Secondary Myelodysplastic Syndrome/Acute Myeloblastic Leukemia During Lenalidomide-Based Regimens in Relapsed and/or Refractory Multiple Myeloma Patients: Single Center Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1867-1867
Author(s):  
Rouslan Kotchetkov ◽  
Esther Masih-Khan ◽  
Chia-Min Chu ◽  
Young Trieu ◽  
Saima Dean ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Myelodysplastic Syndrome ◽  
Median Duration ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Alkylating Agents ◽  
Myelogenous Leukemia ◽  
Median Baseline ◽  
Number Of Patients ◽  
Secondary Myelodysplastic Syndrome

Abstract Abstract 1867 Secondary myelodysplastic syndrome and acute myelogenous leukemia (2° MDS/AML) are well-known complications that can occur after alkylating agent therapy for multiple myeloma (MM) or other cancers. However, until recently, the survival of MM pts was relatively short, a feature which may have contributed to a relatively low reported incidence of this complication in MM. The introduction of novel agents has improved survival rates of MM pts; lenalidomide (len) + dexamethasone–currently approved for MM after one prior therapy– is one of the main regimens that has contributed to this finding. Since alkylating agents, either given orally or as part of high-dose melphalan + ASCT, still remain an important component of MM therapy, more pts may survive to be at risk for 2° MDS/AML. Using the MM database at PMH, we retrospectively reviewed the charts of patients with relapsed/refractory (rel/ref) MM treated with len-based regimens (>1 cycle) to determine the incidence and characteristics of 2° MDS/AML that developed during this therapy. Between 06/2006 and 08/2012 we identified 230 patients having received len-based therapy: len + corticosteroids 222 patients, len alone 8 patients, cyclophosphamide + len + prednisone (CPR) 32 patients. 2° MDS/AML developed in 9 patients (3.9%) at a median of 89.6 months (range 30–188) from the time of diagnosis of MM and 22.4 (2–56.6) months from the time of initiation of len regimens. The median follow-up from start of len was 1.6 years, and from the start of diagnosis 7.5 years. The median duration of len treatment was 9.4 months. The MDS/AML cytogenetic changes were variable, but four patients had deletions of all or part of chromosome 5. None of the 2° MDS/AML had translocation t(4;14), as compared to 5.9% in (−) MDS/AML subgroup. The characteristics of patients at the time of starting len, in those who later developed (+) or did not develop (−) 2° MDS/AML during therapy, are shown in Table 1. Cumulative incidence of 2° AML/MDS from time of diagnosis to time of 2° AML/MDS is 4.5% [95% CI 2.2–9.2%] at 15 years. Cumulative incidence of 2° AML/MDS from starting time of len to time of AML/MDS is 5% [95% CI 2.4–10.4%] at 5 years. The incidence of 2° MDS/AML among those who had prior oral alkylators (OA) and/or concomitant OA was 10.5% (2/19 patients), concomitant cyclophosphamide only 7.6% (1/13), prior OA only 1.9% (3/152), and 6.5% for those who did not receive prior/concomitant OA (3/46). Grade 3–4 neutropenia occurred during len in 44% versus 58% in those with and without 2° MDS/AML, respectively. G-CSF was used in 56% of pts who developed MDS compared with 53% who did not. We conclude: 1) The cumulative incidence of MDS/AML from starting len to time of 2° AML/MDS was 5% at 5 years; 2) patients who developed 2° MDS/AML while on len regimens were slightly older, had slight male predominance, higher beta-2-microglobulin, creatinine and platelet count, less often received prior ASCT, thalidomide, and bortezomib, but had longer exposure to len; 3) the relationship with OA is not entirely certain, but it appears that those with prior and concomitant exposure to OA have the highest incidence of this complication, which is most often seen in prolonged len treatment. Table 1. Patient characteristics (n=230) Feature ALL patients (+) MDS/AML (–) MDS/AML Number of patients 230 9 221 Median age, years 61 (31–80) 68 (53–76) 61 (3–80) Male 134 (58%) 6 (67%) 128 (56%) Median baseline ANC, × 109/L 2.8 (0.9–61.4) 3.0 (1.5–5.1) 2.8 (0.9–61.4) Median baseline β-2 microglobulin (nmol/L) 222 (43–1695) 300 (133–481) 222 (43–1695) Median baseline pl count, × 109/L 156 (5–479) 200 (43–277) 156 (5–479) Median baseline creatinine, μmol/L 87 (39–515) 97 (56–117) 86 (39–515) Median # prior regimens 2 (0–6) 2 (1–5) 2 (0–6) Prior alkylating agents (all) 218 (95%) 9 (100%) 209 (95%) Prior oral alkylators 167 (73%) 6 (67%) 162 (73%) Prior ASCT 187 (81%) 2 (78%) 180 (81%) Prior thalidomide 132 (57%) 3 (33%) 129 (58%) Prior bortezomib 109 (47%) 3 (33%) 106 (48%) Concomitant cyclophosphamide 32 (13.9%) 3 (33%) 29 (13%) G-CSF use 123 (53%) 5 (56%) 118 (53.39%) Median duration of Len (mo, range) 9.4 (0.1–67.2) 22.8 (6.6–56.6) 6.8 (0.1–67.2) Disclosures: Chen: Johnson & Johnson, Lundbeck, Celgene: Consultancy; Roche: Honoraria; Johnson & Johnson, Celgene, GlaxoSmithKline: Research Funding. Kukreti:Roche: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria. Reece:Janssen: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Millennium Pharmaceuticals: Research Funding.

