Importance of Complete Remission on Predicting Overall Survival in Patients with Lower-Risk Myelodysplastic Syndromes (MDS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4332-4332
Author(s):  
Aziz Nazha ◽  
Rami S. Komrokji ◽  
John Barnard ◽  
Najla H Al Ali ◽  
Gail J. Roboz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Complete Remission ◽  
Board Of Directors ◽  
Lower Risk ◽  
Research Funding ◽  
Advisory Committees ◽  
Best Response ◽  
Bone Marrow Blasts

Abstract Background Lower-risk (LR) MDS (Low/Int-1 per International Prognostic Scoring System (IPSS)) are a heterogeneous group of disorders characterized mainly by refractory anemia and transfusion dependency. As survival of this patient (pt) population is measured in years. Goals of therapy focus on decreasing blood transfusions, improving quality of life, while minimizing treatment toxicities. While achieving complete remission (CR) in higher-risk MDS correlates with improved overall survival (OS), its relationship to OS in LR MDS is not well defined. We evaluated the impact of achieving CR on OS in LR MDS and defined the clinical characteristics that may predict for this response in this pt population. Method Included pts were diagnosed with MDS (per 2008 WHO criteria) and had LR disease with clinical and pathologic data collected from MDS Clinical Research Consortium institutions. Only pts with bone marrow blasts of 5-9% who would thus qualify both as having LR MDS and for being eligible to assess CR were included. Responses (including CR, PR, HI, stable disease and progressive disease) were defined per International Working Group 2006 criteria. OS was calculated from the time of achievement of best response to time of death or last follow-up. Cox proportional hazard analysis that included all clinical variables and treatment characteristics was used to identify independent prognostic factors. Results Of 1470 pts included in the database, 999 identified with LR disease, and 174 had bone marrow blasts of 5-9%. The median age was 60 years (range, 22-87), and 37% were female. Median neutrophil count was 1.25 X 109\L (range, .10-51.0), hemoglobin was 9.8 g/dl, platelets were 109 k/ml (range, 18-562), and bone marrow blasts were 6% (range, 5-9%). Best responses to therapy included: 26 pts (15%) with CR, 10 pts (6%) with PR, and 13 pts (7%) with HI. Among pts who achieved CR/PR/HI, 27 received HMA (25 with azacidtine +/- combination and 2 with single agent decitabine), 16 intensive chemotherapy, 2 lenalidomide, and 4 received other therapies. With a median follow up from diagnosis of 31.2 months, the median time from diagnosis to best response was 11.9 months (range, .69-81.0) and was similar in pts who achieved CR compared to PR/HI (11.5 vs. 12.4 months, respectively, p = .74). The median OS from time of CR/PR/HI for the entire cohort was 21.3 months. The median OS for pts who achieved a CR was longer compared to pts with PR/HI (46.5 vs. 18.5 months, respectively, p = .03). In multivariate analyses that included clinical variables and treatment history, achieving CR remained an independent prognostic factor for longer OS (HR .32, p = .03) but no individual demographic, clinical or treatment variables were predictive of CR. Conclusions Similar to pts with higher-risk MDS, LR MDS pts who achieve CR to therapy have improved OS compared to those with PR or HI. CR is thus an important endpoint in LR MDS, though is difficult to predict. As OS is measured in years in LR MDS, CR may be used as a surrogate endpoint for OS in clinical trials in this pt population. Disclosures Komrokji: Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Preliminary Results of a Phase II Study of Lenalidomide-Elotuzumab As Maintenance Therapy Post-Autologous Stem Cell Transplant in Patients with Multiple Myeloma

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 840-840
Author(s):  
Sheeba K. Thomas ◽  
Jatin J. Shah ◽  
Hans C. Lee ◽  
Elisabet E. Manasanch ◽  
Donna M. Weber ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Best Response ◽  
Grade 3

