Quality of Life Scores Improve with Increasing Hemoglobin but Optimal Thresholds Vary According to Transfusion Dependence and Clinical Risk Scores: A Canadian Cross Sectional Study of 689 Patients with 2969 Measurements

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3192-3192
Author(s):  
Rena Buckstein ◽  
Richard A. Wells ◽  
Nancy Y Zhu ◽  
Michelle Geddes ◽  
Mitchell Sabloff ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Advisory Board ◽  
Risk Scores ◽  
Advisory Committees ◽  
Cross Sectional ◽  
And Function

Abstract Background : We previously presented that selected quality of life (QOL) domains in MDS patients are impaired compared with age-matched controls and most impacted by hemoglobin (Hgb) level, transfusion dependence, frailty and comorbidity in an initial cohort of 236 patients from a Canadian MDS registry (Buckstein R. et al, Abstract 699, ASH 2012 and Abstract 2500, ASH 2009). The optimal Hgb threshold associated with improved QOL may vary according to health states that may fluctuate for any given patient. With longer follow up and greater sample size, we now examine the impact of Hgb levels on QOL in transfusion dependent (TD) versus independent (TI) patients and according to IPSS-R risk scores. Methods:Since 2008, we have prospectively assessed QOL in all patients registered in the Canadian national MDS registry using the instruments EORTC QLQ-C30, FACT-F, global fatigue scale (GFS) and EQ-5D, at enrollment and every 4-6 months. These QOL data are paired with disease specific and laboratory information at the same time intervals. Each patient could provide multiple QOL measurements at different time points. Clinically significant score differences were considered 10 points for the EORTC, 0.08 for the EQ-5D and 4 for the FACT F. General linear regression analysis was applied to search for a significant relationship between physical and social functioning, dyspnea, fatigue and QOL with Hgb, according to transfusion dependence, IPSS and IPSS-R measured categorically. To account for multiple comparisons among 5 Hgb categories, Bonferroni adjusted p-value < .01 was considered statistically significant. Results: 689 patients from 15 Canadian sites completed their first QOL assessment at a median time of 7.8 (IQR 2.7-23) months from MDS diagnosis. The median time from MDS diagnosis to death or last follow-up was 2.5 years (IQR 1.2-4.9). The median Hgb at enrollment was 100 g/L (IQR 86-113) and the distribution of risk scores included: very low (13%); low (35%); intermediate (28%); high (15%); and very high (10%). 27% of patients were TD at enrollment and 54% were TD at any time. The median number of QOL assessments per patient completed was 3 (IQR 2-6) with 547 patients completing at least 2, 424 at least 3 and 335 at least 4 serial QOL measurements at a median time interval of 17 weeks (IQR 13-25). When examined by Hgb thresholds, mean physical functioning, dyspnea, fatigue (QLQ-C30 and GFS) and global QOL improved with increasing Hgb. QOL symptom and function scores were clinically and statistically significantly superior in TI versus TD patients (table 1). The optimal discriminating Hgb threshold for improved symptom and function scores was 100 g/L for patients that were TI or with IPSS-R very low, low and intermediate risk MDS; and 90 g/L for high and very high risk disease (table 2). No discriminating threshold was found in TD patients. Conclusions: In the largest reported serial cross sectional population based assessment of QOL in MDS patients, we confirm that higher Hgb and transfusion independence have significant impact on QOL, symptoms and self-reported function and should be considered important surrogate endpoints for clinical improvement. Disclosures Buckstein: Novartis: Honoraria; Celgene: Honoraria, Research Funding. Wells:Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: advisory board; Novartis: Honoraria, Other: advisory board; Alexion: Honoraria, Other: Advisory board. Zhu:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Geddes:Celgene: Other: Advisory Board, Research Funding. Sabloff:Gilead: Research Funding; Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Lundbeck: Research Funding. Leber:BMS Canada: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Keating:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Storring:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Leitch:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. St-Hilaire:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Membership on an entity's Board of Directors or advisory committees. Nevill:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shamy:Celgene: Honoraria, Other: Advisory board; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Delage:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding.

The Effects of Azacitidine On Quality of Life: A Prospective Longitudinal Assessment

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4938-4938
Author(s):  
Eric Tseng ◽  
Richard A. Wells ◽  
Shabbir MH Alibhai ◽  
Adam Lam ◽  
Alex Mamedov ◽  
...  
Keyword(s):  
Health Status ◽  
Global Health ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Global Health Status ◽  
Advisory Committees ◽  
Over Time