Incidence and Characteristics of Secondary Myelodysplastic Syndrome Developing During Lenalidomide-Based Regimens In Relapsed and/or Refractory Multiple Myeloma Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1877-1877 ◽  
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Rashmi S. Goswami ◽  
Sharon Fung ◽  
David Barth ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Myelodysplastic Syndrome ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Alkylating Agents ◽  
Survival Rates ◽  
Myelogenous Leukemia ◽  
Cytotoxic Agents ◽  
High Dose ◽  
Secondary Myelodysplastic Syndrome

Abstract Abstract 1877 Secondary myelodysplastic syndrome and acute myelogenous leukemia (2° MDS/AML) are well-known complications that can occur after alkylating agent therapy for multiple myeloma (MM) or other cancers. However, until recently, the survival of MM pts was relatively short, a feature which may have contributed to a relatively low reported incidence of this complication in MM. The introduction of novel agents has improved survival rates of MM pts; lenalidomide (len) + dexamethasone–currently approved for MM after one prior therapy– is one of the main regimens that has contributed to this finding. Since alkylating agents—either given orally or as part of high-dose melphalan + ASCT—still remain an important component of myeloma therapy, more pts may survive to be at risk for 2° MDS/AML. Using the MM database at PMH, we retrospectively reviewed the charts of pts with relapsed/refractory (rel/ref) MM treated with len-based regimens to determine the incidence and characteristics of 2° MDS/AML that developed during this therapy. Between 06/2006—11/2009, 230 pts with rel/ref MM received ≥ 1 cycle of len + corticosteroids (195 pts), len alone (3 pts) or cyclophosphamide + len + prednisone (CPR) (32 pts). 2° MDS/AML developed in 6 (2.6%) at a median of 76 months (range 43–190) from the time of diagnosis of MM and 61 (21-168) months from the time of initiation of len regimens. The cytogenetic changes were variable, but 4 pts had deletions of all or part of chromosome 5. The characteristics of pts, at the time of starting len, in those who later developed (+) or did not develop (-) 2° MDS/AML during therapy, are shown in Table 1. The median number of len cycles given was 21 (9-35) versus 9 (1-50) and Grade 3–4 neutropenia occurred during len in 50% versus 54% in those with and without 2° MDS/AML, respectively. G-CSF was used in 50% of pts who developed MDS compared with 54% who did not. The cumulative incidence of 2° MDS/AML (95% CI) was 1% (0-5 %) at 1 yr, 3% (1-9 %) at 8 yrs and 7% (2-19 %) at 12 yrs from the time of diagnosis of MM, while the cumulative incidence was 1% (0-5 %) at 1 yr, 4% (1-9 %) at 2 yr and 9% (4-12%) at 3 yrs after commencing len-based regimens. We conclude: 1) pts developing MDS/AML while on len regimens were slightly older and had less often received prior ASCT, thalidomide and bortezomib; 2) the pattern of MDS development is consistent with the hypothesis that extensive exposure to cytotoxic agents, particularly oral alkylating agents (which had been given to 5/6 [83%] of affected pts), increases the risk of 2° MDS/AML; 3) although len is effective therapy in some pts with MDS, its use does not protect heavily pre-treated MM pts from this complication. Disclosures: Reece: Celgene: Honoraria, Research Funding. Off Label Use: Combination of lenalidomide and cylophosphamide plus prednisone in relapsed and refractory myeloma patients. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Trudel:Celgene: Honoraria.

Use of Alkylating Agents Among Patients with Multiple Myeloma in a National Registry, 2006-2008.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4941-4941
Author(s):  
Carla M Van Bennekom ◽  
Theresa E Anderson ◽  
Noopur Raje ◽  
Kenneth C Anderson ◽  
David W Kaufman
Keyword(s):  
Multiple Myeloma ◽  
Median Duration ◽  
Research Funding ◽  
Alkylating Agents ◽  
Initial Therapy ◽  
Novel Agents ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy

Abstract Abstract 4941 Background While alkylating agents were among the earliest treatments for multiple myeloma, newer therapies have been available for several years. Here we describe patterns of use and effectiveness of alkylators in the modern landscape of myeloma treatment, based on a nationwide registry of recently diagnosed patients. Methods The “Patient Registries at Slone: Myeloma” is a national disease-based observational registry conducted by Boston University. All patients with myeloma diagnosed within 4 months of enrollment were eligible for inclusion. Subjects enrolled by mail or over the internet; information on treatment, clinical events, and quality of life was obtained by questionnaire and from medical record review at baseline and at six-month intervals. There were 342 patients with multiple myeloma residing in 43 states who were enrolled from June 2006-October 2008 and completed at least a baseline questionnaire. The median length of follow-up was 8 months after diagnosis (range 0.5-24). Results Alkylators were used as initial treatment in 26 patients (8%), as second-line treatment in 14 (4%), and as part of a transplant regimen in 76 (22%). Patients who received alkylators as initial or second-line therapy tended to be older (median age, 69 vs. 60 years, p<0.0005), and the combined prevalence of use was 17% among patients who did not have prescription drug insurance, compared with 11% among those who did (p=0.36). The prevalence of first-line use was 12% among patients diagnosed in 2006, 9% in 2007, and 4% in 2008 (p=0.09). Further results are confined to 34 of the 40 first or second-line alkylator recipients for whom medical records were available. The regimens used are shown in the table; the majority of patients received regimens that included melphalan. The median duration of initial therapy was 3 months (range 0.5-15); 6 patients (24%) had at least a partial response. Ten patients were still on treatment at the end of follow-up; in 15 (60%), alkylator therapy was changed to another regimen (11) or stopped without new therapy during the follow-up period (4), including 3 due to insufficient response and 5 due to toxicity. The new regimens were thalidomide-based in 2 patients, bortezomib-based in 3, bortezomib+lenalidomide in 1, dexamethasone without novel agents in 2, and 3 patients went directly to autologous stem-cell transplant. Second-line therapy with alkylators was initiated due to insufficient response from the previous regimen in 2 patients, because of side effects in 5, and for cost reasons in 2. The median duration was 2 months (range 0.5-12, with 4 patients still on treatment), and 4 (44%) had a partial or better response. The immediately preceding regimen was thalidomide-based in 5 patients, lenalidomide-based in 1, and bortezomib-based in 3; the median number of previous regimens was 2 per patient (range, 1-4). The median duration of previous therapy was 4 months (range 0.5-9). Conclusions The present population-based results indicate that in the modern era of myeloma treatment, the most prevalent use of alkylating agents is as conditioning for stem cell transplants; the drugs are also still used for initial treatment, mostly in combination with novel agents, although the prevalence was low overall and continued to decline during 2006-2008. Patients who received alkylators for initial or second-line therapy were older and the agents appeared to be somewhat more commonly used among those who did not have prescription drug insurance. The data suggest that there continues to be a useful role for alkylating agents as initial therapy, particularly for myeloma patients who are not transplant candidates, and occasionally as an early replacement for novel agents that prove ineffective or excessively toxic in individual patients. With a relatively short duration of follow-up, there was little information on the use of alkylators in the relapsed setting, where their high level of anti-myeloma activity might be expected to lead to more use. Disclosures Van Bennekom: Cephalon: Research Funding; Celgene: Research Funding; Millennium: Research Funding; Genentech: Research Funding. Anderson:Cephalon: Research Funding; Celgene: Research Funding; Millennium: Research Funding; Genentech: Research Funding. Raje:Celgene: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding. Anderson:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Kaufman:Cephalon: Research Funding; Celgene: Research Funding; Millennium: Research Funding; Genentech: Research Funding.