Abstract Background: Lenalidomide (LEN) monotherapy has been effective in extending progression free survival (PFS) and after myeloablative AuSCT in patients (pts) with multiple myeloma (MM) (Attal et al. NEJM 2012, McCarthy et al. NEJM 2012,). Elotuzumab (ELO), a humanized IgG1 immunostimulatory monoclonal antibody against signaling lymphocytic activation molecule F7 (SLAMF7), is FDA approved in combination with LEN and dexamethasone (DEX) for treatment of pts with MM who have received 1-3 prior therapies. The objective of this phase 2 trial is to evaluate the efficacy and safety of adding ELO to LEN as maintenance therapy post-myeloablative AuSCT. We report preliminary results of the primary (PFS) and secondary (overall survival and toxicity) endpoints. Patients and Methods: Between 4/15/2015-1/27/2016, 28 evaluable pts were treated on 28 day cycles with ELO, 10 mg/kg iv weekly for cycles 1-2 and q2weeks for cycles 3-6, then 20 mg/kg once monthly for cycles 7+. Pts enrolled after 1/28/2016 (n=27 pts) have received ELO, 10 mg/kg IV weekly for cycles 1-2, and 20 mg/kg on day 1 from cycle 3 until progression. LEN has been dosed at 10 mg/day for cycles 1-3, with a dose increase to 15 mg/day at physician discretion starting with cycle 4, in the absence of non-hematologic toxicity > grade 1 and significant cytopenias (ANC < 1000/mL, platelet count < 100,000/ml). For the 1st 8 weeks, pts <75 yrs receive 28 mg of DEX 3-24 hours pre-infusion, while pts ≥75yrs receive 8mg; pts receive 4-10 mg iv DEX immediately pre-infusion for all cycles. Pts also receive herpes zoster prophylaxis and thromboprophylaxis commensurate with standard recommendations. The primary endpoint of the study is PFS, defined as the time from AuSCT to clinical progression or death (whichever occurs first), or the time of last contact. Secondary objectives include best response, overall survival, incidence of second primary malignancies and adverse event (AE) profile. Total enrollment of 100 pts is planned. Pts will be followed for 48 months after the last patient is enrolled in the trial. Eligible pts had received no more than 2 lines of induction therapy, and were between 60-210 days post-AuSCT. Results: Patients (n=55) have been treated for a median of 14 cycles (2-30). At study entry, 13 pts (24%) had complete response (CR), 27 (49%) had very good partial remission (VGPR), 14 (25%) had partial remission (PR) and 1 (2%) had minor remission (MR). Best response achieved to date on study is CR in 28 pts (51%), VGPR in 23 pts (42%) and PR in 4 pts (7%). For those who have converted to CR on study, median time to CR has been 5 months. Of 14 pts in CR who have been tested for MRD while on study, 13 are negative by flow cytometry (minimum of 2 million cells evaluated; sensitivity 10 -4-10-5). Two of these 13 have converted from VGPR to MRD negativity at 4 and 14 months on study, respectively. With a median follow up of 21 months, 95% of pts (n=52) remain alive. Three pts (all with high risk disease) had disease progression at 4 (del 17p), 9 (t [4;14]), and 13 (gain 1q) months; of these, 2 have died of progressive disease while receiving salvage therapy. One patient, in VGPR, died on study after developing acute cerebral encephalopathy with refractory status epilepticus of unclear etiology. Two pts withdrew for logistical reasons; 2 have been taken off study per physician discretion (prolonged cytopenias (1), drug rash (1)). Grade 3-4 Hematologic AEs (no. of pts) were: neutropenia 35% (16), thrombocytopenia 9% (4), febrile neutropenia 7% (3), and anemia 7% (3). Grade 3-4 non-Hematologic AEs (no. of pts): diarrhea 17% (8), fatigue 17% (8), pneumonia 15% (7), other infections 15% (7), peripheral neuropathy 11% (5), myalgias 9% (4), nausea/vomiting 7% (3), maculopapular rash 4% (2), dizziness 4% (2), edema 2% (1), memory impairment 2% (1). Renal cell carcinoma was diagnosed in 1 patient, 15 months after removal from study for disease progression. Conclusions: Lenalidomide-elotuzumab is a well-tolerated maintenance therapy on which 44% of 55 pts have had improvement in quality of response while on therapy, including 28% who have converted to CR and 24% who have tested MRD negative. The number of pts who have experienced improvement on study may, in fact, be underestimated in this analysis due to elotuzumab interference with measurement on electrophoretic studies. Additional follow up is required to determine if the improved quality of responses translate into improvements in PFS and OS. Disclosures Thomas: Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Shah: Kayopharm: Employment. Lee: Pimera Inc: Consultancy; Eutropics Pharmaceuticals: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Manasanch: merck: Research Funding; adaptive biotechnologies: Consultancy; sanofi: Research Funding; celgene: Consultancy; takeda: Consultancy; quest diagnostics: Research Funding. Patel: Juno: Consultancy; Celgene: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Orlowski: BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees.

A Score Based on IPSS-R, Ferritin and EPO Levels Predicts Erythroid Response to ESAs and Survival in Lower Risk Anemic MDS Patients with High Probability of Response to ESAs: Spresas Sub-Analysis from the GESMD

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2896-2896 ◽  
Author(s):  
María Díez Campelo ◽  
Julio Davila ◽  
Sanchez Barba Mercedes ◽  
Maria Lopez-Pavia ◽  
Esperanza Such ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Lower Risk ◽  
Research Funding ◽  
Response Rate ◽  
Significant Variable ◽  
Advisory Committees ◽  
Erythroid Response ◽  
Probability Of Response

