Effect of Standard Dose Versus Risk Adapted Melphalan Conditioning on Outcomes in Systemic AL Amyloidosis Patients Undergoing Frontline Autologous Stem Cell Transplant Based on Revised Mayo Stage

Abstract Introduction High dose chemotherapy and autologous stem cell transplantation (ASCT) is an effective therapy for eligible patients with newly diagnosed systemic AL amyloidosis. Dose attenuated melphalan is used in patients with older age, renal dysfunction, and multi-organ involvement in an effort to limit treatment related mortality. Reducing the dose of melphalan compromises response rates and survival outcomes, but this is often contributed to frailty of these patients. The revised Mayo staging (MS) system improves risk stratification and helps develop risk-adapted therapies. We analyzed the outcomes of ASCT following standard [(200 mg/m2); SD group] versus risk adapted [(140-160 mg/m2); RD group] melphalan conditioning, in the context of the factors typically leading to dose modification. Methods Three hundred and twenty nine patients with newly diagnosed systemic AL amyloidosis who underwent conditioning with melphalan followed by ASCT at Mayo Clinic between 2006 and 2015 were identified using existing databases. The clinical and laboratory data, treatment and follow - up details were collected by chart review and analyzed retrospectively. Overall survival(OS) was defined as the time from start of initial therapy until death from any cause or last follow up. Progression free survival(PFS) was defined as the time to relapse or progression requiring change or reinstitution of treatment or death from any cause. The OS and PFS curves were estimated using Kaplan-Meier method while log rank test was used to estimate their difference. Multivariate survival analysis was performed using the Cox proportional hazards model. Results Among the 329 patients, 240 patients were in SD group and 89 patients were in RD group (1 patient received 120 mg/ m2, 2 received 160 mg/m2 and the rest received 140 mg / m2). In the SD group, median age was 58.5 years (25.6 - 72.3); 59.6% were males; 38.7% / 61.7 %/ 7.5% had cardiac / renal /hepatic involvement; and 47.1% / 35.7% / 8.8% / 8.4% had MS I/II/III/IV. In the RD group, median age was 60.8 years (40 - 73.7); 62.9% were males; 66.3% / 71.9 %/ 11.2% had cardiac / renal /hepatic involvement; and 26.2% / 32.5% / 21.2% / 20% had MS I/II/III/IV. The response rates for patients in the SD group [complete response (CR) - 53.7%, very good partial response (VGPR) - 19.6%, partial response (PR) - 12.5%, no response (NR) - 1.2%, progressive disease (PD) - 1.6%] were significantly higher than patients in the RD group (CR - 34.8%, VGPR - 20.2%, PR - 15.7%, NR - 10.1%, PD - 1.1%) (85.8 vs 70.7%; p < 0.002). The PFS and OS for both the groups according to Mayo stage are presented in Figure 1. Multivariate survival analysis for PFS and OS was performed using age (≤ vs > 70 years), serum creatinine (≤ vs > 2 mg/dL), number of major organs involved (heart, kidney, liver, gastrointestinal tract and autonomic neuropathy), MS (1 vs 2 vs 3 and 4) and dose of melphalan (SD vs RD). The dose of melphalan (p=0.0002), MS (p=0.03) and the number of organs involved (p=0.04) were significant for PFS while the dose of melphalan (p=0.0001) and the MS (p = 0.004) were significant for OS. Conclusion Reducing the dose of melphalan during conditioning for frontline ASCT in systemic AL amyloidosis renders more patients eligible for transplant but compromises on the response rates. There is no impact on PFS and OS in Mayo stage I patients. However the OS as well as PFS in Mayo stage II, III and IV were significantly lower in RD group as compared to SD group. These results suggest a suboptimal outcome with use of reduced dose melphalan, even after accounting for the pother prognostic factors, suggesting that high dose therapy should potentially be limited to those eligible to receive the full dose conditioning. Disclosures Dispenzieri: Jannsen: Research Funding; pfizer: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Takeda: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Kumar:Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; Kesios: Consultancy; Noxxon Pharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding.

Download Full-text

Belantamab Mafadotin in Patients with Relapsed/Refractory AL Amyloidosis with Myeloma

Blood ◽

10.1182/blood-2021-151365 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1670-1670

Author(s):

Yifei Zhang ◽

Amandeep Godara ◽

Stacey Pan ◽

Denis Toskic ◽

Teresa Fogaren ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Response Rates ◽