Characteristics of Patients Presenting with Secondary Myelodysplastic Syndrome During Treatment with Lenalidomide for Relapsed/Refractory Multiple Myeloma: 5q Deletions Can Be Observed

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1876-1876 ◽  
Author(s):  
Rashmi S. Goswami ◽  
David Barth ◽  
Esther Masih-Khan ◽  
Haowei (Linda) Sun ◽  
Manoj Mathew ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Myelodysplastic Syndrome ◽  
Median Time ◽  
Research Funding ◽  
Alkylating Agents ◽  
Chromosome 5 ◽  
First Line ◽  
Line Therapy ◽  
Previously Treated ◽  
Secondary Mds

Abstract Abstract 1876 Multiple myeloma (MM) is a neoplastic process involving plasma cells and the second most common hematologic malignancy after lymphoma. The relative survival rates for MM have been increasing over the last three decades, from 26% in the 1970s to 35% in recent years, due to the introduction of autologous stem cell transplantation (ASCT), and more recently, the introduction of novel agents. Among patients (pts) diagnosed with MM between 1997 and 2006, those who received at least one of the novel agents thalidomide, lenalidomide and bortezomib had double the median survival compared to those who did not receive any of these treatments (Kumar SK, Blood, 2008). Given that improvements are being made in the survival of myeloma pts, they may be more prone treatment-related complications, including treatment-related myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Herein we report seven cases of secondary MDS occurring in MM pts during treatment with lenalidomide-based (len-based) therapy for relapsed/refractory (rel/ref) MM. The pts examined were diagnosed with MM between 2000 and 2006, and consisted of 5 males and 2 females, ranging from 56–79 years of age (median age: 69 years). Five of the seven pts had undergone ASCT whereas the remaining two pts were treated with oral alkylating agents (cyclophosphamide/prednisone or melphalan/dexamethasone) as first-line treatment; one pt received another ASCT as second-line therapy. All pts received len-based regimens as second, third, or fourth-line therapy. The median time to development of MDS after diagnosis of MM was 70.5 months (range: 43.7 to 115.3 months). Of the pts that received ASCT as part of first-line therapy, the median time to development of MDS was 49.9 months (range: 35.6 to 76.1 months) post ASCT, while the median time to development of MDS after initiation of len-based treatment was 19.2 months (range: 1.1 to 33.8 months). All pts presented with decreasing blood counts at the time of MDS diagnosis; at this time the median hemoglobin level was 94 g/L (range 67–107 g/L), ANC 1.7 × 109/L (range 0.9–8.2 × 109/L) and platelet count 62 × 109/L (range 11–148 × 109/L) and only 1 pt had circulating blast cells. Pathological examination of blood films, bone marrow aspirates and biopsies confirmed the presence of MDS in all pts (4 pts with refractory cytopenia with multilineage dysplasia, 2 of whom also had ringed sideroblasts, 2 pts with refractory cytopenia with unilineage dysplasia, and 1 pt with refractory anemia with excess blasts-II); three had concomitant MM in the marrow. Of interest, 3 pts with evidence of dysmegakaryopoiesis demonstrated the presence of hypolobated megakaryocytes, similar to that seen in 5q- syndrome. Conventional cytogenetics demonstrated complex karyotypes in 6 pts, and 4 had structural abnormalities of chromosome 5, with deletion of the long arm, including 2 of the 3 pts with megakaryocyte hypolobation. Four of the 7 pts also had abnormalities involving chromosome 7, including deletion of 7q. In addition, 2 pts had deletions of chromosome 17 including deletion of TP53 (17q13). Although len may be a simple bystander in the development of MDS in rel/ref MM pts previously treated with alkylating agents, the observation of chromosome 5 abnormalities, including 5q deletion, is of note. Therefore, despite its established efficacy in the treatment of MDS, as well as of MM, len may not be able to protect against the development of MDS in pts previously treated with alkylating agents. As in other malignancies in which prolonged survival has been achieved, the increased life span of MM pts mandates monitoring for late complications of therapy. A progressive decrease in peripheral blood counts during treatment with len-based regimens warrants consideration of secondary MDS. Disclosures: Chen: Celgene Corporation: Consultancy, Honoraria, Research Funding. Trudel:Celgene: Honoraria. Reece:Celgene: Honoraria, Research Funding.