Abstract INTRODUCTION Anemia is the most frequent cytopenia in lower-risk MDS. Erythropoietic-stimulating agents (ESAs) are commonly used in these patients. The use of ÒclassicalÓ parameters (EPO and ferritin levels) and the revised IPSS (IPSS-R) has been proposed1 (SantiniÕs score) to predict response to ESAs and overall survival (OS) among patients with lower risk MDS by IPSS and a favorable Nordic group score2. OBJECTIVES The main objective of the study was to evaluate overall response rate (ORR) to ESAs and OS according to the proposed SantiniÕs score in an independent and large cohort of anemic lower risk MDS patients receiving treatment with ESAs. METHODS Data from 530 anemic patients with low/int1 risk IPSS de novo MDS (according to FAB and WHO criteria) and sufficient follow-up data available were recorded in Spresas3 (SPanish Registry of Erythropoietic Stimulating Agents Study from GESMD). Two hundred and twenty six patients (42.6% of the patients) were selected according to specific criteria regarding the published SantiniÕs score1: Hb level </=10 g/dL, serum erythropoietin (EPO) <500 mU/mL and ESA (EPO alfa or B 40000-60000IU/week, or darbepoetin 150-300 ug/week). Applying 1 point to each of the following unfavorable variables for response to ESA, EPO>200mU/mL(=1), serum ferritin (SF) >350 ng/mL(=1) and IPSS-R very low=0, low=1, intermediate=2 and high=3) yielded a score ranging from 0 to 5. ESAs response rate and overall survival were analysed according to these score. Response to treatment was evaluated according to IWG 2006 response criteria and a multivariate logistic regression analysis was used to identify independent predictors of erythroid response (ER). OS were defined as the time between diagnosis and the corresponding event or last follow up (Feb 2015) and were analyzed using univariable and multivariable Cox proportional hazards regression methods. RESULTS Median age was 77 years (interquartile range [IQR] 25%-75%: 71-83 y), median Hb level at start of treatment was 10 g/dL (IQR25-75: 9-10), median EPO level was 90 (IQR25-75: 27,25-108) and median ferritin level was 338,5 (IQR25-75: 146,5-568,75). Among 139 patients with this data available, 85 patients (61,1%) were RBC transfusion dependent before ESAs treatment. Median time from diagnosis to ESAs treatment was 82 (IQR25-75: 27-353) days. According to the IPSS, 68.6% (N=155) and 31.4% (N=71) were in low and Int-1 risk groups, respectively. Regarding IPSS-R, 23% (N=52), 66.8% (N=151), 9.7% (N=22) and 0.4% (N=1) were in very low, low, intermediate and high risk, respectively. ORR to ESA treatment was 71.2% (N=161), with a median duration of response of 2.06 years. Prognosis factors of ER showed a trend toward to a higher ER among patients in the lower IPSS-R (P>0.05), low IPSS (p=0.039) and lower EPO levels (p<0.0001) while in multivariate analysis EPO level was confirmed as most significant variable associated to ER (p<0.001). According to SantiniÕs score, 11.5%(N=26), 42.9%(N=97), 25.8%(N=81), 8%(N=18) and 1.8%(N=4) of the patients were in the 0, 1, 2 3 and 4 score. Erythroid response was better for patients in the lower scores, with response rates of 73.1%, 82.5%, 65.4%, 50% and 0%, for patients in 0, 1, 2, 3 and 4 score, respectively (p<0.001, figure 1). After a median follow up of 3.1 years, median OS from diagnosis was 4.99 years. Interestingly, median OS from diagnosis was clearly related to SantiniÕs score (10.7 years, 6.7y, 4.9y, 3.7y and 6.7y for patients with 0, 1, 2, 3, and 4 points, respectively, p=0.041, Figure 2) whereas median OS from start of ESAs showed also some trend (p=0.26). CONCLUSIONS The present study confirms that SantiniÕs score is useful to identify patients with a higher probability of response to ESAs and better OS among lower risk MDS patients with an expected favorable response to ESA according to Nordic group score. Spresas study was partly supported by Janssen 1.-Santini et al, Blood 122(13), 2013. 2.-Hellstršm-Lindberg, Br J Haematol 120(6), 2003. 3.-D'ez Campelo, EHA 2015 meeting, P244. Disclosures Díez Campelo: Novartis: Research Funding, Speakers Bureau; Janssen: Research Funding; Celgene: Research Funding, Speakers Bureau. Off Label Use: Use of erythropoietic stimulating agents for anemia in patients with myelodysplastic syndromes. Ramos:JANSSEN: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Falantes:Celgene: Honoraria. Garcia:Celgene: Research Funding. Sanz:JANSSEN CILAG: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Outcome of Autologous Stem Cell Transplantation in Waldenström's Macroglobulinemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2149-2149
Author(s):  
Romil Patel ◽  
Neeraj Y Saini ◽  
Ankur Varma ◽  
Omar Hasan ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Advisory Committees ◽  
First Remission ◽  
Relapsed Disease