Abstract Abstract 4938 The effect of azacitidine (AZA) on health related quality of life (QOL) compared with best supportive care in MDS patients has been evaluated by Kornblith A. et al (JCO 2002) in a prospective randomized CALGB trial. The study demonstrated improved fatigue, dyspnea, physical functioning and psychological state in patients receiving AZA. One limitation is the relatively short follow up (last QOL measured at 8. 6 months) and the lack of validation in a non-trial setting. We have been conducting prospective assessments of QOL in all patients registered at our MDS clinic using the instruments EORTC QLQ-C30, FACT-Fatigue, EQ-5D and a global fatigue scale. We present longitudinal data on 56 registered patients registered in our program who were treated with AZA, 50 with serial QOLs. Methods: We examined and compared QOL scores at AZA start (baseline) and over time in all patients. We considered the following co-variates' potential impact on QOL scores: age, sex, IPSS, time from diagnosis, being a responder, # cycles and transfusion dependence. We used univariate linear regression analysis for continuous variables and analysis of variance (ANOVA) for categorical variables to determine their relationship with QOL scores at baseline and over time. For time-dependent covariates, linear mixed model was performed with random intercept and unstructured covariance matrix. Clinically significant (CS) score differences were considered 10 points for the QLQ-C30, 4 for the FACT-Fatigue and 0. 08 for the EQ-5D (7 for the visual analog score). The impact of baseline covariates on the QOL scores for global health, fatigue and dyspnea were determined by backward selection procedure of regression analysis using the Bonferroni adjusted P value of <0. 01 for multiple comparisons. Patients provided informed consent for this REB approved study. Results: 56 MDS patients consented to our registry have been treated with AZA between Oct 2008 and July 2012. The median age was 72, 60% were male and 77% had int-2/high risk IPSS MDS. 64 % were transfusion dependent (TD) at baseline. With a median time to death or last follow up of 16 months (range 1. 5–45) a median of 11 cycles of AZA were administered with 34% remaining on drug for a median of 25 cycles (IQR 8–32). The overall response rate (ORR) was 62%: 25% CR; 5% MCR; 4% PR; 28% HI. Stable disease (SD) was seen in 26% and not considered a response. 53% became transfusion independent (TI). 59% have died and 61% developed leukemia or progressed to > 30% blasts at a median time of 13 months. Overall survival was 18 months (95% CI 14. 5–26). 50 were evaluable for HrQOL with a median time between each serial QOL of 13 weeks (IQR 10–18). QOL was assessed at baseline (within 12 weeks pre-AZA start) in 50 patients, 2x in 44, 3x in 32, 4x in 22 and 5x in 14 patients (exceeding 52 weeks follow up). Looking at all 50 patients, overall, function and symptom domains remained stable over time in all instruments. At baseline, there were no statistically significant differences in QOL scores between responders and non responders. Nevertheless, clinically important differences were seen in physical, role, cognitive and social functioning, global health status (all higher in responders). Assessing QOL changes over time and considering baseline and time-dependent predictive factors in multivariate analysis, responders had significantly superior global health status (p=. 001) and EQ-5D scores (p=. 0002) and lower levels of fatigue (p<. 0001). If transfusion dependence status at time of QOL was included in the model, this often supplanted response as predictive of higher scores over time, likely representing the strong relationship between response and transfusion dependence. Conclusions: In addition to validating the clinical outcomes of AZA-001 study, we validate the importance of clinical response on QOL in MDS patients treated with AZA. Unlike the CALGB study, we observed relative stability in global health status and fatigue scores in responding patients and overall declines in non-responding patients. The higher scores at baseline in the patients destined for response raises the intriguing possibility that QOL at AZA start may be independently predictive of response perhaps because of improved tolerability and ability to remain on drug for the requisite number of cycles to achieve response. Disclosures: Wells: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Buckstein:Celgene: Honoraria, Research Funding.

scholarly journals Carfilzomib, Pomalidomide and Dexamethasone (KPd) in Patients with Multiple Myeloma Refractory to Bortezomib and Lenalidomide. the EMN011 Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 801-801 ◽  
Author(s):  
Pieter Sonneveld ◽  
Sonja Zweegman ◽  
Michele Cavo ◽  
Kazem Nasserinejad ◽  
Rosella Troia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Advisory Board ◽  
Phase 2 ◽  
Advisory Committees ◽  
Grade 3 ◽  
Advisory Role

Abstract Introduction and background The treatment of patients with Multiple Myeloma (MM) with relapse or progressive disease after bortezomib, lenalidomide and high-dose therapy represents an important challenge. In the EMN02 collaborative trial newly diagnosed patients with symptomatic MM were randomized to receive VCD induction followed by HDM/ASCT or VMP, followed by a second randomization for VRD consolidation or no consolidation, followed by lenalidomide maintenance until progression (Cavo et al, ASH2017, abstract #397; Sonneveld et al, EHA2018, abstract #108). The present Phase 2 trial was designed for patients with refractory disease or first progression after inclusion in EMN02 in order to evaluate a salvage treatment with next generation proteasome inhibition and IMId, i.e., Carfilzomib, Pomalidomide and Dexamethasone. The primary endpoints were response and progression-free survival (PFS). This trial is registered at www.trialregister.nl as NTR5349 and EudraCT 2013-003265-34. Methods Patients who were included received four 28-days re-induction cycles of KPd, i.e. Carfilzomib (20/36mg/m2, days 1,2,8,9,15,16) with Pomalidomide (4 mg days 1-21) and Dexamethasone (20mg days 1,2,8,9,15,16). In patients who had not previously received HDM/ASCT, HDM(200 mg/m2) was administered followed by autologous stem cell transplantation with stem cells harvested during after induction therapy in the EMN02 trial. Consolidation consisted of 4 additional cycles of KPd, identical to the induction cycles. Patients with stable disease or better received Pomalidomide 4mg w/o Dexamethasone in 28 days cycles until progression. Results At the time of this first planned interim analysis 82 patients were registered and this analysis was performed in the first 60 patients. 48% were randomized prior HDM/ASCT and 42% VMP, and 10% were not randomized. Prior best responses in the EMN02 trial were 35% CR/sCR , 75% ≥VGPR, 97% ≥PR. The median follow-up from inclusion in EMN02 was 43 months (range 21 - 62 months). In 44 patients cytogenetic risk were known, 15 (34%) of them had high-risk FISH (del17p, t(14;16) or t(4;14)). 57 fifty-seven (95%) of patients had progressed during lenalidomide maintenance, 3 patient's data are not yet available. In the present trial 38 (63%) of patients achieved normal completion of treatment according to of the protocol. Twenty patients received their first HDM plus ASCT. Median time on therapy was 14 months. Full dose re-induction treatment according to protocol could be administered in 68% (for Carfilzomib) and 64% (for Pomalidomide) of patients respectively, while for consolidation this was 62% for both Carfilzomib and Best response on protocol was 31% CR/sCR, 65% ≥VGPR, 87% ≥PR, respectively, with no difference according to response on initial treatments. Median time to response (≥PR) was 2 months. At a median follow-up of 16.3 months (range 3 - 32 months) median PFS was 18 months with better outcome in standard risk cytogenetics (HR=0.27 (0.09, 0.83) 95% CIs vs NR) and in patients with prior VMP treatment (HR=0.49 (0.21, 1.16) 95% CIs vs NR). 48 (80%) of patients are alive and in follow-up. KPd-emerging non-hematologic grade 3 and 4 adverse events included cardiovascular (5%), respiratory (5%), infections (20%) and neuropathy (3%). There were 3 fatal SAEs not related to progression (1 patient cardiac failure, 2 patients pneumonia). KPd-emerging hematological toxicity grade 3 and 4 occurred in 30% of patients. Discussion This Phase 2 clinical trial demonstrates that KPd is a feasible, effective and safe triple drug regimen in RRMM patients who have been previously treated and/or are refractory to bortezomib and refractory to lenalidomide. A 87% overall response rate including 31% CR/sCR is clinically relevant in this population. Since median OS has not been reached, longer follow-up is needed. Acknowledgments This trial was conducted as an investigator sponsored trial in EMN and supported by independent grants and drug supply from Amgen and Celgene. Disclosures Sonneveld: BMS: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Corradini:Roche: Honoraria, Other: Advisory Board & Lecturer; Gilead: Honoraria, Other: Advisory Board & Lecturer; Takeda: Honoraria, Other: Advisory Board & Lecturer; Novartis: Honoraria, Other: Advisory Board & Lecturer; Sandoz: Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board & Lecturer; Abbvie: Honoraria, Other: Advisory Board & Lecturer; Janssen: Honoraria, Other: Lecturer; Sanofi: Honoraria, Other: Advisory Board & Lecturer; Celgene: Honoraria, Other: Advisory Board & Lecturer. Patriarca:Janssen: Other: Advisory role; Celgene: Other: Advisory Role; Travel, accommodations, expenses; Jazz: Other: Travel, accommodations, expenses; MSD Italy: Other: Advisory Role; Medac: Other: Travel, accommodations, expenses. Minnema:Celgene: Consultancy, Research Funding; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Servier: Consultancy. Costa:celgene: Employment. Iskander:amgen: Employment. Boccadoro:Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding.

