scholarly journals Evaluation of International Working Group 2006 Response Criteria in Patients with Higher-Risk Myelodysplastic Syndromes (HR-MDS) Treated with Hypomethylating Agent Monotherapy in the Frontline Setting

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3701-3701
Author(s):  
Jan Philipp Bewersdorf ◽  
Wei Wei ◽  
Anna Jaiani ◽  
Prital Patel ◽  
Rajni Mehta ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Clinical Trials ◽  
Myelodysplastic Syndromes ◽  
Working Group ◽  
Research Funding ◽  
Response Criteria ◽  
The Impact ◽  
Support Research

Abstract Introduction: Monotherapy with hypomethylating agents (HMA) remains the standard of care for patients (pts) with myelodysplastic syndromes (MDS). Response in MDS is based on the modified International Working Group (IWG) 2006 criteria. Prior studies focusing on unselected MDS pts showed that achieving a complete remission (CR) was associated with favorable overall survival (OS). However, the association of other outcomes with OS was less clear and only 20% of HMA-treated MDS pts achieve a CR. For example, pts who achieved <5% bone marrow (BM) blasts are currently classified as marrow CR (mCR), which has not been associated with OS improvement. Therefore, interpreting the significance of mCR reported in various clinical trials is challenging. Clinically meaningful reduction in bleeding or infectious complications can occur at improvements in absolute neutrophil count (ANC) and platelet counts that do not meet the current thresholds used for CR (ANC ≥1.0 × 10 9/L, platelets ≥100 × 10 9/L, and Hb >11 g/dL). To avoid missing clinically meaningful benefits when studying new drugs in clinical trials, a clearly defined response criterion that is less stringent than CR but still captures clinically meaningful hematologic improvement (HI) is needed. Here we sought to evaluate the impact of current IWG 2006 response criteria as well as CRh on OS of pts with HR-MDS treated with frontline HMA monotherapy. Methods: We included all adult (≥18 years) MDS pts treated with frontline HMA (azacitidine [AZA], decitabine [DEC], or ASTX727) monotherapy between 1/1/2012 and 12/31/2020 at Yale University. We decided to use HMA monotherapy as it is the standard care for HR-MDS and to minimize the impact of therapy choice confounding the association of achieved response with OS. Pts were excluded if they received prior treatments for MDS aside from erythropoiesis-stimulating agents and if no baseline with at least one follow-up BM study were available for response assessment. We collected patient and disease characteristics (transfusion burden, IPSS/IPSS-R score, cytogenetics, molecular studies) at baseline. Best responses were assessed based on IWG 2006 criteria for MDS. We defined CRh as <5% BM blasts, platelets ≥50 × 10 9/L, ANC ≥0.5 × 10 9/L and no peripheral blood blasts. We followed pts until death or last follow-up and recorded dates of allogeneic hematopoietic cell transplant (HCT) if applicable. Date of data cut-off for survival status was 5/31/2021. We performed Kaplan-Meier analysis to estimate the duration of overall survival and we used log rank test to test the difference in OS between subgroups of pts. Multiple comparisons were adjusted using the Bonferroni method. Results: A total of 100 pts was included in this analysis (Table 1). Median age was 68 years (yrs; range, 23 - 86), 60% were males, and 79% and 18% of pts received AZA and DEC, respectively. Median number of HMA cycles was 6 (interquartile range [IQR]: 4-10), and 33 pts (33%) underwent HCT. During follow-up, 46 pts (48%) progressed to AML. At a median follow-up of 1.5 yrs (IQR: 0.9 - 2.3 yrs), median OS for the entire pt cohort was 1.9 yrs (Figure 1). OS by response category is shown in Table 2. Median OS was not reached for patients who achieved a CR (95% CI: not reached [NR] - NR) as compared to 1.9 yrs (95% CI: 1.5 yrs - NR) and 2.0 yrs (95% CI: 1.2 yrs - NR) among pts with mCR + HI and mCR without HI, respectively. Median OS among patients with stable disease (SD) was similar (2.0 yrs [95% CI: 1.5 yrs - NR]). Finally, we explored the prognostic value of CRh and found a median OS of 1.9 yrs (95% CI: 1.5 yrs - NR), which appeared comparable to mCR +/- HI or SD. Similar results were found with censoring at time of HCT (Figure 2). Discussion: In this retrospective analysis of MDS pts treated with HMA monotherapy in the frontline setting, achieving CR as best response was associated with improved OS compared with mCR +/- HI and SD. However, as the numbers were small these results should be interpreted with caution, and other clinically relevant outcomes such as freedom of transfusion, infectious or bleeding complications, and patient-reported outcomes were not captured in the current analysis. Our results also apply only to MDS pts treated with HMA monotherapy in the frontline setting. The prognostic implications of CRh need to be evaluated in larger patient cohorts. To overcome these limitations, we are currently in the process of expanding the study to a much larger multi-center, international analysis. Figure 1 Figure 1. Disclosures Neparidze: Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Research Funding. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Podoltsev: PharmaEssentia: Honoraria; Pfizer: Honoraria; CTI BioPharma: Honoraria; Blueprint Medicines: Honoraria; Incyte: Honoraria; Bristol-Myers Squib: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Brunner: GSK: Research Funding; Aprea: Research Funding; Keros Therapeutics: Consultancy; Agios: Consultancy; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Acceleron: Consultancy; Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Janssen: Research Funding. Zeidan: AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Epizyme: Consultancy; Amgen: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Acceleron: Consultancy, Research Funding; Agios: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Genentech: Consultancy; Jasper: Consultancy; ADC Therapeutics: Research Funding; Jazz: Consultancy; Astex: Research Funding; Daiichi Sankyo: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Geron: Other: Clinical Trial Committees; AstraZeneca: Consultancy; Pfizer: Other: Travel support, Research Funding; BeyondSpring: Consultancy; Ionis: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Janssen: Consultancy; Astellas: Consultancy.