scholarly journals Beta-Blockers Improved Survival Outcomes in Patients with Multiple Myeloma: A Retrospective Evaluation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3306-3306
Author(s):  
Yi L. Hwa ◽  
Qian Shi ◽  
Shaji Kumar ◽  
Martha Q. Lacy ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Mayo Clinic ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Beta Blockers ◽  
Multivariable Analysis ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Cardiac Medication

Abstract Introduction: A recent study revealed an antiproliferative and apoptotic effect of propranolol on multiple myeloma (MM) cells. Our previous small matched case-control study showed longer survival in patients with propranolol and other beta-blockers (BB) intake than those without. This larger scale study was conducted to confirm the positive association of BB and MM survival. Methods: We identified 1971 newly diagnosed pts seen at Mayo Clinic between 1995 and 2010. Cardiac medication usage after diagnosis of MM was extracted from patient records and categorized based on BB intake. Cause of death was collected with death due to MM as the primary interest event and death due to cardiac disease or other reasons as competing risk events. The primary outcomes were MM disease-specific survival (DSS) and overall survival (OS). Cumulative incidence functions and Kaplan-Meier method were used to estimate the 5-year cumulative incidence rate (CIR) of MM death and OS rate, respectively. DSS and OS were compared by Gray's test and log-rank test, respectively. Multivarable Cox proportional hazard models were used to estimate the adjusted cause-specific HR (HRCSadj.) and hazard ratio (HRadj.) for DSS and OS, respectively, adjusting for demographics, disease characteristics, diagnosis year, and various chemotherapies. Results: 930 (47.2%) of MM patients had no intake of any cardiac medications; 260 (13.2%) had BB only; 343 (17.4%) used both BB / non-BB cardiac medications; and 438 patients (22.2%) had non-BB cardiac drugs. Five-year CIR of MM death and OS rate were shown in table. Superior MM DSS was observed for BB only users, compared to patients without any cardiac drugs (HRCSadj., .53, 95% confidence interval [CI], .42-.67, padj.<.0001) and non-BB cardiac drugs users (HRCSadj., .49, 95% CI, .38-.63, padj.<.0001). Patients received both BB and other cardiac drugs also showed superior MM DSS than non-cardiac drugs users (HRCSadj.., .54, 95% CI, .44-.67, padj.<.0001) and non-BB cardiac drug users. (HRCSadj., .50, 95% CI, .40-.62, padj.<.0001). MM DSS does not differ between BB users with and without other cardiac drugs (padj.=0.90). Multivariable analysis showed the same pattern for OS. None of the MM therapies impacted the differences in DSS and OS among BB intake groups (interaction padj.>.60). Conclusion: MM patients with BB intake showed reduced risk of death due to MM and overall mortality compared to patients who used non-BB cardiac or never used cardiac drugs. The result warrants further investigation for anti-cancer effect of BB in MM. Disclosures Shi: Mayo Clinic: Employment. Kumar:Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy. Gertz:NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; Annexon Biosciences: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:pfizer: Research Funding; Celgene: Research Funding; Alnylam: Research Funding; Jannsen: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Phase 2 Trial of Entospletinib (GS-9973), a Selective Syk Inhibitor, in Indolent Non-Hodgkin's Lymphoma (iNHL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1545-1545 ◽  
Author(s):  
Jeff P. Sharman ◽  
Leonard M. Klein ◽  
Michael Boxer ◽  
Kathryn S. Kolibaba ◽  
Steve Abella ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Median Duration ◽  
Research Funding ◽  
Alkylating Agents ◽  
Response Assessment ◽  
Baseline Risk ◽  
Phase 2 ◽  
Prognostic Features ◽  
Phase 2 Trial ◽  
First Response

Abstract Background: Spleen tyrosine kinase (Syk) is a mediator of B-cell receptor signaling in normal and transformed B-cells. Entospletinib is an orally bioavailable, selective inhibitor of Syk. Methods: This Phase 2 trial is evaluating entospletinib 800 mg BID in a study of 204 patients with previously treated lymphoid malignancies. Tumor imaging was planned at weeks 8, 16, 24 and then every 12. Tumor response was assessed per Cheson 2007 criteria. Results: A cohort of 69 patients with iNHL (41 follicular lymphoma [FL], 11 lymphoplasmacytoid lymphoma [LPL], 17 marginal zone lymphoma [MZL]) are included in this analysis. Median age was 66 years (range 41 - 89). 58% were male. The median number of prior treatments (Rxs) regimens was 3 (range 1- 14). Prior Rxs included anti-CD20 antibodies (rituximab 99%, ofatumumab 4%), alkylating agents (90%; bendamustine 51%) and anthracyclines (35%). Baseline risk factors: Ann Arbor Stg III-IV (70%), Gr 3a FL (29%), FLIPI ≥3 (34%). Median duration of Rx was 16 weeks with 10 patients continuing on Rx. Entospletinib was generally well tolerated. The most common TEAEs (any Grade/≥Gr 3, independent of causality) were fatigue (54%/13%), nausea (49%/4%), diarrhea(36%/0%), vomiting (26%/0%), headache (23%/1%), pyrexia (23%/3%), decreased appetite (22%/0%), constipation (22%/1%) and common laboratory abnormalities were increased AST (33%/15%), increased ALT (41%/19%), increased total bilirubin (32%/16%), anemia (36%/13%) and neutropenia (38%/13%). 4 patients died while on study from progressive disease. At the time of this analysis, 66 of 69 patients have been treated through first response assessment (1 patient ongoing not reaching first response assessment, 1 patient discontinued due to AE and 1 patient withdrew consent prior to it). 38 out of 61 (62%) patients evaluable for SPD experienced reduced tumor burden, with median duration of Rx 28 weeks (range 4-92). 9/61 (15%) achieved a decrease of ≥ 50% in SPD. The ORR was 13.0% (95% CI: 6.1%, 23.3%), with 7 patients achieving a PR, one LPL patient achieving MR and one patient achieving a CR. Forty-one patients (59.4%) had stable disease. The primary end point of 24 weeks PFS was 48.9% (95% CI: 34.6%, 61.7%). Median PFS was 5.5 months (95% CI: 4.4 months, 8.2 months). There were 39 patients (56.5%) with events of disease progression. Conclusions: Entospletinib monotherapy given with this dose and schedule was well tolerated and demonstrated activity in patients with advanced relapsed iNHL, including those with poor prognostic features. Further development of entospletinib in iNHL will focus on the development of combination approaches with chemotherapy and targeted agents. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Sharman: Calistoga: Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics, Inc.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Roche: Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Off Label Use: Management of CLL/SLL and follicular lymphoma. Kolibaba:Takeda Pharmaceuticals International Co.: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Janssen: Research Funding; GSK: Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding. Abella:Gilead: Employment. Eng:Gilead: Employment. He:Gilead Sciences: Employment. Hu:gilead: Employment. Yasenchak:Seattle Genetics, Inc.: Research Funding.

