with gout recruited from 1992 to 2017. Exposure was defined as the average sUA recorded during the first year of follow-up, dichotomised as ≤ or >0.36 mmol/L. Bivariate and multivariate Cox proportional hazards models were used to determine mortality risks, expressed HRs and 95% CIs.ResultsOf 1193 patients, 92% were men with a mean age of 60 years, 6.8 years’ disease duration, an average of three to four flares in the previous year, a mean sUA of 9.1 mg/dL at baseline and a mean follow-up 48 months; and 158 died. Crude mortality rates were significantly higher for an sUA of ≥0.36 mmol/L, 80.9 per 1000 patient-years (95% CI 59.4 to 110.3), than for an sUA of <0.36 mmol/L, 25.7 per 1000 patient-years (95% CI 21.3 to 30.9). After adjustment for age, sex, CV risk factors, previous CV events, observation period and baseline sUA concentration, an sUA of ≥0.36 mmol/L was associated with elevated overall mortality (HR=2.33, 95% CI 1.60 to 3.41) and CV mortality (HR=2.05, 95% CI 1.21 to 3.45).ConclusionsFailure to reach a target sUA level of 0.36 mmol/L in patients with hyperuricaemia of gout is an independent predictor of overall and CV-related mortality. Targeting sUA levels of <0.36 mmol/L should be a principal goal in these high-risk patients in order to reduce CV events and to extend patient survival.

Can Addition of GM-CSF in Adult Haplo-Identical Transplant Who Cannot Benefit from NK Alloreactivity Improve the Relapse Rate of Advanced Leukemia: A 3 Step Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4975-4975
Author(s):  
Philippe Lewalle ◽  
Alain Delforge ◽  
Berengere Nowak ◽  
Virginie Misplon ◽  
Laurence Lagneaux ◽  
...  
Keyword(s):  
Relapse Rate ◽  
Good Tolerance ◽  
Gm Csf ◽  
Poor Risk ◽  
Advanced Stages ◽  
One Year ◽  
Time To Relapse ◽  
The Impact ◽  
Related Mortality

Abstract Haplo-identical transplant is now established as a procedure of choice for patients who lack a compatible donor. It might even be the best choice for AML, provided there is a GvH NK alloreactivity. However, patients are still referred too late, heavily pre-treated, at very advanced stages. We initiated a three-step phase I study trying improve transplant related mortality, relapse rate and immunity: (1): G-CSF + DLI, (2): GM-CSF + DLI, (3): patient and disease adapted strategy. Thirty-four consecutive leukemia patients, aged 18–55, were investigated (20 very poor risk, 11 poor risk and 3 better risk). GvH type NK alloreactivity was chosen when possible (19/34) and balanced across the 3 groups. In the first 9 patients, G-CSF was used pot-transplant and prophylactic DLI were given at month 1, 2 and 3. The use of G-CSF and 1 to 3 DLI (104 CD3/kg) was found safe. It resulted in faster CD4 recovery and a low rate of infections. However, it was insufficient to induce a protective GVL effect. In the next 12 patients, GM-CSF was used plus 1 DLI (104 CD3/kg) at day 30 unless aGVHD (3 pts). The comparison between the 2 first groups can be summarized as follows: G-CSF + DLI: TRM at day 100: 0, RR: 6/9, severe aGVHD:0. GM-CSF + 1 DLI group: RR: 1/12, TRM at day 100: 3, aGVHD grade 2 or more: 9/12; price to pay: GVHD resulting in 5 deaths in total. Median time to relapse in the 21 first patients was 6 months (range 4 to 9). Step 3 (14 patients) consists of a patient adapted strategy: no more aspecific DLI (selected anti-CMV and aspergillus DLI planned in all patients); in myeloid disorders with NK alloreactivity: no GF. In the other cases, GM-CSF (at a reduced total dose of 500 mcg) is given from day 5 to day 9. The follow-up of these 14 patients, although promising (2 relapses), is currently short (median 5 months), compared to the median of relapse in the 2 first groups (6 months) but will be updated for the meeting (10 months and 17 patients). Overall, TRM at day 100 is 3/29, reflecting the good tolerance of the conditioning in a heavily pre-treated population (median age : 43). Overall NR-mortality at one year is 8/26, but was greater in the GM-CSF + DLI group, reflecting the impact of severe aGVHD. In the current group, its is 2/14 at 3 months. We conclude that the third strategy might improve the outcome and the relapse rate without exposing patients to unnecessary severe GVHD.