scholarly journals Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1589-1589
Author(s):  
Fabian Frontzek ◽  
Marita Ziepert ◽  
Maike Nickelsen ◽  
Bettina Altmann ◽  
Bertram Glass ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
High Dose ◽  
Advisory Committees ◽  
Scientific Advisory Board ◽  
Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

scholarly journals Routine Use of Gemtuzumab Ozogamicin in 7+3-Based Inductions for All "Non-Adverse" Risk AML

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-37
Author(s):  
Gavin Hui ◽  
Abdullah Ladha ◽  
Edna Cheung ◽  
Caroline Berube ◽  
Steven Coutre ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Gemtuzumab Ozogamicin ◽  
Intermediate Risk ◽  
Newly Diagnosed ◽  
Myeloablative Conditioning ◽  
Advisory Committees ◽  
Monosomy 7

Introduction: The addition of gemtuzumab ozogamicin (GO) to 7+3 chemotherapy for newly diagnosed acute myeloid leukemia (AML) has been shown to significantly improve event-free survival (EFS) for cytogenetically favorable-risk AML, with marginal benefit for intermediate-risk AML, and no benefit for cytogenetically adverse-risk AML. Of note, with the exception of mutated FLT3-ITD, little is known about the impact of GO in ELN 2017-defined genotypically adverse-risk AML, and a recent randomized trial found no EFS benefit for 7+3+GO in patients (pts) with genotypically favorable-risk, NPM1-mutated AML. Since 2017, our institution incorporated GO into 7+3-based inductions for all "non-adverse" risk AML pts, as defined by wild-type FLT3 and no abnormalities on rapid FISH analysis for del(5q)/monosomy 5, del(7q)/monosomy 7, and del(20q). We report our experience treating all pts with "non-adverse" risk AML-as defined by this algorithm-with 7+3+GO. Methods: An institutional database was queried in order to identify all pts ≥18 years old who received 7+3-based chemotherapy for newly diagnosed AML between 2017 and 2020; pts who received the FDA-approved fractionated dose of GO were included in the analysis. Data collection included demographic variables, karyotype/FISH, targeted PCR analyses, and multigene NGS panels for AML-related mutations including, but not limited to, mutations in FLT3, NPM1, CEBPA, TP53, RUNX1, and ASXL1. Outcome data included response to induction, relapse, and death, as well as hematopoietic cell transplant (HCT) rates, conditioning regimens, and post-transplant complications. Results: Between January 2017 and July 2020, 96 pts received 7+3-based induction at our institution. Of these, 29 (30%) received 7+3 in combination with GO. Median age at diagnosis was 46 years (range 23-66), with 17 (59%) males. Sixteen (55%) pts had ELN favorable-risk AML (5 [31%] by cytogenetics and 11 [69%] by genotype), 6 (21%) pts had ELN intermediate-risk AML, and 7 (24%) pts had ELN adverse-risk AML (4 [57%] by cytogenetics and 3 [43%] by genotype). Median time from diagnosis to start of induction was 4 days (range 0-43). For cytogenetically adverse-risk pts, median time from diagnostic bone marrow biopsy to receipt of adverse karyotype results was 8 days (7-14). Median time from start of induction to receipt of multigene NGS results for all pts was 15 days (3-32). Overall, 22 (76%) pts achieved remission. All genotypically adverse-risk pts (1 with mutated TP53 and 2 with mutated RUNX1) were refractory to induction, while 3 of 4 (75%) cytogenetically adverse-risk pts (1 with t(6;9), 1 with monosomy 7, and 2 with 11q23 abnormalities) achieved remission. Eight of the 29 (28%) pts proceeded to HCT, including 4 adverse-risk pts. Of the adverse-risk pts, all received myeloablative conditioning prior to HCT and 3 (75%) developed veno-occlusive disease (VOD), with 2 (50%) requiring defibrotide therapy. In favorable/intermediate-risk pts, 4 (18%) proceeded to HCT (2 intermediate-risk pts in first remission and 2 favorable-risk pts in second remission). Of these, 2 (50%) received myeloablative conditioning and 1 (25%) developed VOD. At last follow-up, 23 of 29 pts (79%) remained alive, with a median overall survival not reached (range 1-29 months) and a median EFS of 20 months (9-31). The percentage of ELN favorable-, intermediate-, and adverse-risk pts who remained event-free at last follow-up was 75%, 33%, and 43%, respectively. Discussion: This single-center, retrospective cohort describes the outcomes of pts with "non-adverse" risk AML who received induction chemotherapy with 7+3+GO according to a pre-defined algorithm. Using this algorithm, 30% of all pts receiving 7+3-based inductions received GO. Of these, nearly 25% were ultimately found to have adverse-risk AML as defined by ELN 2017 criteria, largely driven by long turn-around times for karyotyping and NGS multigene panel results. No patient with genotypically adverse-risk AML by ELN criteria responded to induction chemotherapy, and 75% of cytogenetically adverse-risk pts who proceeded to HCT developed VOD. Routine use of 7+3+GO induction outside of the context of cytogenetically favorable-risk AML remains controversial, and further study is needed to define the role of GO, particularly for pts with ELN genotypically adverse-risk AML. Table Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.