scholarly journals Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials

Blood ◽  
2019 ◽  
Vol 133 (10) ◽  
pp. 1020-1030 ◽  
Author(s):  
U. Platzbecker ◽  
P. Fenaux ◽  
L. Adès ◽  
A. Giagounidis ◽  
V. Santini ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Myelodysplastic Syndromes ◽  
Working Group ◽  
Lower Risk ◽  
Response Assessment ◽  
Response To Treatment ◽  
Response Criteria ◽  
Patient Response ◽  
Erythroid Response ◽  
Clinical Responses

Abstract The heterogeneity of myelodysplastic syndromes (MDSs) has made evaluating patient response to treatment challenging. In 2006, the International Working Group (IWG) proposed a revision to previously published standardized response criteria (IWG 2000) for uniformly evaluating clinical responses in MDSs. These IWG 2006 criteria have been used prospectively in many clinical trials in MDSs, but proved challenging in several of them, especially for the evaluation of erythroid response. In this report, we provide rationale for modifications (IWG 2018) of these recommendations, mainly for “hematological improvement” criteria used for lower-risk MDSs, based on recent practical and reported experience in clinical trials. Most suggestions relate to erythroid response assessment, which are refined in an overall more stringent manner. Two major proposed changes are the differentiation between “procedures” and “criteria” for hematologic improvement–erythroid assessment and a new categorization of transfusion-burden subgroups.

scholarly journals Survival of Mantle Cell Lymphoma in the Era of Bruton Tyrosine Kinase Inhibitors: A Population-Based Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 182-182
Author(s):  
Mengyang Di ◽  
Can Cui ◽  
Shalin K. Kothari ◽  
Amer M. Zeidan ◽  
Nikolai Podoltsev ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Research Funding ◽  
Age Groups ◽  
Population Based ◽  
Sensitivity Analyses ◽  
Mantle Cell ◽  
All Cause Mortality ◽  
Bruton Tyrosine Kinase ◽  
Support Research

Abstract Background: Despite advances in chemoimmunotherapy and stem cell transplantation, mantle cell lymphoma (MCL) has historically been difficult to treat. Patients with advanced age and high-risk features (e.g. blastoid/pleomorphic features, high MIPI score, complex karyotype, TP53 mutation) face particularly poor outcomes with standard chemoimmunotherapy. Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), was approved for second-line use in MCL in 2013. Other BTKis - acalabrutinib and zanubrutinib were approved in 2017 and 2019, respectively. BTKi provides a well-tolerated chemotherapy-free option for these hard-to-treat subgroups, especially the older patients. In this population-based study, we evaluated survival outcomes prior to and after the approval of ibrutinib, and hypothesized that survival benefit observed early after approval would be greatest in older patients not typically candidates for consolidative transplantation in the first-line setting. Methods: Using the Surveillance, Epidemiology, and End Results database, we included all adult patients diagnosed with MCL in the years 2007-2018 and followed them to the end of 2018 or death, whichever came first. The pre-BTKi era was defined by year of diagnosis 2007-2011, and the BTKi era was between 2014 and 2018. The years 2012-2013 were considered as a "washout" period to allow practice change related to the approval of ibrutinib. As age plays an important role in treatment decisions, including whether to use consolidative transplantation, patients were divided based on age at diagnosis: <60, 60-69, 70-79, and ≥80 years. Outcomes of interest included all-cause mortality, and mortality from MCL (MFM). We applied multivariable Cox proportional hazards regression model for all-cause mortality, adjusting for age, sex, race, stage, and median household income at census level, and reported adjusted hazard ratio (HR) with 95% confidence interval (CI). We also conducted multivariable competing risk analyses for MFM, considering all other causes of death as the competing events, and reported subhazard ratio (sHR) with 95% CI. To eliminate potential confounding by duration of follow-up among patients diagnosed in different periods, we used only three-year follow-up data for primary analyses, and all available follow-up data for sensitivity analyses. Results: We identified 7,625 individuals diagnosed with MCL during our study period (3,424 and 4,201 diagnosed during 2007-2011 and 2014-2018, respectively). The majority were male (71%) and white (90%), with 49% of patients 70 years or older. The median follow-up was 9.2 and 2.4 years for patients diagnosed during 2007-2011 and 2014-2018, respectively. The 3-year all-cause mortality and 3-year MFM rates were 39.8% and 27.3%, respectively, in the overall population. Both the 3-year all-cause mortality and MFM increased as age increased. The 3-year all-cause mortality was lower in the BTKi era among all age groups, except patients <60 years old, and the 3-year MFM was lower in the BTKi era among all age groups. The numeric difference of 3-year outcomes was more substantial in patients aged 70-79 for both all-cause mortality (pre-BTKi era: 47.8%, BTKi era: 40.4%) and MFM (pre-BTKi era: 33.9%, BTKi era: 27.5%) (Table, Figure A and B). In the multivariable analyses, risk of death was significantly lower during the BTKi era in the 60-69 (HR:0.85, 95% CI: 0.72-1.00) and 70-79 (HR: 0.80, 95% CI: 0.70-0.92) age groups. MFM was also significantly lower during the BTKi era in these two age groups (60-69: sHR: 0.78, 95% CI: 0.64-0.94; 70-79: sHR: 0.76, 95% CI: 0.65-0.90, Table). The results were largely unchanged in sensitivity analyses (results not shown). Conclusion: In this large population-based cohort analysis of individuals diagnosed with MCL, overall and lymphoma-specific survival improved in the BTKi era. At a median follow up of 2.4 years in our BTKi cohort, significant survival benefits were observed in those older than 60 but less than 80 years of age, and the observed benefits were greatest in the 70-79 age group. Future real-world studies should examine the impact of novel agents on treatment patterns and outcomes of MCL over a longer follow up period. Figure 1 Figure 1. Disclosures Kothari: Incyte pharmaceuticals: Consultancy, Honoraria; Karyopharm pharmaceuticals: Consultancy, Honoraria. Zeidan: Amgen: Consultancy, Research Funding; Astellas: Consultancy; Jasper: Consultancy; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; BeyondSpring: Consultancy; Acceleron: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Ionis: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Astex: Research Funding; AstraZeneca: Consultancy; Epizyme: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy; Agios: Consultancy; ADC Therapeutics: Research Funding; Jazz: Consultancy; Genentech: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Geron: Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; Daiichi Sankyo: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding. Podoltsev: PharmaEssentia: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Bristol-Myers Squib: Honoraria; CTI BioPharma: Honoraria; Celgene: Honoraria; Blueprint Medicines: Honoraria; Pfizer: Honoraria. Neparidze: Janssen: Research Funding; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Ma: Celgene/Bristol Myers Squibb: Consultancy, Research Funding. Huntington: AbbVie: Consultancy; TG Therapeutics: Research Funding; SeaGen: Consultancy; DTRM Biopharm: Research Funding; Flatiron Health Inc.: Consultancy; Novartis: Consultancy; Bayer: Honoraria; Pharmacyclics: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Genentech: Consultancy; Servier: Consultancy; Thyme Inc: Consultancy; Celgene: Consultancy, Research Funding.