Abstract Introduction: The role of autologous hematopoietic stem cell transplantation (auto-HCT) in the management of patients with Waldenström Macroglobulinemia (WM), a rare, indolent lymphoma, has not been established. We had previously published our experience with auto-HCT in a small cohort of WM patients1. Here, we present an updated analysis of auto-HCT with a larger cohort of WM patients. Methods and study population: The study cohort was comprised of 29 patients who underwent high-dose chemotherapy and auto-HCT at MD Anderson Cancer Center (MDACC). The Kaplan-Meier method was used to create survival curves. Overall survival (OS) was defined as the duration from date of transplant to death or last date of follow-up in living patients. Progression-free survival (PFS) was defined as the duration from date of transplant to either progressive disease or death, whichever occurred first. Results: Median age at auto-HCT was 60 (range, 43-75 years). Eight patients (28%) had concurrent light chain amyloidosis (AL). Of the five patients who had MYD88 testing completed, 3 were positive for the MYD88 mutation. Additionally, of these 3 patients, 2 were also positive for CXCR4 mutation. Patients received a median of 2 lines (range 1-6) of therapy prior to auto-HCT; 3(10%) patients had primary refractory disease, 8(28%) were in first remission, and 18 (62%) had relapsed disease. Median time from transplant to last follow-up for the surviving patients was 5.3 years. Preparative regimens received by the patients were: Melphalan (n=20), BEAM-R (n=2), Busulfan/Melphalan (n=1), Cyclophosphomaide/Etoposide/total body irradiation (n=1), Thiotepa/Busulfan/Cyclophosphamide (n=1), and Carmustine/Thiotepa (n=1). Three patients further went on to receive allogeneic transplant either after relapse from auto-HCT or due to disease transformation to aggressive lymphoma. Twenty-eight patients achieved engraftment with a median time to neutrophil engraftment of 11 days (range, 10-15 days). One patient suffered primary graft failure due to progression of disease and died 84 days after transplant. Non-relapse mortality was 3.4% at 1 year. All patients were eligible for response evaluation. The median OS from diagnosis was 12.2 years. Overall response rate was 96%: complete response (n=8, 27.6%), very good partial response (n=5, 17.3%), partial response (n=15, 51.7%), and progressive disease (n=1, 3.4%). PFS and OS at 5 years were 43.3% and 62.9%, respectively. Median PFS and OS from auto-HCT were 4.1 and 7.3 years (Fig. 1A). The median OS from auto-HCT in first remission + primary refractory and relapsed disease was 8.2 years and 4.1 years, respectively.16 patients were alive at the time of censoring while 13 patients had died. Causes of death include relapsed disease (n=6), secondary malignancy (n=2), infection (n=1), chronic graft-versus-host disease (n=1), and unknown (n=3). 8 patients (28%) were positive for concurrent AL amyloidosis. The sites of amyloid involvement were kidneys (n=2), lungs (n=1), bone marrow (n=1), heart(n=1), lymph nodes(n=1), gastrointestinal tract (n=1) and subcutaneous fat aspirate(n=5). The median overall survival for patients with amyloid involvement (n=8) was 12 years. On univariate analyses, the number of chemotherapy regimens prior to transplant (≤ 2 vs >2 lines) was the strongest predictor of overall survival (p=0.03, HR 0.3, CI: 0.09-0.9, log-rank) and PFS (p=0.001, HR 0.24, CI: 0.07-0.85, log-rank). The median PFS in patients with ≤ 2 lines and > 2 lines of therapy was 71 months versus 19 months, respectively (Fig. 1B). Conclusion: Auto-HCT is safe and feasible in selected patients with WM, with a high response rate and durable remission even in patients with relapsed or refractory disease. References: Krina Patel et.al. Autologous Stem Cell Transplantation in Waldenstrom's Macroglobulinemia. Blood 2012 120:4533; Disclosures Thomas: Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Array Pharma: Research Funding; Amgen Inc: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Takeda: Consultancy; Celgene: Consultancy; Spectrum Pharma: Research Funding; Janssen: Consultancy; Kite Pharma: Consultancy; Sanofi-Aventis: Consultancy; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

scholarly journals Phase I Study of Ixazomib Added to Chemotherapy in the Treatment of Acute Lymphoblastic Leukemia in Older Adults

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Philip C. Amrein ◽  
Karen K. Ballen ◽  
Kristen E. Stevenson ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
Survival Estimate ◽  
Grade 3 ◽  
Experienced Grade

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients &gt;60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

scholarly journals Minimal Residual Disease Eradication with Venetoclax in Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-14
Author(s):  
Alexander Coltoff ◽  
Joseph G. Jurcic ◽  
Peter Campbell ◽  
Daniel J. Lee ◽  
Mark L Heaney ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Median Overall Survival ◽  
Residual Disease ◽  
Institutional Research ◽  
Negative Group ◽  
Advisory Committees ◽  
Research Grants