Alemtuzumab Plus Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Transplantation in Ultra High-Risk CLL: Interim Analysis of a Phase II Study of the GCLLSG and fcgcll/MW

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2854-2854 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Florence Cymbalista ◽  
Véronique Leblond ◽  
Alain Delmer ◽  
Dirk Winkler ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Response Rates ◽  
Long Term Results ◽  
High Dose ◽  
Significant Difference ◽  
Ultra High Risk ◽  
Grade 3 ◽  
The Impact

Abstract Abstract 2854 Alemtuzumab (A) proved to be efficacious in CLL patients (pts) with very poor prognosis, either due to fludarabine (F) refractoriness or due to unfavorable cytogenetics (17p-). However, rate and duration of remissions still remain unsatisfactory. Therefore, the French and German CLL study groups jointly embarked on this trial, trying to achieve higher overall response rates (ORR) by adding high-dose dexamethasone (D) to A and, simultaneously, investigating the consolidation effect of prolonged A maintenance or allogeneic stem-cell transplantation (allo-SCT), respectively. Induction treatment consisted of subcutaneous A 30 mg weekly × 3 for 28 days, combined with oral D 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg on days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or A maintenance with 30 mg every 14 days for up to 2 years (y), at the discretion of pt and physician. Between January 2008 and July 2011, 124 pts were recruited at 26 centers, 120 of whom were eligible. Pts were generally subdivided into three cohorts: 55 pts were refractory (i.e. no response or relapse within 6 months) to regimens containing F or a similar drug (i.e. pentostatin, cladribine, bendamustine). Non-refractory pts all exhibited 17p- and had either untreated (n=39) or relapsed CLL (n = 26) requiring therapy. The median age was high with 66/64/66 y in 17p- 1st line, 17p- relapse, and F-refractory pts, respectively. The three cohorts had 46/54/75% Binet C disease, 41/35/27% B symptoms, 38/42/53% reduced performance status (ECOG 1/2), median thymidine kinase levels of 35/49/24 U/L, median ß2MG levels of 3.8/5.5/4.6 mg/L, and IGHV was unmutated in 89/96/87%. In the F-refractory group, 53% exhibited 17p deletion and 22% had 11q deletion. Pretreated patients had received a median of 3 (F-refractory) or 2 prior lines (17p- relapse). 5 pts had previously undergone autologous and 1 pt allo-SCT. Treatment and efficacy data are currently available for 87 pts who completed induction therapy :17p- 1st-line (n=30), 17p- relapse (n=17), and F-refractory (n=40). Of these, 80/53/55% received the full induction of 12 weeks. ORR (best observed status) was generally high with 97/76/70%. CR was achieved in 20/0/5%. After a median follow-up of 11.8 months (mo), median progression-free survival (PFS) was 16.9/10.4/8.4 mo. Deaths are recorded in 13/27/36% of pts, with median overall survival (OS) not yet reached (>24 mo) in the 17p- 1st line group, and 15/12 mo in 17p- relapse/F-refractory pts. Consolidation treatment was performed as maintenance A (median duration 32 weeks, range 2 – 89) in 34%, and allo-SCT in 30%, with a median age of 66 and 61 y in these subgroups. The main reasons for going off-study without consolidation were death due to infection (14%, n=11, of these 6 without response, and 10 in the F-refractory cohort), CLL progression (12%), and other toxicity (5%). Among the 28 pts not receiving consolidation, there were 19 (68%) deaths, 15 of them in the F-refractory cohort. When comparing A maintenance and allo-SCT for consolidation, there were 9 (35%) and 7 (30%) PD events, respectively and there was so far no significant difference in PFS (median 17 mo in both groups) or OS. During induction, grade 3/4 hematotoxicity consisted of anemia in 28%, neutropenia in 47%, and thrombopenia in 44%. Grade 3/4 non-CMV infection occurred in 29% of 17p- 1st-line, 15% of 17p- relapsed, and 56% of F-refractory pts. CMV reactivation was observed in 54/25/40%, without severe sequelae recorded. During A maintenance, grade 3/4 toxicity consisted of neutropenia in 39% pts and thrombopenia in 4% pts with 6 SAEs (ITP, diarrhea, infection, erythema, tachycardia, and thrombosis). Conclusions: The combination of A and D shows high response rates in ultra high-risk CLL, with promising preliminary findings for PFS and OS, despite the high median age of the pts. The results compare favorably to ORR/CR of 68%/5%, and median PFS of 11.3 mo in the 17p- subgroup of the CLL8 study treated with FCR, consisting of younger pts (median 61 y). In F-refractory CLL however, when compared to the preceding CLL2H study with single agent A, the improved initial response by adding dexamethasone does not seem to translate into improved long-term results. More mature follow-up is needed, especially with respect to the impact of allo-SCT. Disclosures: Stilgenbauer: Amgen: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: Alemtuzumab in 1st line CLL treatment. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding. Hinke:WiSP (CRO): Employment.