scholarly journals Development and Testing of a Lymphoma Clinical Trials Specific Frailty Index: A Secondary Analysis of the LY.12 Clinical Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4076-4076
Author(s):  
Abi Vijenthira ◽  
Xinzhi Li ◽  
Michael Crump ◽  
Annette E. Hay ◽  
Lois E. Shepherd ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Frailty Index ◽  
Secondary Analysis ◽  
Advisory Committees ◽  
Frail Patients ◽  
The Impact

Abstract Background: Frailty is common in older patients with lymphoma. However, it remains unknown whether frailty is prevalent in patients included in clinical trials of lymphoma, as those with frailty may meet inclusion criteria of a trial which do not include functional information beyond performance status (PS). Understanding the prevalence and impact of frailty in clinical trials is important to direct future stratification criteria, as well as to have robust data to counsel frail patients on their potential outcomes. Methods: We conducted a secondary analysis using data from the phase III LY.12 clinical trial in which patients with relapsed aggressive non-Hodgkin lymphoma were randomized to gemcitabine-dexamethasone-cisplatin or dexamethasone-high dose cytarabine-cisplatin chemotherapy prior to autologous stem cell transplant. The primary objective of our study was to construct a lymphoma clinical trials specific frailty index (FI) using previously described methods (Searle. BMC Geriatr. 2008;8:24). Secondary objectives were to describe the association of frailty (binary variable) with overall survival (OS), event-free survival (EFS), hospitalization, adverse events (AE), serious adverse events (SAE), and proceeding to transplant, and to describe the association of frailty with these outcomes, controlling for important covariates (age, sex, immunophenotype, revised international prognostic index score (rIPI), Eastern Cooperative Oncology Group (ECOG) PS, stage, and response to previous chemotherapy). Results: 619 patients in the LY12 trial were used to construct the frailty index (Table 1). Using a binary cut-off for frailty (<0.2), 15% (N=93) of patients were classified as frail. There were no differences in age or sex between frail and non-frail patients; however they differed in terms of other lymphoma-related characteristics (Table 2). Frailty was strongly associated with OS (HR 2.012, 95% CI 1.57-2.58), EFS (HR 1.94, 95% CI 1.53-2.46), frequency of the worst overall Grade >3 AE (OR 2.65 (15% vs. 6%), p=0.003), and likelihood of proceeding to ASCT (OR 0.26, 95% CI 0.15-0.43), but not hospitalization (OR 1.52, 95% CI 0.97-2.40) or SAE (6% vs. 4%, p=0.3). In multivariable analysis, frailty was not significantly associated with OS, EFS, likelihood of proceeding to ASCT, nor hospitalization (Table 3), though there was a trend to significance for ASCT. However, rIPI remained significantly associated with OS and EFS, ECOG remained significantly associated with OS (Table 3) Conclusion: A potentially broadly applicable lymphoma clinical trials specific FI was constructed through secondary analysis of LY12 data. 15% of patients were classified as frail. Frailty was significantly associated with OS, EFS, frequency of grade >3 AE and likelihood of proceeding to transplant. However, this relationship no longer was significant when controlling for lymphoma-related prognostic variables, suggesting that the impact of poor prognostic features of lymphoma supersede the impact of frailty alone in this younger clinical trial population. Interestingly, rIPI and ECOG demonstrated their value as simple predictors that are highly associated with OS and/or EFS even when controlling for other important covariates including frailty. These findings require further testing in an external data set, and would be particularly valuable to test in an older population. Calibration of the FI against clinical frailty assessment (e.g. Clinical Frailty Scale, Comprehensive Geriatric Assessment) would also be meaningful to confirm its ability to classify frail versus non-frail patients. Figure 1 Figure 1. Disclosures Crump: Epizyme: Research Funding; Roche: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hay: Merck: Research Funding; Roche: Research Funding; Abbvie: Research Funding; Amgen: Research Funding; Karyopharm: Research Funding; Seattle Genetics: Research Funding. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria.

scholarly journals Patient Related Factors Have an Indepedent Impact on Overall Survival in Myelodysplastic Syndrome Patients: A Report of the MDS-Can Registry