Introduction The combination of the BCL-2 inhibitor venetoclax with an HMA (HMA/Ven) has improved outcomes in previously untreated patients with AML not eligible for intensive induction therapy. In a phase Ib study, 67% of patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) with a median overall survival (OS) of 17.5 months (DiNardo CD et al. Blood 2019; 133(1):7-17). HMA/Ven has also demonstrated efficacy in a heavily pretreated population with relapsed or refractory (R/R) AML, the majority of whom had prior HMA exposure (DiNardo CD et al. Am J Hematol 2018; 93(3):401-7). Measurable residual disease (MRD) is recognized as an independent prognostic indicator important for risk stratification and treatment planning (Schuurhuis GJ et al. Blood 2018; 131(12):1275-91). To date, however, there have been few reports on the effect of HMA/Ven on MRD. Methods This is a retrospective case series of patients with AML at a single-center tertiary-care institution. Patients ≥ 18 years of age who were treated with HMA/Ven between January 2017 and June 2020, either in the upfront or salvage setting, for AML were included. Outcomes included CR/CRi rate, MRD response, relapse free survival (RFS), and OS. MRD was assessed via multicolor flow cytometry with a sensitivity of 10-3 (0.1%). Results Nineteen patients were identified, 12 (63%) of whom were female. The median age at the time of HMA/Ven initiation was 71 years (range, 21 - 87 years). Ten (53%) patients had de novo AML and 9 had secondary or therapy-related AML. By 2017 ELN criteria, 3 (16%) patients had favorable-risk, 9 (47%) had intermediate-risk, and 7 (37%) had adverse-risk AML. Nine (47%) patients had R/R AML; 5 received HMA/Ven as first salvage therapy, and 4 as 2nd or greater salvage. Three (16%) patients had prior HMA exposure. No patient had prior venetoclax exposure. Median follow-up was 9.1 months (range, 1-21.1 months). Ten (53%) patients received azacitidine and 9 (47%) were given decitabine. Venetoclax doses ranged from 50 to 400 mg daily, depending on participation in a clinical trial and concomitant medications. Eight patients achieved a CR and 7 patients achieved a CRi for a combined CR/CRi rate of 79%. The CR/CRi rate was 90% (9/10) in the upfront setting, and 66% (6/9) in the salvage setting. The median time and number of cycles to best clinical response was 2.3 months (range, 0.9-3.9 months) and 2 (range, 1-3 cycles), respectively. Eleven (73%) of the 15 responders achieved MRD clearance after a median of 2 cycles (range, 1-3 cycles) (Table 1). Two of 4 (50%) MRD-positive patients relapsed, while 4 (36%) of 11 MRD-negative patients relapsed (Figure 1). Relapse occurred at a median of 2.0 months (range, 1.3-2.7 months) in the MRD positive group and 11.0 months (range, 2.8-14 months) in the MRD negative group. One patient died of infectious complications while MRD negative. Three patients, all of whom were treated for R/R disease, proceeded to an allogeneic stem cell transplant (HSCT). Two were MRD negative at the time of HSCT and all remained in remission. At the time of data cutoff, 7 (64%) of 11 MRD-negative patients were alive, and all 4 MRD-positive patients were alive. Causes of death in the MRD-negative group included disease relapse (3 patients) and infection (1 patient). Median overall survival in the entire cohort (range, 32 days-NR) was not reached. Conclusions HMA/Ven was highly effective as both upfront and salvage therapy. Surprisingly, the salvage CR/CRi rate in this series was 66%, allowing half of the responders to proceed to HSCT. The majority (73%) of responders achieved MRD negativity. While MRD status influenced RFS, 36% of MRD-negative patients relapsed. Additionally, the same percentage of MRD-negative patients died during follow-up, versus none of the patients with MRD-positivity. This indicates the need for more sensitive methods to assess MRD and for novel therapeutic strategies to eliminate MRD, thereby improving long-term outcomes. Larger prospective studies are needed to define the role of MRD assessment with venetoclax-containing regimens. Disclosures Jurcic: AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Syros Pharmaceuticals:Research Funding;PTC Therapeutics:Research Funding;Arog Pharmaceuticals:Research Funding;Kura Oncology:Research Funding;Forma Therapeutics:Research Funding;Astellas:Research Funding;Genentech:Research Funding;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS:Consultancy, Research Funding.Campbell:AstraZeneca:Consultancy.Lee:Genentech:Research Funding;Sumitomo Dainippon Pharma Oncology, Inc.:Research Funding;AbbVie:Research Funding;Novartis:Research Funding;Bayer:Research Funding;Celgene:Consultancy;Forty Seven:Research Funding.Heaney:Blueprint Medicines Corporation:Research Funding;BMS:Research Funding;CTI Biopharma:Consultancy, Research Funding;Deciphera:Research Funding;Incyte:Research Funding;Novartis:Consultancy, Research Funding;Sierra Oncology:Research Funding;AbbVie:Consultancy;Partner Therapeutics:Consultancy.Lamanna:Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Octapharma:Research Funding;Juno:Other: Institutional research grants, Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astra Zeneca:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Pharmacyclics:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Bei-Gene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Abbvie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Oncternal, Verastem, TG Therapeutics:Other: Institutional research grants, Research Funding;MingSight:Other: Institutional research grants, Research Funding;Loxo:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Columbia University Medical Center:Current Employment.

Multiple Myeloma In Complete Remission After Autologous Stem Cell Transplantation: Impact of Bone Marrow Plasma Cell Assessment by Conventional Morphology on Disease Progression

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2946-2946
Author(s):  
Carlos Fernández de Larrea ◽  
Natalia Tovar ◽  
María Rozman ◽  
Laura Rosiñol ◽  
Juan I. Aróstegui ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Bone Marrow Aspirate ◽  
Advisory Committees ◽  
Bone Marrow Plasma ◽  
Serum And Urine

Abstract Abstract 2946 Background: The achievement of complete remission (CR) is the crucial step for a long-lasting response and prolonged survival after autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). The European Group for Blood and Marrow Transplantation (EBMT) criteria for CR include the negativity of serum and urine immunofixation (IFE) and less than 5% of bone marrow plasma cells (BMPCs). Additionally, the International Myeloma Working Group (IMWG) has even proposed a stringent CR category, which requires to rule out the clonal nature of the BMPCs. However, few studies have addressed this issue in patients with MM and negative IFE. The aim of the present study was to determine the impact of plasma cell count in the bone marrow aspirate on the long-term outcome of patients with MM with negative IFE after ASCT. Methods: Thirty-five patients (16M/19F; median age at ASCT 55 years, range 26–68) with MM who underwent ASCT from March 1994 to December 2008, were studied. All patients had achieved a negative serum and urine IFE after high dose therapy with melphalan-based regimens. Bone marrow aspirate was performed when negative serum and urine IFE was achieved and at least three months from ASCT (median 3.24 months). The analysis was based on microscopic revision for May-Grünwald-Giemsa stained bone marrow smears performed according to standard procedures. BMPC percentage was calculated independently by two observers counting 500 bone marrow total nucleated cells in random areas from two different slides (1000 cells on each patient). Results: Median BMPCs percentage was 0.8 (range 0.1–5.8). Only two patients had more than 3% BPMCs. These results are in contrast with a recent report from the Mayo Clinic group, where 14% of the patients with MM and negative IFE had 5% or more BMPCs. In univariate Cox-model regression analysis, the number of BMPCs significantly correlated with progression-free survival (PFS)(p=0.021) with no impact on overall survival (OS)(p=0.92). This statistical significance on PFS was retained in the multivariate analysis, when baseline prognostic factors such as age, hemoglobin level, serum creatinine, β2-microglobulin and Durie-Salmon stage were added to the model (p=0.003). To establish the best predictive cut-off for progression and survival, a receptor-operator curve (ROC) analysis was developed. It showed the value of 1.5% BMPCs, with a sensitivity of 53%, specificity of 90% and area under the curve of 0.66 for predicting progression. Ten patients had more than 1.5% BMPC, and 25 equal or less than 1.5% BMPC. Median PFS was 8.5 years (CI 95% 2.6 to 14.3) and was not reached in patients with ≤1.5% BMPCs versus 3.1 years in patients with >1.5% BMPCs, with a hazard ratio probability to progression of 3.02 (CI 95% 1.18 to 9.71)(p=0.016) in the group with more than 1.5% of BMPCs (Figure 1). Median OS was not reached in patients with ≤1.5% compared with a median of 9.7 years in those with more than 1.5% BMPCs (p=0.195) (Figure 2). It is likely that serological CR with very low percentage of BMPCs (i.e. ≤1.5%) is equivalent to negative MRD assessed by MFC or molecular studies. In fact, all 8 patients in continued CR between 9 and 16 years beyond ASCT (“operational cures”) are in the group with ≤1.5% BMPCs, while all patients in the group with >1.5% BPMC have relapsed within the first 9 years from ASCT (Figure 1). Conclusion: The percentage of BMPCs in patients with MM in CR after ASCT is a strong predictor of progression. Bone marrow morphology examination is an easy, inexpensive, and non-time consuming test and it should be the first step in the estimation of the residual tumor mass in patients with MM in CR after ASCT. Disclosures: Rosiñol: Janssen-Cilag: 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. Cibeira:Janssen-Cilag: 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. Blade:Janssen-Cilag: 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.