Long-Term Safety, Efficacy, and Survival Findings From Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 801-801 ◽  
Author(s):  
Francisco Cervantes ◽  
Jean-Jacques Kiladjian ◽  
Dietger Niederwieser ◽  
Andres Sirulnik ◽  
Viktoriya Stalbovskaya ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Extension Phase ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 801 Background: Ruxolitinib is a potent JAK1 & 2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In the two phase 3 COMFORT studies, ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. COMFORT-II is a randomized, open-label study evaluating ruxolitinib versus BAT in patients (pts) with MF. The primary and key secondary endpoints were both met: the proportion of pts achieving a response (defined as a ≥ 35% reduction in spleen volume) at wk 48 (ruxolitinib, 28.5%; BAT, 0%; P < .0001) and 24 (31.9% and 0%; P < .0001), respectively. The present analyses update the efficacy and safety findings of COMFORT-II (median follow-up, 112 wk). Methods: In COMFORT-II, 219 pts with intermediate-2 or high-risk MF and splenomegaly were randomized (2:1) to receive ruxolitinib (15 or 20 mg bid, based on baseline platelet count [100-200 × 109/L or > 200 × 109/L, respectively]) or BAT. Efficacy results are based on an intention-to-treat analysis; a loss of spleen response was defined as a > 25% increase in spleen volume over on-study nadir that is no longer a ≥ 35% reduction from baseline. Overall survival was estimated using the Kaplan-Meier method. Results: The median follow-up was 112 wk (ruxolitinib, 113; BAT, 108), and the median duration of exposure 83.3 wk (ruxolitinib, 111.4 [randomized and extension phases]; BAT, 45.1 [randomized treatment only]). Because the core study has completed, all pts have either entered the extension phase or discontinued from the study. The primary reasons for discontinuation were adverse events (AEs; ruxolitinib, 11.6%; BAT, 6.8%), consent withdrawal (4.1% and 12.3%), and disease progression (2.7% and 5.5%). Overall, 72.6% of pts (106/146) in the ruxolitinib arm and 61.6% (45/73) in the BAT arm entered the extension phase to receive ruxolitinib, and 55.5% (81/146) of those originally randomized to ruxolitinib remained on treatment at the time of this analysis. The primary reasons for discontinuation from the extension phase were progressive disease (8.2%), AEs (2.1%), and other (4.1%). Overall, 70 pts (48.3%) treated with ruxolitinib achieved a ≥ 35% reduction from baseline in spleen volume at any time during the study, and 97.1% of pts (132/136) with postbaseline assessments experienced a clinical benefit with some degree of reduction in spleen volume. Spleen reductions of ≥ 35% were sustained with continued ruxolitinib therapy (median duration not yet reached); the probabilities of maintaining the spleen response at wk 48 and 84 are 75% (95% CI, 61%-84%) and 58% (95% CI, 35%-76%), respectively (Figure). Since the last report (median 61.1 wk), an additional 9 and 12 deaths were reported in the ruxolitinib and BAT arms, respectively, resulting in a total of 20 (14%) and 16 (22%) deaths overall. Although there was no inferential statistical testing at this unplanned analysis, pts randomized to ruxolitinib showed longer survival than those randomized to BAT (HR = 0.52; 95% CI, 0.27–1.00). As expected, given the mechanism of action of ruxolitinib as a JAK1 & 2 inhibitor, the most common new or worsened grade 3/4 hematologic abnormalities during randomized treatment were anemia (ruxolitinib, 40.4%; BAT, 23.3%), lymphopenia (22.6%; 31.5%), and thrombocytopenia (9.6%; 9.6%). In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 wk of treatment and then recovered to levels similar to BAT from wk 24 onward; there was no difference in the mean monthly red blood cell transfusion rate among the ruxolitinib and BAT groups (0.834 vs 0.956 units, respectively). Nonhematologic AEs were primarily grade 1/2. Including the extension phase, there were no new nonhematologic AEs in the ruxolitinib group that were not observed previously (in ≥ 10% of pts), and only 1 pt had a new grade 3/4 AE (epistaxis). Conclusion: In COMFORT-II, ruxolitinib provided rapid and durable reductions in splenomegaly; this analysis demonstrates that these reductions are sustained over 2 years of treatment in the majority of pts. Ruxolitinib-treated pts showed longer survival than those receiving BAT, consistent with the survival advantage observed in previous (Verstovsek et al. NEJM. 2012) and current analyses of COMFORT-I, as well as with the comparison of pts of the phase 1/2 study with matched historical controls (Verstovsek et al. Blood. 2012). Disclosures: Cervantes: Sanofi-Aventis: Advisory Board, Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Pfizer: Advisory Board, Advisory Board Other; Teva Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Speakers Bureau; Novartis: AdvisoryBoard Other, Speakers Bureau. Kiladjian:Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Hunter:Incyte: Employment. Levy:Incyte: Employment, stock options Other. Passamonti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barbui:Novartis: Honoraria. Gisslinger:AOP Orphan Pharma AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Knoops:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

Observational Prospective Registry for the Assessment of the Clinical Impact of Starting Anti-Myeloma Treatment at Biological Relapse

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4765-4765
Author(s):  
Adrian Alegre ◽  
Merche Gironella ◽  
Juan Miguel Bergua ◽  
Esther Gonzalez ◽  
Fernando Escalante ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Marrow Transplant ◽  
Clinical Relapse ◽  
First Line ◽  
Advisory Committees ◽  
Free Survival