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 165-165
Author(s):  
Rena Buckstein ◽  
Richard A. Wells ◽  
Nancy Zhu ◽  
Thomas J. Nevill ◽  
Heather A Leitch ◽  
...  
Keyword(s):  
Overall Survival ◽  
Physical Performance ◽  
Predictive Factors ◽  
Research Funding ◽  
Performance Tests ◽  
Related Factors ◽  
Risk Of Death ◽  
The Impact ◽  
Very High

Abstract Introduction: MDS is a disease of the elderly; yet, the impact of clinical frailty (an age-related vulnerability state created by a multidimensional loss of reserves) and patient-reported outcomes on overall survival (OS) are unknown. Rockwood et al. have developed a simple 9-point clinical frailty scale (CFS) that correlated highly with the risk of death, institutionalization, worsening health and hospital use (Rockwood K., CMAJ 2005). In a prospective, national MDS registry, participants have undergone annual evaluations with the following: (a) 3 geriatric physical performance tests, (b) Charlson (CCI) and Della Porta comorbidity index (DP-CCI) scores, (c) graded frailty using the Rockwood CFS, (d) disability assessments with the Lawton Brody SIADL, and (e) QOL using the EORTC QLQ C-30 and the EQ-5D. The results of these frailty assessments and the effects of these patient-related factors and reported outcomes on OS, in addition to the IPSS/revised IPSS, will be presented. Methods: Overall survival was measured from time to enrollment. Results from physical performance tests were divided into quintiles with higher scores indicating better performance. We used univariate and multivariable Cox proportional hazard model to determine significant predictive factors of overall survival (OS). The variables considered included age, IPSS, R-IPSS, ferritin, LDH, transfusion dependence, hemoglobin (hgb), ECOG, frailty, CCI and DP-CCI, grip strength, 4 M walk test, stand-sit test, modified short physical performance battery (SPPB), Lawton Brody SIADL, time from diagnosis and selected QOL domains including the EQ-5D summary score, EORTC physical functioning, dyspnea and fatigue scores. Results: 453 MDS patients (pts) have been consented and enrolled locally since January 2008 (n=231) and nationally since January 2012 (n=222). Median time from diagnosis was 5.8 mos (IQR 1.4-21). Median age was 73 y (range, 26-95 y), 65% were male and the R-IPSS scores were very low (14%), low (46%), intermediate (24%), high (10%) and very high (6%). Thirty-three % of pts were transfusion dependent at enrollment. Median CCI and DP-CCI scores were 1 (0-12) and 0 (0-6) respectively with 18% and 24% falling into the highest category scores. Median frailty scale score (n=346) was 3 (1-9) with 25% having scores indicating moderate (4-5) or severe (6-9) frailty. The CCI and DP-CCI strongly correlated (r=0.6; p< .0001) with each other, while frailty significantly but modestly correlated with them (r=0.3-0.35, p<.0001). With a median follow up (from enrollment) of 15 mos (95% CI: 13-16), 159 (35%) pts have died and 28 pts lost to follow up. Actuarial survival was 41.0 mos (range, 33.6 - 48.5 mos). When considering patient related factors - age, frailty, comorbidity (both indices), sex, ECOG, the 10 x stand sit test, the SPPB, Lawton Brody SIADL, and all QOL domains considered above were significantly predictive of OS. The multivariable model with the highest R2 included R-IPSS (p=.0004), frailty (1-3 vs 4-9, p= .004), CCI (0-1 vs >2, p=.03) and EORTC fatigue (p=.01) as summarized in Table 1 below. A frailty score > 3 predicted for worse survival (figure 1: 2 year OS 68.5% vs. 83.8%) and further refined survival within the R-IPSS categories (Figure 2). Frailty was also the single most predictive factor for OS from the start of azacitidine therapy (not shown). Conclusions: Patient-related factors such as frailty and comorbidity (that evaluate physiologic reserve and global fitness) should be considered in addition to traditional MDS prognostic indices. Abstract 165. Table. Independent Covariate Predictive factors at baseline Coefficient SE p -value HR 95% CI of HR R2 (%) Time from diagnosis (months) * 0.0335 0.1076 0.7557 1.034 0.837 1.277 17.29% R-IPSS (5 categories) <.0001 Very high vs. very low 2.5701 0.7289 0.0004 13.066 3.131 54.524 High vs. very low 2.1156 0.6437 0.0010 8.294 2.349 29.285 Intermediate vs. very low 1.0466 0.6430 0.1036 2.848 0.808 10.043 Low vs. very low 0.6346 0.6181 0.3045 1.886 0.562 6.334 Frailty (1-3 vs. 4-9) -0.8323 0.2905 0.0042 0.435 0.246 0.769 Comorbidity Charlson (0-1 vs. ³2) -0.5915 0.2749 0.0314 0.553 0.323 0.949 EORTC fatigue * 0.3671 0.1546 0.0176 1.443 1.066 1.954 natural log-transformation was applied for normalizing distribution Figure 1 Overall survival by Frailty (n=346) Figure 1. Overall survival by Frailty (n=346) Figure 2 Overall Survival by Frailty and R-IPSS Figure 2. Overall Survival by Frailty and R-IPSS Disclosures Buckstein: Celgene Canada: Research Funding. Wells:Celgene: Honoraria, Other, Research Funding; Novartis: Honoraria, Research Funding; Alexion: Honoraria, Research Funding. Leitch:Alexion: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Educational Grant Other, Honoraria, Research Funding. Shamy:Celgene: Honoraria, Other.

scholarly journals Pre-Transplant Monocytic Myeloid-Derived Suppressor Cell Frequency Has No Prognostic Role for Outcome after Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia in Remission

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5255-5255
Author(s):  
Colin Godwin ◽  
Jonathan R. Fromm ◽  
Brenda M. Sandmaier ◽  
Marco Mielcarek ◽  
Brent Wood ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Median Frequency ◽  
Prognostic Role ◽  
Support Research ◽  
Acute Myeloid