Consistent Benefit of Ruxolitinib Over Placebo in Spleen Volume Reduction and Symptom Improvement Across Subgroups and Overall Survival Advantage: Results From COMFORT-I

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 278-278 ◽  
Author(s):  
Srdan Verstovsek ◽  
Ruben A. Mesa ◽  
Jason Gotlib ◽  
Richard S. Levy ◽  
Vikas Gupta ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Symptom Severity ◽  
Research Funding ◽  
Risk Group ◽  
Spleen Volume ◽  
Advisory Committees ◽  
Disease Subtype ◽  
Baseline Hemoglobin

Abstract Abstract 278 Background: Overactive JAK-STAT signaling as a result of gain-of-function mutations (eg, JAK2V617F) and/or high circulating levels of inflammatory cytokines is considered to play a key role in the pathogenesis of myeloproliferative neoplasms. Ruxolitinib, a selective oral inhibitor of JAK1 and JAK2, demonstrated a significant reduction in spleen volume (SV) and improvements in myelofibrosis (MF)-related symptoms in a double-blind placebo-controlled trial (COMFORT-I). The objective of this analysis was to evaluate the efficacy of ruxolitinib across patient (pt) subgroups in COMFORT-I. Methods: Pts with MF were randomized to start placebo or ruxolitinib at a dose of 15 mg or 20 mg PO BID depending on baseline platelet count (100–200 ×109/L or >200 ×109/L, respectively). The dose was optimized for efficacy and safety during treatment. SV change was measured by MRI; MF symptoms were assessed using a daily diary (modified Myelofibrosis Symptom Assessment Form [MFSAF] v2.0) over 1 wk prior to dosing and throughout the 24 wks of dosing. The percent changes from baseline to wk 24 in SV and MFSAF Total Symptom Score (TSS, a measure of combined scores for abdominal discomfort, pain under ribs on left side, early satiety, itching, night sweats, and bone/muscle pain) were compared for ruxolitinib and placebo pts across the following subgroups: MF disease subtype, age, International Prognosis Scoring System (IPSS) risk group, presence/absence of JAK2V617F mutation, baseline hemoglobin, baseline spleen size (palpable spleen length), and baseline TSS. Survival was estimated by Kaplan-Meier method. Changes in SV and TSS Across Subgroups: 309 pts were randomized: 155 to ruxolitinib and 154 to placebo. Ruxolitinib demonstrated consistent benefit compared with placebo in both SV and TSS across all subgroups evaluated (Table). The impact of symptom severity on response was evaluated by baseline TSS quartiles (maximum score for TSS = 60). Ruxolitinib pts with baseline TSS of <8.5, 8.5-<16.5, 16.5-<25.5 and ≥25.5 had mean percent changes in SV of −28.0, −31.4, −31.7 and −34.8, respectively, vs +8.1 for all placebo pts combined. The mean percent change in TSS for these same subgroups was −40.5, −47.2, −48.1 and −48.2 vs +41.8 for all placebo pts combined. These data indicate that pts with modest to marked symptoms all benefit from ruxolitinib therapy in terms of both SV and TSS. Survival Analysis: 13 ruxolitinib and 24 placebo pts died during the study or during extended follow-up (median follow-up of 52 and 51 wks, respectively), representing a hazard ratio (95% CI) of 0.499 (0.254, 0.98) (p=0.0395). For ruxolitinib- and placebo-treated pts, respectively, the probability of survival (95% CI) >48 wks was 0.98 (0.92, 0.99) and 0.90 (0.81, 0.95) for pts with baseline hemoglobin values ≥10 g/dL and 0.84 (0.72, 0.91) and 0.77 (0.63, 0.86) for pts with baseline hemoglobin <10 g/dL. Conclusions: Pts receiving ruxolitinib had higher response rates than placebo based on reductions in SV and improvements in TSS at wk 24 regardless of baseline subgroup: MF disease subtype, age (≤65 or >65 y), IPSS risk group (intermediate-2 or high-risk), presence or absence of JAK2V617F mutation, hemoglobin level (≥10 g/dL or <10 g/dL), palpable spleen length (≤10 cm or >10 cm), and symptom severity (TSS quartile). In addition, the overall survival analysis suggested a benefit with ruxolitinib therapy over placebo. Disclosures: Verstovsek: Incyte: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding. Gotlib:Incyte: Consultancy, Research Funding. Levy:Incyte: Employment, Equity Ownership. Gupta:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Catalano:Incyte: Honoraria; Novartis: Honoraria. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Winton:Incyte: Consultancy. Arcasoy:Incyte: Research Funding. Lyons:Alexion: Consultancy, Honoraria; Telik: Research Funding; Incyte: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Vaddi:Incyte: Employment. Erickson-Viitanen:Incyte: Employment. Sun:Incyte: Employment. Sandor:Incyte: Employment. Kantarjian:Incyte: Research Funding; Novartis: Consultancy, Research Funding.