Safety, Pharmacokinetics, and Efficacy of BP-100-1.01 (Liposomal Grb-2 Antisense Oligonucleotide) in Patients with Refractory or Relapsed Acute Myeloid Leukemia (AML), Philadelphia Chromosome Positive Chronic Myelogenous Leukemia (CML), Acute Lymphoblastic Leukemia (ALL), and Myelodysplastic Syndrome (MDS)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3801-3801 ◽  
Author(s):  
Maro Ohanian ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Gautam Borthakur ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Lymphoblastic Leukemia ◽  
Myelodysplastic Syndrome ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Myelogenous Leukemia ◽  
Average Decrease ◽  
Acute Myeloid

Abstract Background: Essential to cancer cell signaling, the growth receptor bound protein-2 (Grb-2) is evolutionarily conserved and utilized by oncogenic tyrosine kinases including Bcr-Abl to activate Ras, ERK, and AKT. BP-100-1.01is a neutrally-charged, liposome-incorporated antisense designed to inhibit Grb-2 expression. Aim: To define the safety, maximum tolerated dose (MTD), optimal biologically active dose, pharmacokinetics and anti-leukemia activity of BP-100-1.01 in patients (pts) with hematologic malignancies. Methods: This is a standard 3+3 phase I dose-finding study in pts with relapsed or refractory acute myeloid leukemia (AML), chronic myeloid leukemia in blast phase (CML-BP), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS). The starting dose was 5 mg/m2 twice weekly, IV over 2-3 hours for 28 days. Dose escalation proceeded through 5, 10, 20, 40, 60, and 90 mg/m2.Uponcompletion of single agent phase 1, combination of cytarabine 20 mg SubQ BID x 10 days + 60 mg/m2 of BP-100-1.01 was studied (Cohort 1B). Flow cytometric analysis was performed on peripheral blood samples from cohorts 3, 4, 5, 6 and 1B collected at baseline, on day 15 and at end-of-treatment (EOT). Fluorescent-labeled antibodies specific for Grb-2 or phosphorylated Erk (pErk) were utilized to determine Grb-2 protein levels and pErk levels in CD33-expressing cells. Results: A total of33 pts were included (13 in Cohort 1, 6 in Cohort 2, 3 each in Cohorts 3, 4, 5, and 4 in cohort 6). One patient has been treated in cohort 1B. The median age was 64 yrs (range, 32-89) and diagnoses were AML (n=24), CML-BP (n=5) and MDS (n=4). The median number of prior therapies was 4 (range, 1- 8). Of 33 pts, 21 were evaluable and 11 failed completion of a full 28-Day cycle due to disease progression (with no toxicity) and were replaced, per protocol. Only one pt (treated at 5 mg/m2) experienced dose limiting toxicity (DLT), grade 3 mucositis and hand-foot syndrome, while receiving concurrent hydroxyurea for proliferative CML-BP. The patient had a previous history of hydroxyurea-induced mucositis. Being the first patient to receive BP-100-1.01, these toxicities were considered possibly related to BP-100-1.01. The cohort was expanded to a total of 6 pts. No other DLTs have been noted in any pt. Among 21 evaluable pts, 11 experienced at least a 50% reduction in peripheral or bone marrow blasts from baseline. Additionally 2 pts with improvement in leukemia cutis lesions received 1 cycle each. Furthermore, 6 pts demonstrated transient improvement (n=3) and/or stable disease (n=3). Among the 21 evaluable pts, a median of 1 cycle was administered (1-5): Four pts received 2 cycles, 3 pts received 5 cycles, and all others received 1 cycle. Notably one pt (treated at 5 mg/m2)with CML-BP showed a significant reduction in blasts from 81% to 5%. Due to leptomeningeal disease progression therapy was discontinued before a full cycle. The 1st patient treated in cohort 1B achieved CR after 1 cycle. The patient did not experience any DLTs, but came off study due to failure to thrive in the context of dementia. The levels of Grb-2 and pErk proteins were indicated by their respective median fluorescent signals and are shown in the table. Median fluorescent signals of Grb-2 and pErk on days 15 and EOT were compared to baseline. On day 15 Grb-2 levels decreased by >25% in 7 out of 12 samples tested, and pErk levels by >25% in 6 out of 12 samples. The average decrease in Grb-2 levels was 61% (range: 47 to 85%) and in pErk levels 52% (range: 28 to 82%). On the last measured sample (EOT or day 22), BP-100-1.01 decreased >25% Grb-2 levels in 11 out of 13 samples, and >25% pErk levels in 7 out of 13 samples. The average decrease in Grb-2 levels was 49% (range: 28 to 91%) and in pErk levels was 52% (range: 27 to 91%). Table 1. Patient Number Grb-2 decrease (Day 15) pErk decrease (Day 15) Grb-2 decrease (Day 22 or EOT) pErk decrease (Day 22 or EOT) 022 0 0 57 0 023 0 3 28 45 024 56 28 47 35 025 63 82 54 91 026 47 0 0 0 027 NS NS 34 27 028 0 0 30 54 029 57 51 65a 0a 030 54 55 43 47 031 0 0 0 0 032 85 54 91 63 033 6 13 53 2 034 63 42 40 0 NS = no sample collected aFewer cells were used in the analysis of this sample than other samples, because this sample had less cells than other samples Conclusions: BP-100-1.01, at dose range 5 mg/m2 to 90 mg/m2 is well tolerated with no MTD yet identified. There is suggestion of Grb-2 target protein down-regulation, and possible anti-leukemia activity. Disclosures Konopleva: Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Tari:Bopath Holdings: Employment. Cortes:BerGenBio AS: Research Funding; Teva: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Novel Targeted Therapies and Their Impact on Survival from Multiple Myeloma (MM) and Chronic Lymphocytic Leukaemia (CLL) in the Real World