Abstract INTRODUCTION: Emerging data indicate myeloid-derived suppressor cells (MDSCs) adversely impact outcomes of patients with a variety of malignancies. However, it is less clear how MDSCs affect acute myeloid leukemia (AML) disease biology or the response of AML patients to treatment. Here, we studied a cohort of people with AML undergoing hematopoietic cell transplantation (HCT) in first complete remission (CR1) to examine the relationship between the monocytic subtype of MDSCs (M-MDSCs), pre-transplant measurable residual disease (MRD) status, and outcome after HCT. PATIENTS AND METHODS: Adults ≥18 years of age were included if they underwent first allogeneic HCT with myeloablative or nonmyeloablative conditioning for AML in CR1 from April 2006 until October 2014. Prospective MRD testing in bone marrow aspirates was performed routinely via 10-color multiparameter flow cytometry (MFC) as part of the pre-transplant work-up. Pre-transplant MFC data were used retrospectively to quantify M-MDSCs as the proportion of monocytes (identified by side scatter properties and CD14 positivity) with low or negative expression of HLA-DR. M-MDSC frequency was then expressed as a percentage of the total number of viable cells in the sample. Available combinations of antigens measured by MFC did not allow for the identification of other MDSC subsets (e.g. granulocytic MDSCs). RESULTS: We identified 349 adults undergoing allogeneic HCT for AML in CR1 for whom pre-transplant MRD testing was performed and for whom follow-up data were available. Of these, 8 had to be excluded because of insufficient MFC events available for identification of M-MDSCs. In the remaining 341 patients, M-MDSC frequency ranged from <0.001% to 6.53%, with a median of 0.18% (25th percentile: 0.06%; 75th percentile: 0.40%). Patients with lower (i.e. <median) frequency of M-MDSCs were less likely male (p=0.01) and more likely had recovered neutrophil and platelet counts (p=0.001) than patients with higher (i.e. ≥median) frequency of M-MDSCs. There was no difference with regard to all other examined characteristics (age, WBC and cytogenetic risk at diagnosis, type of AML, median CR duration before HCT, donor type, and conditioning intensity). The proportion of MRD positive ("MRDpos") patients was similar between those with lower vs. higher M-MDSC frequency (18.8 vs. 24.6%, p=0.20). Moreover, while MRD negative ("MRDneg") patients (n=267) differed statistically significantly from MRDpos patients (n=74) with regard to several characteristics such as more favorable disease risk and lower proportion of secondary AML, there was only a statistically non-significant trend toward lower M-MDSC frequency in MRDneg patients (0.16% [range <0.001-5.61%] vs. 0.22% [range <0.001-6.53%], p=0.09). The median follow-up time after HCT among all survivors was 5.8 (range, 2.0-11.4) years. The time was slightly longer for survivors with lower compared to those with higher M-MDSC frequency (6.1 [range 2.6-11.4] vs. 5.1 [range 2.0-11.3] years; p=0.0076). Stratified by the median M-MDSC frequency, the 3-year estimates of overall survival were similar for patients with lower and higher pre-HCT M-MDSCs (58.2% [95% confidence interval 50.4-65.2%] vs. 57.6% [49.8-64.7%]), as were 3-year estimates for relapse free survival (53.5% [45.7-60.7%] vs. 48.3% [40.6-55.6%]), 3-year estimates of the cumulative incidence of relapse (31.8% [24.9-38.8%] vs. 34.6% [27.6-41.8%]), and 3-year estimates of non-relapse mortality (14.7% [9.9-20.5%] vs. 17.0% [11.8-23.0%]). Analyses restricted to the subset of patients undergoing myeloablative (MA) conditioning or those undergoing MA conditioning in MRDneg remission showed qualitatively similar results. CONCLUSIONS: In the largest study to date examining the role of M-MDSCs in AML, we found no convincing evidence for a prognostic role of these cells for adults undergoing allografting in CR1. Disclosures Walter: Actinium Pharmaceuticals, Inc.: Other: Clinical trial support, Research Funding; Amgen Inc.: Other: Clinical trial support, Research Funding; Amphivena Therapeutics: Consultancy, Equity Ownership, Other: Clinical trial support, Research Funding; Aptevo Therapeutic: Consultancy, Other: Clinical trial support, Research Funding; Covagen AG: Consultancy, Other: Clinical trial support, Research Funding; Seattle Genetics, Inc.: Consultancy, Other: Clinical trial support, Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy; Pfizer: Consultancy.

Continued Improvement in Survival in Multiple Myeloma and the Impact of Novel Agents

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3972-3972 ◽  
Author(s):  
Shaji K. Kumar ◽  
Angela Dispenzieri ◽  
Morie A Gertz ◽  
Martha Q Lacy ◽  
John A Lust ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Initial Therapy ◽  
Novel Agents ◽  
The Novel ◽  
Newly Diagnosed ◽  
Entire Cohort ◽  
The Past ◽  
The Impact