The Ki67/CD138 Ratio Independently Predicts Overall Survival in the Upfront Treatment of Newly Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2016-2016
Author(s):  
Tomer M Mark ◽  
Peter Forsberg ◽  
Ihsane Ouansafi ◽  
Adriana C Rossi ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Newly Diagnosed ◽  
First Line ◽  
Advisory Committees ◽  
Line Therapy

Abstract Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) but the test requires specialized technical expertise and is not widely available. Ki67 is a well-known protein marker of cellular proliferation on immunohistochemical (IHC) staining with prognostic utility in other malignancies. In an effort to develop a simpler system to provide analogous information to PCLI, we used a novel IHC co-staining technique for CD138 and Ki67 to quantify plasma cells in active cycling. We then performed a retrospective analysis of the ratio of Ki67/CD138 (Ki67%) in newly diagnosed patients with multiple myeloma receiving 1st-line therapy to correlate with clinical outcomes. Methods: A retrospective cohort study of patients (pts) with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital. For inclusion in the analysis, subjects must have started first-line treatment in the period of 2005-2010, and had available bone marrow biopsies. Double-staining with Ki67 and CD138 was performed by IHC. The Ki67% was calculated as the percent of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on %Ki67. Response was determined by monthly serum protein electrophoresis / immunofixation (IFX) with free light chain analysis according to International Multiple Myeloma Working Group (IMWG) guidelines. Pts who were IFX negative but had no subsequent bone marrow biopsy were classified as being in unconfirmed complete remission. Results: We identified 151 patients with newly diagnosed MM and available %Ki67 expression who received first-line therapy over the period of 2005-2010. Patient were subdivided into two groups based on %Ki67: Low: %ki67 <= 5%, n = 87; and High: %Ki67 >5, n=64, to allow for comparison of treatment response and survival analysis. Specific therapeutic agent exposure history did not differ significantly between patients. Both groups had similar depth of response rates (ORR) to front-line therapy, Table 1. Median progression-free survival for the high versus low %Ki67 groups approached statistical significance at 54 months (95% CI 30.8,67.4) versus 26.9 months (95% CI 21.6,40.2), respectively (P = 0.083). At data cut-off, there were 30 deaths in the low %Ki67 group (1-yr OS 93%, 5-yr OS 71%) and 36 deaths in the high %Ki67 group (1-yr OS 94%, 5-yr OS 62%). Median overall survival (OS) was not reached for Ki67% <= 5% (95% CI 97.3,NR) vs. 78.9 months (95% CI 55.9,93.1) for Ki67% > 5%, (P = 0.0434), Figure 1. Multivariate cox regression for factors with influence on OS showed that only high-risk cytogenetics (HR 2.05, 95% CI 1.17, 2.92, P = 0.027), ISS (HR 1.835, 95% CI 1.33, 3.60, P = 0.000), and %Ki67 group status had an independent effect on survival outcome. Low (<=5%) versus high (>5%) %Ki67 influenced overall survival with a hazard ratio of 1.76 (CI 1.07,2.92, P = 0.027). Survival after ASCT was significantly longer in the low %Ki67 group with median OS not reached (95%CI, 97.3, NR) versus 86.9 months (95% CI 43.9, NR) for high %Ki67 group (P = 0.04). Discussion: The ratio of IHC double positive Ki67 and CD138 of > 5% is an independent prognostic marker for overall survival in newly diagnosed MM undergoing 1st line therapy. The %Ki67 serves as a simpler and widely available analog to PCLI that can be presently performed in most hematopathology laboratories. Table 1: First Line Treatment and Best Response (modified IMWG Criteria) Ki67% <= 5(N = 87)n (%) Ki67% > 5(N = 64)n (%) P Treatment Exposure* Lenalidomide 59 (67.8) 48 (75) 0.34 Thalidomide 30 (34.5) 14 (21.9) 0.09 Bortezomib 25 (28.7) 14 (21.9) 0.34 Alkylating agent 11 (12.6) 4 (6.3) 0.19 ASCT 27 (31) 22 (34.4) 0.66 Best Response Overall Response (>= Partial response) 77 (88.4) 57 (89.1) 0.41 Complete response 15 (17.2) 22 (34.4) Unconfirmed complete response** 14 (16.1) 8 (12.5) Very good partial response 23 (26.4) 15 (23.4) Partial response 25 (28.7) 12 (18.8) Stable disease 9 (10.3) 5 (7.8) Progressive disease 1 (1.2) 2 (3.1) * Percentages do not add to 100% due to instances of concurrent therapy use ** Unconfirmed complete response: immunofixation negative, but no confirmatory bone marrow biopsy available Figure 1 Overall Survival by %Ki67 Figure 1. Overall Survival by %Ki67 Disclosures Mark: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Pekle:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Honoraria. Niesvizky:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, 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.