24-Month Analysis of the Impact of Chelation on Clinical Outcomes in a 600 Patient Registry of Lower-Risk MDS Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2800-2800 ◽  
Author(s):  
Roger M. Lyons ◽  
Billie J. Marek ◽  
Surabhi Sharma ◽  
Carole Paley ◽  
Jason Esposito ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Lower Risk ◽  
Research Funding ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Disease Status ◽  
Cardiac Events ◽  
Leukemic Transformation ◽  
The Impact

Abstract Abstract 2800 Introduction: Many patients with MDS require regular transfusions. Several reviews have documented poorer clinical outcomes and overall survival (OS) in transfusion-dependent MDS patients. A US registry of 600 lower-risk MDS patients prospectively collected data on clinical outcomes in chelated and non-chelated transfused patients. This 24-month interim analysis reports on cardiac events, leukemic transformation and OS. Methods: This is a 5-year, non-interventional registry in MDS patients (aged ≥18 years) with lower-risk MDS (based on WHO, FAB and/or IPSS criteria) from 107 US centers. Patients had to have transfusional iron overload (serum ferritin ≥1000 μg/L and/or ≥20 packed red blood cell units and/or ongoing transfusion requirement of ≥6 units every 12 weeks). Follow-up was every 6 months for up to 60 months or death. Use of chelation therapy was not required. Chelated patients were those who had ever used iron chelation; a sub-analysis was done on patients with ≥6 months chelation. Assessments included demographics, disease status, MDS therapy, comorbidities, and causes of death. Differences between non-chelated and chelated patients are reported. Results: 600 patients enrolled; as of May 26, 2011, 249 continued in the registry. 351 patients discontinued due to: lost to follow-up (n=51, 8.5%); death (n=278, 46.3%); other (n=22, 3.7%). 263/600 patients received chelation therapy, of whom 191 received ≥6 months. Leukemic transformation and cardiac events were more common in non-chelated patients (Table 2). Time to leukemic transformation was significantly shorter in non-chelated versus chelated patients. A greater percentage of deaths occurred in non-chelated patients; time to death was significantly shorter in non-chelated versus chelated patients. The most frequent reasons for death were MDS/AML, cardiac, and infection. At baseline, non-chelated patients had a higher incidence of cardiac disorders than chelated patients (51.3% vs 35%). While on the registry, non-chelated patients had a higher incidence of comorbidities than did chelated patients, predominantly vascular, cardiac and endocrine. Lifetime use of MDS therapies (pre- and on-registry) was lower among non-chelated versus chelated patients (88.4% vs 94.3%). Conclusions: At the 24-month analysis, use of chelation was associated with lower AML transformation, fewer cardiac events, and better OS. The two patients groups had similar age, gender, and risk status breakdown (IPSS); however the non-chelated group had a higher prevalence of cardiac comorbidities. Ongoing follow-up for the 5-year duration of this registry will provide further data on differences in outcomes between chelated and non-chelated patients. Disclosures: Lyons: Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Telik: Research Funding; Alexion: Consultancy, Honoraria; Novartis: Research Funding. Sharma:Novartis: Employment. Paley:Novartis: Employment. Esposito:Novartis: Employment.