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3546-3546
Author(s):  
Alexandra G Smith ◽  
Timothy Bagguley ◽  
Eve Roman ◽  
Andy C Rawstron ◽  
James R Bailey ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukaemia ◽  
Combination Chemotherapy ◽  
Real World ◽  
Research Funding ◽  
Lymphocytic Leukaemia ◽  
Alkylating Agents ◽  
First Line ◽  
Time Periods ◽  
Line Chemotherapy

Abstract Introduction The treatment landscape for many mature B-cell malignancies is evolving rapidly, with patients and clinicians facing increasingly complex choices about therapeutic options that differ in efficacy, toxicity and cost. Accounting for around a quarter of all haematological cancer diagnoses, multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) are two conditions where increases in the number and combinations of potentially life-prolonging therapies has been particularly marked; ranging from the use of single alkylating agents to immunomodulatory drugs and proteasome inhibitors for MM, and combination chemotherapy, immuno-chemotherapy, novel monoclonal antibodies and tyrosine-kinase inhibitors (TKIs) for CLL. Contemporary data enabling the success of such therapeutic changes to be evaluated in the general patient population is, however, lacking. With centralized diagnostics and a unified clinical network covering a catchment population of 4 million, the UK's Haematological Malignancy Research Network (www.hmrn.org) was specifically established to provide timely real-world data to answer such questions; and findings from this unique population-based cohort are reported here. Methods Patients newly diagnosed 2004-13 with MM (n=2084) or CLL (n=1866) were followed-up until January 2016. Demographic, prognostic, first-line treatment and outcome data for the time-periods 2004-07, 2008-10 and 2011-15 were examined using standard statistical methods; relative survival (RS) was estimated using national life tables. Results The median age at diagnosis of MM was 73 years (17% <60 years); 39% of patients presented with an ISS score of III and 25% were asymptomatic (CRAB score 0). In total, 1514 (73%) patients received first-line chemotherapy either at diagnosis or as a consequence of disease progression. Regimens were classified by their main agent, and the therapy changes over the 11-year period are shown in Figure 1a; in 2004-07, 44% of treated patients received single-agent alkylating therapy, in 2008-10 76% were treated with combination immunomodulatory therapy and by 2011-15 this had increased to 92%. The 3-year overall survival (OS) and RS estimates for all patients combined were 45.9% (95% Confidence Interval 43.4-48.4) and 52.0% (49.1-54.8) respectively. Differences in outcome by treatment year are clearly evident (Figure 1b): 3-year RS 2004-07, 46.5% (41.8-51.2); 2008-10, 48.4% (43.5-53.2); and 2011-15, 62.1% (56.8-66.9). The improvement in survival for patients treated in 2011-15 compared to 2004-07 was confirmed by multivariate Cox regression (Hazard Ratio 0.65, 0.56-0.76). With a median diagnostic age of 71 years (18% <60 years); the majority of CLL patients had early-stage disease (BinetStage A, 78%). In total 547 patients were treated with first-line chemotherapy, with the regimen again changing over time (Figure 1c). Patients treated 2004-07 generally received single alkylating agents (56%) or combination chemotherapy (42%), by 2008-10 32% of patients had a monoclonal antibody added to chemotherapy (chemo-immunotherapy), increasing to 72% among those treated 2011-15. The 3-year OS and RS for all treated patients combined were 69.5% (65.3-73.3) and 80.3% (75.5-84.3) respectively. However, there was no incremental statistically significant change in 3-year RS (Figure 1d); 2004-07, 76.4% (65.2-84.4); 2008-10, 78.3% (69.8-84.6); and 2011-15 84% (76.3-89.4); and taking 2004-07 as the reference, the corresponding hazard ratios for the 3 time-periods were 1 (reference), 1.00 (0.78-1.37) and 0.79 (0.58-1.09). The cost implications of the changing treatment landscape are currently being examined, and by December 2016 the findings presented above will include more recently diagnosed patients (2014-15), which is particularly pertinent for CLL, where a step-change may have occurred due to the introduction of TKIs. Conclusions Our analyses confirm that first-line chemotherapy for MM and CLL is changing markedly; highlighting the importance of monitoring the impact of therapeutic change in a real-world setting. The improvement in MM survival currently contrasts with CLL, suggesting that encouraging results from clinical trials may not always translate directly into similar improvements at a population level. Clearly, additional analysis of data from patients diagnosed >2014 are required. Figure 1 Figure 1. Disclosures Smith: Novartis: Research Funding; Janssen-Cilag: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Cook:Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Glycomimetics: Consultancy. Patmore:Roche: Honoraria; Janssen Cilag: Honoraria.