Response to Treatment Among SF3B1 Mutated Myelodysplastic Syndromes (MDS): A Case-Control Study from the MDS Clinical Research Consortium (MDS CRC)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1697-1697 ◽  
Author(s):  
Rami S. Komrokji ◽  
Amy E. DeZern ◽  
Katrina Zell ◽  
Najla H. Al Ali ◽  
Eric Padron ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Lower Risk ◽  
Research Funding ◽  
Somatic Mutations ◽  
Response To Treatment ◽  
Wild Type ◽  
Advisory Committees ◽  
Baseline Characteristics ◽  
Matching Criteria

Abstract Introduction Somatic mutations in SF3B1 ,a gene encoding a core component of RNA splicing machinery, have been identified in patients (pts) with myelodysplastic syndrome (MDS). The SF3B1 mutation (MT) is more commonly detected in pts with ring sideroblasts (RS) morphology and is associated with favorable outcome. The pattern of response among SF3B1 mutated MDS pts to available treatment options, including erythropoiesis stimulating agents (ESA), hypomethylating agents (HMA) and lenalidomide is not known. The distinct underlying disease biology among such pts may alter response to treatment. Methods Pts treated at MDS CRC institutions with MT vs wild-type SF3B1 (WT) controls were matched 1:2. Matching criteria were age at diagnosis, year of diagnosis and International Prognostic Scoring System (IPSS) category at diagnosis. IPSS category was split into two groups (Low or Int-1 vs. Int-2 or High). Matching was performed using the R package by calculating a propensity score, which was then used to determine the two most similar WT SF3B1 patients for each SF3B1-mutated pt, without replacement. Additionally, to be included in the population, pts also had to have been treated with one of the following: ESAs, HMA, or lenalidomide. Response to treatment was evaluated by international Working Group criteria (IWG 2006) and classified as response if hematological improvement or better was achieved (HI+). Survival was calculated from date of treatment until date of death or last known follow-up, unless otherwise noted. Results: We identified 48 Pts with MT and 96 matched controls. Table 1 summarizes baseline characteristics comparing MT vs WT SF3B1 cohorts. SF3B1 MT was detected more often in association with RS, as expected. The majority of pts had lower-risk disease by IPSS and revised IPSS (IPSS-R). Pts with MT had higher platelets than controls. The most common concomitant somatic mutations observed were TET2 (30%), DNMT3A (21%), and ASXL1 (7%). Median follow-up time from diagnosis was 35 months (mo). Median overall survival (OS) from diagnosis was significantly longer for patients with SF3B1 MT (108.5 mo (68.8, NA)) than wild-type controls (28.3 mo (22.3, 36.4); p < 0.001). Patients with an SF3B1 MT had a decreased hazard of death (hazard ratio [HR]: 0.49 (95% confidence limits [95% CL]: 0.29, 0.84); p = 0.009) ESA was the first line therapy for 43 pts (88%) with MT and 55 WT Pts (56%). For ESA treated pts, 14 out 40 MT Pts responded (35%) compared to 9/56 among WT Pts (16%), p 0.032. Among those treated with HMA therapy, 5 out 21 (24%) MT pts responded compared to 11/46 (24%) WT Pts (p 0.99). Finally, for Pts treated with lenalidomide 4/16 (25%) and 4/21 (19%) responded among SF3B1 MT and WT Pts respectively, p 0.7. Conclusions SF3B1 somatic mutation in MDS is commonly associated with RS, lower risk disease, and better OS. Pts with SF3B1 mutation had higher response to ESA compared WT SF3B1. No difference in response to HMA or lenalidomide was observed compared to WT patients. Response rates to lenalidomide and HMA were low in both MT patients and controls. Biologically rational therapies are needed that target this molecular disease subset. Table 1. Baseline characteristics SF3B1 MT (n=48) SF3B1 WT (n=96) P value Age median 65 67 0.6 Gender male 29 (60%) 64(67%) 0.5 Race White 44/45 (98%) 83/90 (92%) 0.34 WHO classification RA RARS RCMD RARS-T Del5 q RAEB-I RAEB-II MDS-U MDS/MPN CMML 3 24 8 4 1 3 3 2 0 0 6 9 17 2 6 10 9 3 11 9 IPSS Low Int-1 Int-2 High 29 (60%) 16 (33%) 3 (6%) 0 21 (22%) 69 (72%) 4 (4%) 2 (2%) < 0.001 IPSS-R Very low Low Intermediate High Very High 15 (31%) 26 (54%) 5 (10%) 2 (4%) 0 11 (11%) 37 (39%) 26 (27%) 18 (19%) 4 (4%) <0.001 Lab values (mean) Hgb Platelets ANC myeloblasts 9.7 274 2.63 1 9.6 108 1.92 2 0.46 <0.001 0.04 0.05 Disclosures Komrokji: Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Incyte: Consultancy; Pharmacylics: Speakers Bureau. Padron:Novartis: Speakers Bureau; Incyte: Research Funding. List:Celgene Corporation: Honoraria, Research Funding. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

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