Equivalent Outcome Between Reduced Intensity Versus Conventional Myeloablative Conditioning Hematopoietic Stem Cell Transplantation for Patients Older Than 35 Years with Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3103-3103
Author(s):  
Marie Sebert ◽  
Raphaël Porcher ◽  
Marie Robin ◽  
Lionel Ades ◽  
Emmanuel Raffoux ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Cox Regression ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Abstract 3103 Introduction: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) provides the best chance of long-term survival for patients with intermediate or high-risk acute myeloid leukemia (AML). The major limitation of this procedure is the risk of treatment related mortality (TRM). Use of reduced intensity conditioning (RIC) regimen has become standard practice among older candidates with comorbidities. Although RIC regimen have been used for over a decade in older patients, the benefit of this approach in younger patients with AML compared with the risk of toxicity of standard regimen (MAC) is still discussed. We compared the outcomes for patients with AML over 35 years using RIC or MAC HSCT. Patients, methods, and transplantation characteristics: From January 2000 to December 2010, 132 consecutive patients older than 35 years with AML (18 secondary AML) received HSCT in our center, either from siblings (n=87) or HLA 10/10 allele-matched donors (n=45). MAC (n=72) and RIC (n=60) regimens were defined as previously described (Bacigalupo, 2009). Seventy-three patients were in first complete remission (CR1); 30% of patients had poor risk cytogenetics (MRC classification). Karnofsky performance status was scored at time of HSCT. Engraftment, acute and chronic graft-versus-host disease (GvHD), transplantation-related mortality (TRM), relapse rate as well as overall survival (OS) at 4 years were compared according to the intensity of the conditioning regimen. First a classical multivariable Cox analysis was conducted. In a second step, baseline confounding factors were adjusted for using inverse probability-of-treatment weighting (IPTW). Results of the comparison: Patient characteristics according to the intensity of the conditioning regimen were similar for AML type (de novo versus secondary), gender, karnofsky performance status, CR#, donor type and number of CD34+ infused. Particularly, cytogenetic risks were comparable in both groups. Patients were younger in the MAC group (median age 44 years [range 35 to 56 years] vs 54[37 to 66] for RIC, p<0,0001), received mainly bone marrow as source of stem cells (54% versus 2% for RIC, p<0,0001) and GvHD prophylaxis using cyclosporine plus methotrexate (89% versus 5% for RIC, p<0,0001). Moreover, ATG in the conditioning regimen (more ATG in RIC: 51 vs. 14%, p<0.0001), donor age (older for RIC: 49 vs. 39 years, p=0.002) and number of nucleated cells infused (higher in RIC: 11 vs. 4 × 108/kg, p<0.0001) were also different. The median follow-up was 47 months (10 to 134), and 25% of patients had a follow-up of at least 74 months. During evolution, all patients engrafted. The cumulative incidence (CIf) of acute GVHD grade II-IV was 49% (35% after RIC vs 61% after MAC, p=0.001). The 5-year CIf of chronic GVHD was 37% (40% after RIC vs 30% after MAC, p=0.32). During FU, 71 patients died. The 5-year CIf of TRM was 21% (13% after RIC vs 28% after MAC, p=0.009). Adjusting for cytogenetic risk, gender donor/recipient mismatch and infused nucleated cells, no difference was observed between RIC and MAC (HR 0.9, p=0.16). The 5-year CIf of relapse was 42% (51% after RIC vs 35% after MAC (p=0.22)). Adjusting for gender donor/recipient mismatch, donor/recipient CMV serostatus and infused CD34+ cells, no marked difference was observed between RIC and MAC (HR 0.8, 95%CI 0.4–1.5, p=0.50). The 5-year OS was 39% (50% after RIC vs 34% after MAC, p=0.38). Using both Cox regression and IPTW to account for imbalance in patients characteristics, similar OS was found after RIC and MAC (Figure 1), with adjusted HRs for MAC vs RIC of 0.9 (95%CI 0.4–1.8, p=0.68) with Cox regression and 0.9 (95%CI 0.4–1.8, p=0.76) with IPTW. Conclusion: In patients with AML over 35 years, MAC regimen lead to a non significant higher rate of treatment related mortality with no benefit in terms of relapse when compared with RIC regimen. Until prospective trials are completed, this study supports the use of a RIC regimen for patients with AML older than 35 years who are transplanted either from siblings or matched unrelated donors. Disclosures: Fenaux: Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Early CMV Reactivation Still Remains a Cause of Increased Transplant Related Mortality in the Current Era: A CIBMTR Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 47-47 ◽  
Author(s):  
Muthalagu Ramanathan ◽  
Pierre Teira ◽  
Minoo Battiwalla ◽  
A. John Barrett ◽  
Caroline A Lindemans ◽  
...  
Keyword(s):  
Research Funding ◽  
Negative Impact ◽  
Multivariable Analysis ◽  
Time Dependent ◽  
Positive Serology ◽  
Increased Risk ◽  
The Impact ◽  
Cmv Reactivation ◽  
Risk Of Relapse ◽  
Related Mortality