scholarly journals Subsequent Primary Malignancies Among Myelodysplastic Syndrome Patients Treated with or without Lenalidomide

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 413-413 ◽  
Author(s):  
Dana E Rollison ◽  
Kenneth H. Shain ◽  
Ji-Hyun Lee ◽  
Shalaka S Hampras ◽  
Kate Fisher ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Myelodysplastic Syndrome ◽  
Stock Options ◽  
Research Funding ◽  
Case Control ◽  
Cancer Center ◽  
Control Analysis ◽  
Increased Risk ◽  
Nested Case Control ◽  
Disease Specific

Abstract Introduction: Lenalidomide is approved by the FDA for treatment of transfusion-dependent, lower risk, deletion 5q (del(5q)) MDS patients and used widely in practice for non-del(5q) MDS patients with anemia. Recently, subsequent primary malignancies (SPM) have been reported to be associated with lenalidomide treatment of multiple myeloma, and it is unclear if this observation is disease-specific or more broadly related to a particular therapy. The SPM risk in lenalidomide-treated MDS patients has not been evaluated previously. To investigate whether lenalidomide is associated with an increased risk of SPM in MDS patients, we conducted a large, retrospective cohort study of 1,248 MDS patients treated with or without lenalidomide at the Moffitt Cancer Center (MCC). Methods: Patients treated for MDS at MCC in 2004-2012 were identified through MCC's enterprise wide data warehouse which combined clinical information from a variety of sources, including the Cancer Registry, electronic medical records and disease-specific databases. A total of 1,248 MDS patients, ages 18+ years, were identified, corresponding to International Classification of Diseases for Oncology Third Edition (ICD-O-3) codes 99801, 99803, 99833, 99843, 99853, 99863, 99873, 99891 and 99893. A total of 41 cases of SPM were verified by two hematologists for confirmation of both the baseline MDS diagnosis and the SPM diagnosis. SPM incidence rates were estimated based on the Poisson distribution. Cox proportional hazards ratios (HR) and 95% confidence intervals (CI) were calculated to estimate the age-adjusted association between lenalidomide treatment and SPM in the overall cohort, and stratified by lower versus higher risk IPSS. To obtain additional details on lenalidomide treatment and potential confounders, medical chart abstraction was conducted for all SPM cases in addition to a sample of MDS patients from the baseline cohort who had not developed SPM; these controls were matched to cases 1:1 on age at MDS diagnosis (<60 versus 60+ years), gender, follow-up time (+/- 6 months), date of diagnosis, (+/- 1 year), lower versus higher risk IPSS, and presence or absence of del (5q). Based on the medical record data abstracted for the nested case-control sample, associations between lenalidomide and SPM were estimated using odds ratios (OR) and 95% CI's calculated through conditional logistic regression, with adjustment for age at diagnosis, use of erythroid-stimulating agents (ESA), use of azacitidine and MDS histology. Results: Overall, 1,248 MDS patients were followed for an average of 30 months, including patients treated with (n=210) or without (n=1,038) lenalidomide. Incident SPM's were observed for 5 patients treated with lenalidomide (0.7 per 100 person-years) and 36 patients treated without lenalidomide (1.4 per 100 person-years), corresponding to an age-adjusted HR of 0.53 (95% CI=0.21-1.36) (Figure 1). Of the 41 SPM's observed, 33 were solid tumors comprised of 15 types, and 8 were hematological malignancies other than AML; no differences in SPM risk were observed by type of SPM. When stratified by IPSS, there was no increased risk of SPM observed for patients with low risk or intermediate-1 MDS (HR=0.36, 95% CI=0.11-1.20) nor for patients with intermediate-2 and high risk MDS (HR=2.30, 95% CI=0.45-11.65). Of the 41 SPM cases and 41 matched controls included in the nested case-control analysis, 12.2% (n=5) and 29.3% (n=12) were treated with lenalidomide, respectively, corresponding to an adjusted OR of 0.03 (95% CI=0.01-0.63). Similar associations were observed for lenalidomide whether given as part of first line treatment or subsequent therapy, and for lenalidomide given alone or in combination with other drugs. Conclusion: To our knowledge this is the first report to address rate of SPM among MDS patients treated with lenalidomide. SPM was not associated with lenalidomide treatment among a large cohort of patients with a broad spectrum of MDS diagnoses. Figure 1: Incidence of subsequent primary malignancies (SPM) among patients treated for myelodysplastic syndrome (MDS) with or without lenalidomide, Moffitt Cancer Center 2004-2012 Figure 1:. Incidence of subsequent primary malignancies (SPM) among patients treated for myelodysplastic syndrome (MDS) with or without lenalidomide, Moffitt Cancer Center 2004-2012 Disclosures Rollison: Celgene, Inc.: Research Funding. Off Label Use: Lenalidomide for the treatment of non-del(5q) MDS and/or multiple myeloma. Shain:Envision/Celgene: Research Funding, Speakers Bureau; L&M Healthcare/Onyx/Amgen: Research Funding, Speakers Bureau. Lee:Celgene, Inc.: Research Funding. Hampras:Celgene, Inc: Research Funding. Fisher:Celgene, Inc: Research Funding. Al Ali:Celgene, Inc: Research Funding. Padron:Icyte: Speakers Bureau; Novartis: Speakers Bureau. Lancet:Celgene: Consultancy, Research Funding. Olesnyckyj:Celgene: Employment, stock options Other. Kenvin:Celgene: Employment, stock options Other. Knight:Celgene, Inc: Employment, stock options Other. Dalton:Genentech: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene, Inc.: Research Funding. List:Celgene, Inc.: Consultancy. Komrokji:Celgene: Consultancy, Research Funding.