Abstract Abstract 3972 Background: The treatment paradigm for myeloma has undergone a dramatic shift in the past decade with the introduction of the novel agents and their application at every stage of the treatment. We and others had previously shown that survival of patients with myeloma had improved in the earlier half of the last decade and attributed this to a combination of novel therapies as well as increased use of stem cell transplant. It is not clear if this momentum in improving survival has been maintained. We examined the survival trends of patients with newly diagnosed myeloma seen within the past decade to examine this question. Patients and Methods: We studied 1056 patients with newly diagnosed myeloma, who were seen at Mayo Clinic between January 1, 2001 and December 31, 2010; who were seen within 30 days of their diagnosis. For examination of the time trends, we grouped the time interval into two five year periods, 2001–2005 and 2006–2010. Survival was estimated using Kaplan Meier method and survival curves were compared by log rank test. Impact of various prognostic factors was evaluated using Cox proportional hazards test. Results: The median age at diagnosis was 65 (range; 22–92), and 59% were male. The median estimated follow up for the entire cohort was 4.6 years (95% CI; 4.4, 4.9) and 57% of the patients were alive at last follow up. The median overall survival (OS) for the entire cohort was 5.4 years (95% CI; 5, 6.3). The overall survival for patients in the 2001–2005 group was 4.6 years compared with not reached for the 2006–2010 cohort (P< 0.001). The five-year estimated OS was 48% for the earlier group compared with 66% for the latter group. The estimated 1-year survival was 90% for the recent cohort compared with 83% for the earlier cohort, suggesting improvements in the early mortality. Interestingly, the improvement was predominantly seen in the older age group (>65 years; 49%). The 5-year survival of the older patients improved significantly from 31% (2001–2005) to 56% (2006–2010) (P<0.001). In contrast, among younger patients (≤65 years of age), the 5-year survival improved only marginally from 63% (2001–2005) to 73% (2006–2010) (P=NS). One or more novel agents (Lenalidomide, thalidomide or bortezomib) were used as part of initial therapy in 631 (62% of 1021 in whom treatment data was available). The OS among of this group was 7.3 years (95% CI; 5.9, NR) compared with 3.8 years (95% CI; 3.1, 4.6). In a multivariate model that included both use of novel agent and the year group, only the novel agent use was associated with improved survival suggesting that the improvement in the survival is related to the increased use of novel agents in the initial therapy. No significant differences were observed between the groups in terms of conventional prognostic factors. Conclusions: The current results confirm continued improvement in the overall survival of patients, even within the last 10 year period, and highlight the impact of initial therapy with novel agents. Most importantly, we demonstrate that the improved survival has primarily benefited older patients. Our study highlights that urgent need for additional new agents to provide further survival improvement for younger patients, and in order achieve a cure for this disease. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Dispenzieri:Celgene: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Janssen Research & Development: Research Funding. Gertz:Binding Site: Honoraria.

Results of the ECOG E1900 Trial in Younger Adults with AML Using an Event Free Survival Endpoint Are Concordant with Results Based on Overall Survival: Potential for a Surrogate Endpoint to Facilitate Rapid Approval of Therapies in AML

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2599-2599 ◽  
Author(s):  
Marlise R. Luskin ◽  
Ju-Whei Lee ◽  
Hugo F. Fernandez ◽  
Hillard M. Lazarus ◽  
Jacob M. Rowe ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Treatment Failure ◽  
Induction Treatment ◽  
High Dose ◽  
Event Free Survival ◽  
Npm1 Mutation ◽  
Free Survival ◽  
The Impact

Abstract Background: Novel therapies are required to improve the outcome of patients with AML. New agents are asked to demonstrate an overall survival (OS) benefit before qualifying for FDA approval. The long duration of clinical trials required in order to achieve this endpoint hampers quick evaluation of candidate therapies, including novel agents. Identification of reliable surrogate endpoints for OS in AML is needed. Here we compare the results of therapy for patients with untreated AML ages 16-60 years on the Eastern Cooperative Oncology Group 1900 trial (E1900) of induction chemotherapy followed by consolidation and autologous transplant in order to evaluate the validity of an event free survival (EFS) endpoint as a surrogate for OS. Methods:OS was measured from randomization for induction therapy to death from any cause (censored at last contact). EFS was measured from randomization to induction treatment failure, relapse after compete response (CR), or death in remission (censored at last contact). Hazard ratios (HR) were computed using Cox proportional hazards models. The association between EFS and OS was evaluated using the Kendall tau-a rank correlation for censored data. Results:There were657 patients enrolled of which 426 patients relapsed or had induction treatment failure before death or date of last contact. Median EFS and OS were 8.0 months (95% CI, 6.3 to 9.7 months) and 23.6 months (95% CI, 16.9 to 23.6 months), respectively. With a median follow-up of 80.1 months, there is a statistically significant correlation between EFS and OS (Kendall tau-a = 0.467, 95% confidence interval (CI) = (0.425, 0.510), p<0.001). This correlation was similarly significant at a median follow-up of 25.2 months (Kendall tau-a = 0.361, 95% CI (0.323, 0.400), p <0.001) when the E1900 trial was originally reported (Fernandez et al. NEJM 2009). Key findings reported based on the original OS endpoint are similar when analyzed with an EFS endpoint (Table 1). High-dose daunorubicin (90 mg/m2) (DNR 90) confers both an EFS and OS benefit in patients aged < 50 years and patients with intermediate cytogenetic risk, and does not confer an EFS or OS benefit in older patients and patients with unfavorable cytogenetic risk, on univariate analysis. Divergent results are only seen in the small subset of favorable cytogenetic risk patients, where DNR 90 conferred an OS benefit (p=0.027) without an EFS benefit (p=0.32). Both EFS and OS endpoints consistently reflect the impact of mutation status on survival. The presence of a FLT3-ITD or DNMT3A mutation has a negative impact on both EFS and OS while an IDH2 mutation has a favorable impact on EFS and OS. The presence of a NPM1 mutation confers a favorable impact on EFS and OS in patients who received DNR 90 and did not impact EFS or OS in patients receiving standard-dose daunorubicin (45 mg/m2) (DNR 45). The presence of an IDH1 mutation does not impact EFS or OS. Conclusions:The results of E1900 demonstrating superiority of DNR 90 in AML induction in patients up to age 60 are concordant when using an EFS or OS endpoint. This is true for the group as a whole as well as for subgroups for which targeted agents are in development (FLT3/IDH2 inhibitors). Further investigation of whether EFS is a reliable surrogate for OS is warranted in AML. If confirmed, its use as a primary endpoint could be adopted by regulatory agencies in order to allow more rapid completion of clinical trials in AML and bring new therapies to AML patients in a timely fashion. Table 1. Results of E1900 based on an EFS endpoint versus an OS endpoint. Subgroup N OS HR (DNR 90/DNR 45) & 95% CI Wald P EFS HR (DNR 90/DNR 45) & 95% CI Wald P DNR 45 DNR 90 Age < 50 yrs ³ 50 yrs 188 142 172 155 0.66 (0.50, 0.85) 0.81 (0.62, 1.06) 0.002 0.118 0.64 (0.50, 0.82) 0.86 (0.67, 1.10) 0.0004 0.23 Cytogenetic Favorable Intermediate Unfavorable 38 141 59 51 127 63 0.51 (0.28, 0.93) 0.68 (0.50, 0.92) 0.79 (0.54, 1.16) 0.027 0.012 0.225 0.76 (0.44, 1.31) 0.63 (0.47, 0.83) 0.72 (0.49, 1.05) 0.32 0.001 0.09 Subgroup N OS HR (MUT/WT) & 95% CI Wald P EFS HR (MUT/WT) & 95% CI Wald P FLT3-ITD WT MUT 456 147 1.62 (1.31, 2.01) <.0001 1.48 (1.21, 1.82) 0.0002 DNMT3A WT MUT 371 119 1.30 (1.03, 1.65) 0.03 1.23 (0.98, 1.54) 0.07 IDH1 WT MUT 465 36 0.88 (0.59, 1.33) 0.55 0.91 (0.62, 1.34) 0.64 IDH2 WT MUT 451 50 0.63 (0.43, 0.93) 0.02 0.68 (0.48, 0.97) 0.03 NPM1 DNR 45 DNR 90 245 257 0.84 (0.61, 1.16) 0.60 (0.41, 0.89) 0.30 0.01 0.90 (0.66, 1.22) 0.59 (0.41, 0.84) 0.49 0.004 Disclosures No relevant conflicts of interest to declare.