Abstract Introduction: Since the early days of allogeneic hematopoietic cell transplantation (HCT), positive serology for cytomegalovirus (CMV) in either the recipient or the donor, and CMV reactivation have been associated with poorer outcomes. In the 90’s, development of effective monitoring and potent antiviral drugs minimized and occasionally abrogated this negative impact. Recently, some studies have reported an unexpected association between early CMV reactivation and decreased incidence of relapse in AML. The Center for International Blood and Marrow Research (CIBMTR) sought to conduct a retrospective large scale study to reassess the impact of CMV serology and CMV reactivation in the current era. Methods: The analysis includes comprehensive data of 11,153 patients undergoing first allogeneic HCT between 2003 and 2010 reported to the CIBMTR. Separate analyses were conducted for each of the 6 patient categories: AML transplanted with bone marrow (BM) or peripheral blood stem cell (PBSC) (n=5310), AML transplanted with cord blood (CB) (n= 925), ALL with BM/PBSC (n=1883), ALL with CB (n= 759), CML with BM/PBSC (n=1079) and MDS with BM/PBSC (n=1197). CMV serology from the donor (D) or recipient (R), and reactivation of CMV (as a time-dependent co-variate) within the first year after HCT were analyzed as risk factors for outcomes. The median duration of follow up was 56 months (1 – 127 months). Results: The median time to CMV reactivation was 40 days (1 – 362 days) after HCT and 98% of reactivations occurred before day 100 (D+/R+ 32%, D+/R- 11%, D-/R+ 34%, D-/R- 4%). In multivariable analysis, throughout the 6 groups, a positive serology (D+/R+, D+/R-, D-/R+) vs a negative serology (D-/R-),had no effect on the risk of GVHD (acute or chronic) or the risk of relapse, except for an increased risk of chronic GVHD for BM/PBSC recipients with ALL. CMV positive serology was associated with a higher transplant related mortality (TRM) and a poorer overall survival (OS). For a R+ patient, a D- compared to a D+, had no negative impact except for ALL with BM/PBSC where a D- was associated with a poorer OS. After PBSC/BM transplantation, CMV reactivation was associated with a higher TRM for MDS (RR=1.61, p=0.0002), CML (RR=1.86, p=0.0004), AML (RR=1.68; p<0.0001) and ALL (RR=1.95; p<0.0001), translating into lower OS (range of RR from 1.27 to 1.49; p value from 0.003 to <0.0001). Only among AML patients following CB transplantation, CMV reactivation did not worsen OS. Moreover, CMV reactivation had no effect on the incidence of relapse irrespective of the diagnosis or the source of stem cells. Finally, we conducted a subset analysis focusing on the group of AML, transplanted with PBSC after a myeloablative conditioning regimen and with a GVH prophylaxis relying on Ciclosporine and Methotrexate only. In multivariable analysis, there was no difference in the risk of relapse based on CMV reactivation as a time-dependent co-variate [RR 0.96 (0.65 – 1.4), p=0.8385]. Conclusion: Positive D/R CMV serology still results in increased TRM and decreased OS after HSCT in the current era. Early CMV reactivation did not prevent relapse in patients with AML, MDS, CML or ALL after HCT. Disclosures Boeckh: Chimerix: Consultancy, Research Funding; Viropharma: Research Funding; Genentech/Roche: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Clinigen: Consultancy.

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