Abstract Introduction: Despite the great medical advances associated with the introduction of thalidomide, bortezomib (BORT), and lenalidomide (LEN) for the treatment of multiple myeloma (MM), it remains an incurable disease. Most patients (pts) show disease progression, consistent with the clinical evolution of MM, and only a low percentage achieve long-term responses and extended progression-free survival (PFS). The heterogeneous nature of MM in both the clinical and biological setting is reflected in the heterogeneity of MM relapses. The International Myeloma Workshop Consensus Panel (Rajkumar, Blood 2011) states that treatment (Tx) shall begin either at clinical relapse with symptoms (clinR), or in the event of asymptomatic relapse with significant paraprotein relapse, biological relapse (BR). The purpose of this Spanish registry is to describe MM relapse patterns comparing the impact of Tx decisions in pts who meet the criteria for biological relapse (BR) according to IMWG criteria with those in whom Tx was delayed until clinical relapse (clinR). Here, the preliminary results of this study are presented. Methods: MM pts in (or previous to) first or second BR who have achieved ≥ PR since their last Tx are eligible for inclusion in this observational prospective registry at the time BR is detected. Evaluations performed at least bi-monthly are mandatory. A total of 41 Spanish sites participated in the registry following approval from their independent ethics committees, with 410 pts expected to be included, without physician’s decision of prescribing Tx affecting the inclusion. The main objective of the registry is to assess the time to progression (TTP) from the start of anti-MM Tx at the onset of asymptomatic BR vs. the start of Tx at the time of clinR. Secondary objectives are to describe demographics of BR; to assess the median time elapsing from BR to clinR; to assess overall response rate (ORR), event-free survival (EFS), PFS, overall survival (OS) at BR and at clinR (if appropriate); to asses safety and quality of life (QoL) using 2 validated questionnaires (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and QLQ-MY24); to document the tolerability profile of the Tx; and to describe the use of associated resources. Here, we summarize baseline characteristics and preliminary results from 83 pts (out of 126 registered pts) who had basal data in the registry at the time of this report. Results: Overall, 79% of pts presented with a BR and 21% were in a bi-monthly watchful waiting follow up. The mean age of pts was 67 years, 53% were female, 57% were in first relapse, 43% and 27% had an ECOG performance status (PS) of 0 and 1, respectively, while the ECOG PS was unknown in 30% of pts at the time of this report. In total, 30% of pts had ISS stage I, 26% had ISS stage II, and 22% had ISS stage III, while ISS stage data were not available or unknown for 12% and 10% of pts, respectively. MM types were IgG Κ (37% of pts), IgG λ (23%), IgA Κ (13%), IgA λ (9%), and type was unknown in 17% of pts. 28% of IgG/IgA MM types were Bence-Jones. Cytogenetic risk assessments were available in 66% of pts. Among those pts with a BR, 51% received active Tx without waiting for a ClinR. First-line Tx was BORT-based in 70% of pts. Overall, 55% of pts had undergone autologous stem cell transplantation, 15% had received consolidation Tx and 34% had received maintenance Tx. After first-line Tx, 17% of pts achieved a stringent complete response (sCR), 31% achieved a CR, 24% achieved a very good partial response (VGPR), and 10% achieved a PR. The median time to BR was 24.53 months. Most (63%) pts who registered after second relapse received LEN-based Tx. Conclusions: To our knowledge, this is the first prospective study in MM to evaluate BR as well as the effects of Tx based on the decision to start Tx at BR vs. clinR. In this preliminary cohort, the physicians’ decision to start active Tx at BR, before the onset of clinR in 50% of cases, was noteworthy. Further follow-up is needed to identify the differences between these two strategies. Updated clinical results will be presented at the meeting. MM-BR Study, Spanish Myeloma Group-GEM/PETHEMA Bibliography Alegre A, et al. Haematologica. 2002;87:609-14. Brioli A, et al. Blood. 2014;123:3414-9. Fernández de Larrea C, et al. Bone Marrow Transplant. 2014;49:223-7. Lenhoff S, et al. Haematologica. 2006;91:1228-33. Rajkumar SV, et al. Blood. 2011;117:4691-5. Zamarin D, et al. Bone Marrow Transplant. 2013;48:419-24. Disclosures Alegre: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lahuerta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ruiz:Celgene: Celgene Stock options as part of the employee's compensation plan Other, Employment. Vilanova:Celgene: Contracted by Celgene Other.

Evaluation of Health Related Questionnaire Among Mycosis Fungoides and Lymphomatoid Papulosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5603-5603 ◽  
Author(s):  
Rakhshandra Talpur ◽  
Iris Wieser ◽  
Casey Wang ◽  
Lyons Genevieve ◽  
Madeleine Duvic
Keyword(s):  
Quality Of Life ◽  
Board Of Directors ◽  
Mycosis Fungoides ◽  
Research Funding ◽  
Brentuximab Vedotin ◽  
Function Score ◽  
Advisory Committees ◽  
Significant Difference ◽  
And Function