scholarly journals Determinants of Clinical Trial Participation and Impact on Survival Outcomes Among Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5833-5833
Author(s):  
Gabriella C Malave ◽  
Prashant Kapoor ◽  
Angela Dispenzieri ◽  
Morie A. Gertz ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Trial Participation ◽  
Newly Diagnosed ◽  
Clinical Trial Participation ◽  
Advisory Committees ◽  
Baseline Characteristics

Background: The overall participation of cancer patients in interventional clinical trials in the United States remains very low, with ~5% of patients being enrolled in clinical trials nationwide. The outcomes of patients with MM have improved significantly over the past decade, but available data suggest that the participation rates for patients with MM is comparable to other cancers. The drivers of participation and the potential impact of clinical trial participation have not been systematically studied in MM. Patients and Methods: We identified 228 patients who were enrolled into clinical trials for initial therapy of newly diagnosed MM between 2004 and 2018, and 4 controls for each of these patients. Controls were patients with NDMM, who were diagnosed closest in time to the index patients and did not participate in an interventional treatment trial. Various baseline characteristics as well as overall survival were compared between the two groups. Results: The baseline characteristics of the two groups are as shown in the Table. Patients who entered clinical trials were more likely to be female, resided closer to the clinic, and were more likely to have a prior history of MGUS. They were more likely to have higher ISS Stage, and a higher serum LDH, but there was no difference in the FISH risk status. Other indices of disease burden such as lower hemoglobin and platelets, higher serum creatinine were all seen more often in the control group, but may have been influenced by the trial entry criteria. Looking at the outcomes, the overall survival was longer among those enrolled into clinical trials compared to those who did not [median 103 (95% CI; 86, 136) vs. 63 (95% CI; 53, 69) months, p<0.001 (Figure). Conclusions: The current study provides important clues regarding demographic determinants of trial participation and disease biology related features that reflect likelihood of trial participation. Overall survival was significantly longer among the trial participants, which likely represent a mix of reasons including baseline status of patients, intensity of monitoring and efficacy of novel treatment approaches. Table Disclosures Kapoor: Janssen: Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding; Takeda: Honoraria, Research Funding. Dispenzieri:Alnylam: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Akcea: Consultancy; Intellia: Consultancy. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy. Leung:Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees. Russell:Imanis: Equity Ownership. Kumar:Takeda: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

scholarly journals Impact of Red Blood Cell Transfusion Burden Status in Patients with Lower-Risk Myelodysplastic Syndromes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3013-3013
Author(s):  
Montserrat Arnan Sangerman ◽  
Helena Pomares ◽  
Esther Alonso ◽  
Javier Grau ◽  
Mercedes Galiano ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Progression Free Survival ◽  
Low Risk ◽  
Age At Diagnosis ◽  
Free Survival ◽  
The Impact ◽  
Rbc Transfusion