scholarly journals Second Attempt to Discontinue TKI in CML Patients Who Have Sustained CMR for over 2 Years Is Rarely Successful Even with the Use of Second Generation TKIs

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1887-1887 ◽  
Author(s):  
Eri Matsuki ◽  
Masatoshi Sakurai ◽  
Daiki Karigane ◽  
Hidenori Kasahara ◽  
Taku Kikuchi ◽  
...  
Keyword(s):  
Median Time ◽  
Median Duration ◽  
Research Funding ◽  
Second Generation ◽  
Treatment Discontinuation ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Initial Report ◽  
Study Enrollment ◽  
Tki Discontinuation

Abstract Background: Tyrosine kinase inhibitor (TKI) remains to be the mainstay of treatment for patients with chronic myelogenous leukemia (CML). Second generation TKIs have been shown to successfully treat patients who are resistant or intolerant to imatinib, as well as induce faster and deeper molecular response when used as first line therapy. Since the initial report of the French STIM study (Mahon FX, et al. Lancet Oncol 2010; 11: 1029-35) that showed successful discontinuation of imatinib therapy in approximately 50% of patients who have sustained complete molecular response (CMR), several groups have confirmed that a subset of patients can discontinue TKI for a long period. While factors associated with successful discontinuation are not yet well defined, it also remains an open question whether patients who have failed the initial attempt of discontinuation will have to remain on life-long treatment with TKIs. Patients and Methods: Patients who have been treated at Keio University Hospital for CML, who had been in confirmed stable CMR for over 2 years at the time of study enrollment, and who had no history of accelerated phase/ blastic phase while on treatment with TKI, were eligible to enroll in the study. Patients were monitored monthly for the first 6 months after discontinuation, every 2 months until 12 months, and every 2 to 3 months thereafter. Treatment with a TKI was initiated if the peripheral blood quantitative PCR (TMA method) value exceeded 100 copies. Once the patient was restarted on TKI therapy, and regained sustained CMR for over 2 years, they were allowed to reenter the study and discontinue treatment, upon patients' choice. Results: Sixty-seven patients have been enrolled in the study, of which 53 patients who have been observed for over 2 years since first TKI (imatinib 48; dasatinib 1; nilotinib 4) discontinuation were analyzed. The median age of the patients was 54 (range 28-83) years. Thirty-seven (69.8%) patients were male. In terms of baseline characteristics, 18 (34.0%) had been treated with interferon prior to TKI use, and 41 (77.4%) were CMV positive. The Sokal risk score was low in 34 (64.2%), intermediate in 11 (20.8%) and high in 4 (7.5%) patients. Among the 53 patients, 45 (84.9%) were checked for the existence of BIM deletion, among which 7 (13.2%) patients were positive. The median time on TKI treatment was 98 (range 32-147) months and the median duration of CMR was 38 (range 24-106) months. The median follow-up of the patients at the time of this analysis since study enrollment was 61 (range 26-66) months. Treatment was restarted in 28 (45%) patients (imatinib 7; dasatinib 20; nilotinib 1). While this occurred within the first 6 months of treatment discontinuation in most patients, 6 patients were started on treatment beyond 12 months of drug-free survival (DFS) (at month 14, 20, 23, 36, 36, and 52, respectively). Five patients presented with a fluctuating copy number early after TKI discontinuation, whereas 1 patient only became positive for bcr-abl after 30 months of treatment discontinuation. The estimated 24-months DFS was 52.8% (95% confidence interval (CI) 39.5-65.8%) (Fig 1). All patients have restored CMR at least at one occasion after recommencing TKIs. No single factor was significantly associated with success of discontinuation. Among the patients who had sustained CMR for over 24 months after re-initiation of TKI, 10 patients elected to challenge discontinuation of TKI for the second time. All patients were on dasatinib at the time of discontinuation. The median age of these patients was 58.5 (range 31-75) years. The median time on TKI prior to second discontinuation was 33 (range 26-45) months and the median duration of CMR after treatment re-initiation was 26.5 (range 25-44) months. All but one patient were restarted on treatment at the time of the analysis (median observation 26 (range 13-35) months), leading to a DFS of 20% (95% CI 5.0-54.1%) at 12 and 24 months (Fig 1). Conclusion: Long-term observation of the outcome of TKI discontinuation in CML patients who had sustained CMR for over 2 years showed cases of late relapses as well as small chance of success on the second attempt of TKI discontinuation even with the use of second generation TKIs. While the result of first discontinuation was similar to previous reports, attempt of second discontinuation was less successful compared to the French group, despite changing the drug of use from imatinib to dasatinib. Figure 1 Figure 1. Disclosures Matsuki: Nippon Shinyaku: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Sakurai:Celgene: Honoraria. Karigane:Celgene: Honoraria. Kikuchi:Celgene: Honoraria; Takeda Pharmaceutical Company: Honoraria; Kyowa Hakko Kirin: Honoraria. Yokoyama:BMS: Research Funding. Okamoto:Eisai Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Alexion Pharmaceuticals, Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Asahi Kasei Pharma Corp.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Teijin Pharma Limited: Research Funding; Pfizer Inc.: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding.

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