Abstract INTRODUCTION AND OBJECTIVES: Mycosis Fungoides (MF) andlymphomatoid papulosis (LyP) are relatively rare and itchy skin disorders. The cosmetic disfigurement and severe pruritus dramatically affects the patient's quality of life. The focus is to examine the validity and reliability of the skindex-29, M.D. Anderson symptom inventory (MDASI) and itch-related quality of life (IQOL) questionnaire in 62 patients in a phase II trial of Brentuximab Vedotin. MATERIALS AND METHODS: Patients completed survey questionnaires related to symptoms and quality-of-life several times over the course of Brentuximab Vedotin. We compared patients' baseline scores to their end-of-study (EOS) scores. Patients were grouped by diagnosis into Mycosis Fungoides and Lymphomatoid papulosis group. Questionnaires included skindex-29, focusing on the skin conditions the patient was bothered the most. (MDASI) for patients with cancer and following the symptoms of cancer and the itchy quality of life (I-QoL) questionnaire was developed to measure the symptoms associated with cancer therapeutic agents and their effect on daily activities. Scoring for the Skindex-29, M. D. Anderson Symptom Inventory (MDASI) and the Quality of Life (QOL) survey were done according to the questionnaire specific scoring guide. Responses were compared between 2 groups using the Wilcoxon rank-sum test. RESULTS Questionnaires from 62 patients (23 LyP and 39 MF) were studied at baseline and end of study. Patients were 33 males and 29 females with median age of 60 years (range: 27-86 years). The median overall survival (OS) was significant P = 0.041, when comparing patients with MF to LyP. The median survival time for patients from time of diagnosis with MF was 14.66 years and LyP was not reached. There was no significant difference in progression free survival (PFS) between MF and LyP. The median number of Brentuximab Vedotin cycles was 7 (1-19). Skindex-29 scales, showed change in emotion scale and function scale from baseline to EOS, both groups had a decrease, patients with LyP had a larger decrease in emotion score (P = 0.069) and function score (P =0.096) over the course of the study. There was no difference in the symptom scale from baseline to EOS. The patients with LyP had a larger decrease in function score from baseline to EOS. When comparing patients with MF to those with LyP for MDASI, there is no evidence of a difference, from baseline to EOS, in either symptom severity or symptom interference in daily life. In the IQOL when comparing the LyP patients' QOL responses from baseline to EOS, did not show significant difference. Table 1. Change in Skindex-29 scales, by group Skindex Scale MF LYP p-value Change from baseline to end-of-study: N Median Min Max N Median Min Max Emotion 35 -10 -65 35 20 -22.50 -61.94 12.5 0.0698 Symptoms 35 -7.14 -46.43 42.86 20 -10.71 -53.57 28.57 0.4782 Function 35 -2.08 -50.38 27.08 20 -16.29 -44.70 14.58 0.0962 Table 2. Change in MDASI scales, by Diagnosis MDASI Scale Item MF LYP p-value Change from baseline to end-of-study: N Median Mean Std. Dev Range N Median Mean Std. Dev Range Severity 35 0.23 0.18 1.96 (-5.85, 3.15) 21 0.38 0.46 1.61 (-1.69, 5.0) 0.9595 Interference 35 0.17 0.06 3.07 (-9.17, 5.17) 19 0.0 0.11 1.59 (-3.0, 4.67) 0.6764 CONCLUSIONS A significant improvement in emotions and functional part of skindex-29 was observed when comparing patients with MF to patients with LyP. While both groups had a decrease, the patients with LyP had a larger decrease in emotion and function score over the course of the study. Disclosures Duvic: Celgene: Membership on an entity's Board of Directors or advisory committees; Rhizen Pharma: Research Funding; Allos (spectrum): Research Funding; Therakos: Research Funding, Speakers Bureau; Soligenics: Research Funding; Huya Bioscience Int'l: Consultancy; Spatz Foundation: Research Funding; MiRagen Therapeutics: Consultancy; Eisai: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics: Research Funding; Array Biopharma: Consultancy; Cell Medica Ltd: Consultancy; Tetralogics SHAPE: Research Funding; Innate Pharma: Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals A Phase I/II Study of Lenalidomide Plus Obinutuzumab in Relapsed Indolent Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 348-348 ◽  
Author(s):  
Nathan H Fowler ◽  
Loretta J. Nastoupil ◽  
Collin Chin ◽  
Paolo Strati ◽  
Fredrick B. Hagemeister ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Marginal Zone ◽  
Advisory Board ◽  
Indolent Lymphoma ◽  
Advisory Committees ◽  
Grade 3

Background: Patients with advanced indolent non-Hodgkin lymphoma (iNHL) can develop chemoresistance and most relapse following standard therapy. Although multiple treatment options exist, most are associated with short remission or intolerable side effects. Lenalidomide activates NK cells ± T cells and leads to in vivo expansion of immune effector cells in NHL models. The combination of rituximab and lenalidomide (R2) in relapsed iNHL is highly active and was recently approved. Obinutuzumab is a glycosylated type II anti-CD20 molecule with enhanced affinity for the FcγRIIIa receptors leading to improved ADCC. The primary objective of this phase I/II study was to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide and obinutuzumab in relapsed indolent lymphoma. Methods: Patients with relapsed small lymphocytic lymphoma (SLL), marginal zone, and follicular lymphoma (gr 1-3a) were eligible. Patients enrolled in three predefined dose cohorts of lenalidomide (10mg,15mg, 20mg) given on days 2-22 of a 28 day cycle. Obinutuzumab was given at a fixed dose (1000mg) IV on days 1,8,15 and 22 of cycle 1 and day 1 of subsequent cycles for 6 cycles. The combination was given for up to 12 cycles in responding pts. Antihistamines were given in pts who developed rash. Prophylactic growth factor was not allowed. In the absence of progression or toxicity, single agent obinutuzumab was continued every 2 months for maximum of 30 months on study. Traditional 3+3 dose escalation was used with dose limiting toxicities (DLT) assessed during cycle 1. Once the MTD was established, 60 additional patients were enrolled in the phase II portion of the study. Adverse events were graded using CTCAE version 4.03. Results: 66 pts were enrolled between May 2014 until March 2019, and all are eligible for safety and response assessment. No DLTs were observed in dose escalation, and 60 pts were enrolled in the phase II portion of the study at 20mg of lenalidomide daily. Histologies included follicular lymphoma (FL) n=57, marginal zone n=4, SLL n=5. The median age was 64 (36-81), with 2 (1-5) median prior lines of treatment. For 53% of pts, the combination represented the third or greater line of treatment. The overall response (OR) rate for all pts was 98% with 72% attaining a complete response (CR). Eighteen pts (27%) had a partial response, and stable disease was noted in 1 (2%). At a median follow up of 17 months, 14 pts have progressed, with an estimated 24mo progression-free survival (PFS) of 73% (57-83% 95% CI). The estimated 24 mo PFS for ≥ third line pts was 63%. Twenty five pts (38%) remain on treatment and 95% remain alive at last follow up. The most common grade ≥ 3 non-hematologic toxicities included fatigue (5 pts), rash (4 pts), and cough (3 pts). Grade ≥3 neutropenia and thrombocytopenia occurred in 11 (17%) and 7 (11%) pts respectively. Two pts stopped treatment due to adverse events, including 1 transient bradycardia and 1 grade 3 fatigue. Conclusion: The combination of 20 mg of lenalidomide and 1000mg obinutuzumab is safe and effective in patients with relapsed indolent lymphoma. Adverse events appeared similar to our prior experience with lenalidomide and rituximab and were generally well tolerated. Overall response rates were high, with many pts achieving prolonged remission, including pts who had relapsed after 2 or more lines of prior therapy. Validation studies in the frontline and salvage setting are ongoing. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; MorphoSys: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Neelapu:Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding; Cellectis: Research Funding; Novartis: Consultancy; BMS: Research Funding; Karus: Research Funding; Acerta: Research Funding; Poseida: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Celgene: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Allogene: Consultancy; Pfizer: Consultancy; Cell Medica: Consultancy.