Background: RBC-transfusion dependency (RBC-TD) is associated with a decreased probability of overall survival (OS) and progression free survival (PFS) in patients with myelodysplastic syndromes (MDS) (Malcovati L et al. J Clin Oncol 2007 25:3505) but it is unclear if transfusion dose burden is an independent prognostic factor. The purpose of this study was to assess the impact on lower-risk MDS patients, of RBC-transfusion (RBCT) burden status defined according to revised 2018 IWG criteria (Platzbecker et al; Blood 2018). Material and Methods: According to the R-IPSS selection criteria, we identified in our database 474 lower-risk (R-IPSS risk very low, low and intermediate) MDS patients diagnosed at the Catalan Institute of Oncology of Barcelona (01/1992-07/2018). Transfusion burden history was prospectively registered in our database. Data on the transfusion burden was calculated dividing the cumulative total of units of blood received at the end by the time since the beginning of the interval in which the first transfusion was received. RBCT burden, defined according to 2018 IWG criteria, divided patients into 3 categories (non-transfused [NTD], low transfusion burden [LTB] (3 to 7 units in 16 weeks) and high transfusion burden [HTB] patients (³ 8 units in 16 weeks). In this analysis, patients who had received 1 or 2 RBC units in 16 weeks, where included in the NTD category. Overall survival (OS) and progression free survival (PFS) were measured in years since diagnosis. Results: Median age at diagnosis was 72 years (range 32-101). 332 (70%) patients were male. WHO diagnosis was: 3% CRDU, 7% RA, 42% RCMD, 14% RAEB-1, 4% RAEB-2, 26% CMML, the remaining 4% were MDS-U and isolated 5q deletion. R-IPSS categories were: 178 (38%) very low risk, 219 (46.2%) low risk and 77 (16%) intermediate risk. Median follow up time for survivors was 5.4 years (range 0.25-23.8). 132 (28%) of patients were transfusion dependents (LTB and HTB patients). Mean dose density of packed red blood cells amongst those who were transfusion dependents was 3.2 units per month, with a median of 2.9 units per month (IQR 1.9-4.3). At the time of last follow up, 274 (58%) patients had died and 72 (15%) had progressed to AML. According to 2018 IWG criteria, RBCT burden categories were 342 (72%) NTD, 35 (7%) LTB and 97 (21%) HTB patients. Median OS for RBCT burden categories: NTD (8 years; 95% CI 6.6-9.5), LTB (6.2 years; 95% CI 4.2-8.1) and HTB (3.1 years; 95% CI 2.4-3.8) were significantly different (p<0.001; Figure 1). Moreover, the rate of progression to acute myeloid leukemia was 39 (11%), 7 (20%) and 26 (27%) for categories NTD, LTB and HTB respectively (p<0.001). Multivariate analysis performed included gender, age at diagnosis, IPSS-R and RBCT burden status and showed that RBCT burden status was associated with poor OS and PFS, independent of R-IPSS category, age and gender (Table 1). Transfusion burden was inversely associated with OS and PFS with an increasing effect on hazard ratio. Conclusions: Our results confirm in our single-centre experience the negative impact on survival and progression-free survival of RBCT treatment, even at relatively low dose burden. As therapeutical decisions are based on the initial prognostic risk assessment, the inclusion of RBCT burden categories may provide more precise prognostic information with impact on the therapeutic approach. Disclosures Sureda: Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Roche: Honoraria; BMS: Consultancy, Honoraria; Gilead: Consultancy; Janssen: Consultancy, Honoraria.

The Outcome of Patients (pts) with Chronic Myeloid Leukemia (CML) Treated with Imatinib Outside of a Clinical Trial or On a Clinical Trial At a Single Institution

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1693-1693
Author(s):  
Musa Yilmaz ◽  
Hagop M. Kantarjian ◽  
Elias J. Jabbour ◽  
Susan M. O'Brien ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Single Institution ◽  
Free Survival ◽  
Excellent Outcome ◽  
Significant Difference

Abstract Abstract 1693 Background: Outcomes of CML chronic phase (CP) pts treated in clinical trials are frequently perceived to not be representative of those treated outside of clinical trials (Lucas et al, Haematologica 2009; 94: 1362–7). The latter is frequently referred to as “the real world” world experience. Some reports have suggested that outcome of pts treated outside of clinical trials have an inferior outcome. We investigated the outcomes of pts receiving imatinib on and off a clinical trial for CML-CP at a single institution. Methods: We reviewed the medical records of all pts with CML-CP treated at MDACC between 2000 and 2012 to identify pts that received initial therapy with imatinib 400 mg on a clinical trial or as standard therapy outside of a clinical trial (“off protocol” group). Only pts who had not received any prior therapy, or only hydroxyurea, or interferon alpha for less than 1 month, and that initiated on 400 milligram daily dose of imatinib within 6 months of diagnosis were included. Event-free survival (EFS) was measured from the start of treatment to the date of any of the following events: loss of major cytogenetic response (MCyR), loss of complete hematologic response (CHR), transformation to accelerated phase (AP) and blast phase (BP), and death while on imatinib. Transformation-free survival (TFS) was measured from the start of treatment to the date progression to AP/BP during therapy, last follow-up, or death from any cause. Overall survival (OS) was measured until death form any cause at any time. Results: We identified 65 pts treated with imatinib off protocol during the period of interest. During this time 71 pts were treated on clinical trials with imatinib. The median age was 49 yrs (15–79) for pts on clinical trials and 49 yrs (15–84) for those off protocol, respectively. The median follow-up was 125 months (13 to 142) for pts on clinical trials and 51 months (2 to 117) for those off protocol. The overall complete cytogenetic response (CCyR) rates were 84% and 83% for patients treated on and off protocol, respectively. CCyR rates, 12 months after initiation of imatinib, were not different (60% vs 66%, respectively; p=.15). Pts treated on protocol had higher rates of major molecular response (MMR) (79% vs 58%, P=.012) and complete molecular response (CMR = undetectable with sensitivity of at least 4 logs) (42% vs 32%, P=.045) at any time compared to the pts treated off protocol. This is likely due to the longer follow-up for pts on protocol as MMR takes longer to occur. In fact, the MMR rate at 12 months were 30% and 24% in pts treated on and off protocol, respectively (p=.28). Analyzing earlier responses, 3-month rates of MCyR were 71% on protocol and 69% off protocol (p=.82). Corresponding rates at 6 months were 82% and 85%, respectively (p=.68). The 5-year EFS rates were 86% and 84% for on and off protocol patients, respectively. There was also no significant difference in 5-year TFS (96% vs 94%) and OS (90% vs 96%). Conclusion: These results suggest that pts with CML treated outside of a clinical trial may have the same excellent outcome as those treated on a clinical trial provided they are followed with the same rigor. Disclosures: Ravandi: BMS: Research Funding. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

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