scholarly journals Pediatric-Inspired Chemotherapy Incorporating Pegaspargase Is Safe and Results in High Rates of MRD Negativity in Adults Ages 18-60 with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4013-4013 ◽  
Author(s):  
Mark Blaine Geyer ◽  
Ellen K. Ritchie ◽  
Arati V. Rao ◽  
M. Isabella Cazacu ◽  
Shreya Vemuri ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Advisory Board ◽  
Lymphoblastic Lymphoma ◽  
Advisory Committees ◽  
Grade 3

Abstract Introduction: Among adolescents and young adults with (w/) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL), treatment using a pediatric (vs. adult) regimen appears to achieve superior event-free (EFS) and overall survival (OS); this observation has driven increased interest in adapting pediatric regimens for middle-aged adults w/ ALL/LBL. However, greater risk of toxicities associated w/ asparaginase complicates administration of pediatric-inspired regimens in adults. We therefore designed a pediatric-inspired chemotherapy regimen w/ doses of pegaspargase (PEG) rationally synchronized to limit overlapping toxicities w/ other chemotherapeutic agents. Methods: We conducted a phase II multi-center trial in adults ages 18-60 w/ newly-diagnosed Philadelphia chromosome-negative (Ph-) ALL/LBL (NCT01920737). Pts w/ Ph+ ALL or Burkitt-type ALL were ineligible. The treatment regimen consisted of 2-phase induction (I-1, I-2), followed by consolidation w/ 2 courses of alternating high-dose methotrexate-based intensification and reinduction, followed by 3 years of maintenance (Figure 1). PEG 2000 IU/m2 was administered in each of the 6 intensive courses of induction/consolidation at intervals of ≥4 weeks. Minimal residual disease (MRD) was assessed in bone marrow (BM) by multiparameter flow cytometry (FACS) on day (d) 15 of I1 and following I-1 and I-2. Any detectable MRD (even <0.01% of BM WBCs) was considered positive. Toxicities were assessed by CTCAE v4.0. Results: 39 pts were enrolled (30M, 9F), w/ B-ALL (n=28), T-ALL (n=7), B-LBL (n=3), and T-LBL (n=5). Median age at start of treatment was 38.3 years (range 20.2-60.4), w/ 18 pts age 40-60. Grade 3-4 toxicities associated w/ PEG are summarized in Table 1. Grade 3-4 hyperbilirubinemia was observed post-PEG in I-1 in 9 pts, but only recurred thereafter in 1/8 pts resuming PEG. Pts completing consolidation on protocol (n=16) received median of 6 doses of PEG (range, 2-6). Four pts developed hypersensitivity to PEG and subsequently received Erwinia asparaginase. PEG was discontinued in 4 additional pts due to hepatotoxicity (n=2), pancreatitis (n=1), and physician preference (n=1). Of pts w/ available response assessments, 35/36 (97%) achieved morphologic complete response (CR) or CR w/ incomplete hematologic recovery (CRi) following I-1 (n=34) or I-2 (n=1). Both pts not achieving CR/CRi after I-I had early T-precursor ALL; one of these pts was withdrawn from study, and the other (w/ M2 marrow after I-1) achieved CR after I-2. Of the pts w/ ALL (excluding LBL) w/ available BM MRD assessments, 11/28 (39%) achieved undetectable MRD by FACS following I-1; 18/22 (82%) achieved undetectable MRD by FACS following I-2. Of the pts w/ LBL w/ available BM MRD assessments, 7/7 (100%) achieved or maintained undetectable MRD by FACS following I-1 and I-2. Ten pts underwent allogeneic hematopoietic cell transplantation (alloHCT) in CR1. Seven pts experienced relapse at median 15.2 months from start of treatment (range, 5.4-30.4), of whom 6 subsequently underwent 1st (n=5) or 2nd (n=1) alloHCT. Of the 11 pts w/ ALL w/ undetectable MRD following I-1, only one has relapsed. Five patients have died, including 2 pts in CR1 (from sepsis and multi-organ system failure), and 3 pts in relapse. At median follow-up of 22.3 months among surviving pts (range, 1.0-48.1), median EFS and OS (Figure 2A&B) have not been reached (EFS not censored at alloHCT). 3-year EFS was 62.1% (95% CI: 38.4-78.9%) and 3-year OS was 80.0% (95% CI: 57.5-91.4%). Conclusions: PEG can be incorporated into pediatric-inspired chemotherapy regimens w/ manageable toxicity for appropriately selected adults up to age 60 w/ Ph- ALL/LBL. While PEG-related AEs are common, few pts require permanent discontinuation of asparaginase. Grade 3-4 hyperbilirubinemia was common, particularly post-I-1, but recurred infrequently when PEG was continued. Two induction courses resulted in a high rate of MRD negativity post-I-2 and translated to a low rate of relapse. Though further follow-up is required, 3-year EFS is encouraging. Data regarding asparaginase enzyme activity and silent inactivation w/ neutralizing anti-PEG antibody will be presented. Ongoing and future studies will additionally investigate whether incorporating novel therapies (e.g. blinatumomab, nelarabine) into frontline consolidation therapy may reduce risk of relapse among adults receiving PEG-containing regimens. Disclosures Geyer: Dava Oncology: Honoraria. Ritchie:Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding. Rao:Kite, a Gilead Company: Employment. Tallman:Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Cellerant: Research Funding; AbbVie: Research Funding; BioSight: Other: Advisory board; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding. Douer:Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Pfizer: Honoraria; Spectrum: Consultancy. Park:Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Novartis: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Adaptive Biotechnologies: Consultancy.

scholarly journals Health-Related Quality of Life in a Biologic Assignment Trial of Reduced Intensity Hematopoietic Cell Transplantation Based on Donor Availability in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 421-421
Author(s):  
Rachel Cusatis ◽  
Michael Martens ◽  
Ryotaro Nakamura ◽  
Corey Cutler ◽  
Wael Saber ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Health Related Quality ◽  
Advisory Committees ◽  
No Donor ◽  
Free Survival ◽  
Related Quality ◽  
Health Related

Abstract Introduction The Blood and Marrow Transplant Clinical Trials Network study (BMT CTN 1102, NCT02016781) was a multicenter, biologic assignment trial in older adults aged 50-75 with higher risk de novo MDS (IPSS Intermediate-2 or High) who were candidates for reduced-intensity conditioning (RIC) allogeneic HCT. The trial compared outcomes of those with a suitable HLA-identical sibling or unrelated donor (Donor arm) to those where no donor was identified (No Donor arm) within a search window of 90 days. The trial reported a survival benefit for patients in the Donor arm compared to the No Donor arm [Nakamura et al, JCO 2021, in press]. Here, we compare the health-related quality of life (QOL) for patients between the two arms through 36 months after enrollment. We also describe the predictors and trajectories of QOL. Methods English and Spanish-speaking subjects were invited to complete patient-reported outcome (PRO) measures, including the Functional Assessment of Cancer Therapy - General (FACT-G), the SF-36 yielding a Physical Component Score (PCS) and Mental Component Score (MCS), and the EQ-5D, at enrollment and every 6 months until 24 months, then 36 months after enrollment. Validation studies indicate a clinically meaningful difference of 5 points for FACT-G, PCS, and MCS and 2 points for associated subscales. To account for the missingness of assessments, including those missing due to death, we compared each score between arms using an inverse probability weighted - independent estimating equation (IPW-IEE) model, which models the scores in surviving patients while using IPW to account for baseline variables and follow-up outcomes that impact the likelihood of missingness. Since 4 scores were evaluated, a Bonferroni corrected significance level of 1.25% = 5% / 4 was used. Cox regression models were used to evaluate the impact of QOL measures on overall and leukemia free survival. The IPW-IEE models adjust for baseline score and follow-up assessment time as well as age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy; the Cox models adjusted for the 6 latter variables and treatment arm. Trajectories of QOL are shown by plotting mean +/- standard error by group over time. Results Between January 2014 and November 2018, 384 subjects (median age 66.7 years, range: 50.1-75.3) were enrolled at 34 centers and biologically assigned to Donor (n=261) or No Donor arm (n=123) by 90 days from enrollment. For the Donor arm the median duration from registration to HCT was 3.9 months (range 0.3-20.7). Completion rates were generally high at 65-78% of eligible survivors at each timepoint. At enrollment, 204 subjects (78.2%) in the Donor arm and 85 subjects (69.1%) in the No Donor arm completed at least one QOL form, with 4 patients unable to complete due to language (non-English or Spanish speaking). While there were some small differences at 18 months favoring the Donor arm, no clinically significant differences in PRO scores or subscales were seen between the arms at any timepoint (Figure 1) or in the scores over time. In general, similar trajectories for the Donor arm were seen for each PRO, with most decreasing or stable from baseline to 6 months and improving thereafter. Compared to published averages of U.S cancer populations, FACT-G means in both arms were higher beginning at 18 months. Baseline and 6-month PRO scores were the strongest predictors of later PRO scores despite adjusting for patient demographic and clinical factors. Overall survival was predicted by baseline FACT-G &lt;70 (HR=1.61, p&lt;.01) and PCS scores &lt;40 (HR=1.82, p&lt;0.001), while leukemia-free survival was predicted by baseline FACT-G &lt;70 (HR=1.61, p&lt;0.01) and PCS &lt;40 (HR=1.80, p&lt;0.002). No associations of PROs with AML transformation, relapse, or acute or chronic GVHD were found. Non-compliance with biologic assignment was less likely in Donor arm compared to No Donor, but baseline QOL was not a confounding factor. Conclusion In older adults with MDS, the survival advantage associated with Donor availability and HCT does not come at the cost of worse QOL in comparison to the No Donor arm. Baseline PRO scores were the strongest independent predictors of subsequent QOL outcomes and survival, even after controlling for clinical and patient-level factors. These results should reassure older patients and clinicians who prefer curative approaches to MDS. Figure 1 Figure 1. Disclosures Cutler: Mallinckrodt: Consultancy; Editas: Consultancy; CareDx: Consultancy; Kadmon: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; Cimeio: Consultancy; Deciphera: Consultancy; Omeros: Consultancy; Syndax: Consultancy; Mesoblast: Consultancy; Jazz: Consultancy. Saber: Govt. COI: Other. Lee: Takeda: Research Funding; Syndax: Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kadmon: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Janssen: Other; Incyte: Research Funding; AstraZeneca: Research Funding; Amgen: Research Funding. Shaw: mallinkrodt: Other: payments; Orca bio: Consultancy. Horowitz: Magenta: Consultancy, Research Funding; Astellas: Research Funding; Jazz Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Genentech: Research Funding; CSL Behring: Research Funding; Gamida Cell: Research Funding; Allovir: Consultancy; Daiicho Sankyo: Research Funding; Amgen: Research Funding; bluebird bio: Research Funding; Chimerix: Research Funding; Actinium: Research Funding; Medac: Research Funding; Kiadis: Research Funding; Xenikos: Research Funding; Vor Biopharma: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Pharmacyclics: Research Funding; Pfizer, Inc: Research Funding; Orca Biosystems: Research Funding; Omeros: Research Funding; Novartis: Research Funding; Miltenyi Biotech: Research Funding; Mesoblast: Research Funding; Kite/Gilead: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Seattle Genetics: Research Funding; Shire: Research Funding; Sobi: Research Funding; Stemcyte: Research Funding; Takeda: Research Funding; Tscan: Research Funding; Vertex: Research Funding.

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