Cardiac Response ◽

Clinical Activity ◽

Al Amyloidosis ◽

Advisory Committees ◽

Renal Response

Abstract Introduction: Daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone (Dara/CyBorD) is the only FDA approved therapy for newly diagnosed systemic light-chain (AL) amyloidosis (N Engl J Med 2021;385:46). Belantamab mafodotin is a novel anti-BCMA immunoconjugate with humanized IgG1 anti-BCMA monoclonal antibody conjugated to a microtubule-disrupting agent, monomehtyl auristatin F (MMAF) via a non-cleavable linker (Blood 2014;123:3128). Phase I/II studies in heavily pre-treated multiple myeloma patients showed single agent clinical activity with overall response rates ranging from 30-60%, with majority of responses being durable at 13 months of follow-up. Toxicity profile included keratopathy, thrombocytopenia and anemia (Blood Cancer J 2019;9:37; Lancet Oncol 2020;21:207). Based on these results, belantamab mafadotin (BLM; Blenrep) was FDA approved for relapsed myeloma. A role for new agents such as BLM in AL has not been previously reported. Here we report outcomes of six patients who received BLM at different centers for relapsed refractory (RR) AL associated with myeloma. Methods: In this retrospective study we identified AL patients with RR disease who received at least one dose of BLM. In a multi-institutional collaboration we collected demographic, medical history, laboratory, pathologic and treatment/response data on patients with myeloma and biopsy-proven AL who had received BLM. Laboratory assessment including evaluations for hematologic and organ response was done as per standard criteria and toxicity assessed as per CTCAE v6.0. Results: We identified 6 patients, 3M/3F, from 4 centers; baseline characteristics and treatment data are provided in Table 1. Baseline median age was 61 years (range, 51-74) and median marrow plasmacytosis and iFLC were 40% (10-90) and 868mg/L (145-5324). Four patients had AL λ-type and 2 κ-type, and 5 of 6 had cardiac involvement while 3 had additional organ involvement (renal, GI, nervous system). Prior to initiating BLM the median number of lines of prior therapy was 6 (range, 5-10), including daratumumab, bortezomib and lenalidomide, and prior to initiating BLM marrow assessment showed a median plasmacytosis of 23%. BLM at 2.5 mg/kg was given as an intravenous infusion over the course of 30 minutes every three weeks after ophthalmologic exam clearance until discontinuation for progression or toxicity. At a median follow-up of 4.5 months, 5 patients (83%) achieved hematological responses (HR) with 3 (50%) achieving complete hematological responses (CR) by standard criteria (J Clin Oncol 2012;30:4541). Time to HR ranged from 3 to 150 days. Cardiac response was seen in all but 1 patient, with time to response ranging from 11 to 96 days. One patient had a renal response; response assessment is not yet available for 2 other patients with renal involvement. The most common toxicity was keratopathy (grade 1-2). BLM was held after the first dose in one patient who had been heavily pre-treated and had extensive cardiac and pulmonary AL and multiple sites of FDG-avid progressive myeloma bone disease. Two days after administration of the first dose of BLM, this 51-year-old man was admitted to hospital for dyspnea, developed atrial fibrillation and ventricular tachycardia, and briefly required cardiac resuscitation without intubation with return of spontaneous circulation after 6 minutes. This patient achieved a CR after one dose of BLM that has been stable for over 5 months with marked clinical improvement. A 62 year-old woman with cardiac and renal AL has achieved a CR durable for over 16 months with cardiac and renal responses. Conclusions: In this group of 6 patients with RR AL with myeloma, HR and cardiac response rates were impressive at 83% and 80%, respectively. One patient who had 24-hour urine protein evaluation also achieved a renal response. Time to response was rapid with 2 patients achieving HR within a week of starting treatment, and the rest within five months. Additionally, 3 of 6 patients achieved CR, 1 had no clonal plasma cells in the marrow and another clonal disease detectable only by MRD. In this retrospective multi-institutional cohort BLM resulted in rapid reduction of iFLC and induced critical organ responses. These data provide preliminary evidence for the clinical activity of BLM in RR AL. Results of the on-going phase 2 clinical trial in the European Myeloma Network (EMN27; NCT04617925) are awaited with great interest. Figure 1 Figure 1. Disclosures Sborov: Sanofi: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; SkylineDx: Consultancy. Comenzo: Karyopharm: Research Funding; Prothena Biosciences: Consultancy, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum: Consultancy, Research Funding; Janssen: Patents & Royalties: WO2016187546A1, Research Funding. Kansagra: Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Cota Health: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Alynylam: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

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

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

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

Download Full-text

Cladribine Combined with Idarubicin and High-Dose AraC (CLIA2) As a Frontline and Salvage Treatment for Young Patients (≤65 yrs) with Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-119271 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4039-4039 ◽

Cited By ~ 1

Author(s):

Mansour Alfayez ◽

Hagop M. Kantarjian ◽

Farhad Ravandi ◽

Guillermo Garcia-Manero ◽

Marina Y. Konopleva ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Young Patients ◽

Multiparameter Flow Cytometry ◽

Intrathecal Therapy ◽

High Dose ◽

Advisory Committees ◽

Genetics Research ◽

Equity Ownership

Abstract Background Nucleoside analogues such as cladribine can increase the efficacy of cytarabine (araC) by modulating deoxycytidine kinase. The addition of cladribine to standard 7+3 chemotherapy has been shown to improve survival in pts with AML (Holowiecki JCO 2012). Results of our part-1 phase-2 clinical trial (cladribine combined with intermediate dose araC and idarubicin (CLIA1)) reported promising results that exceeded pretreatment expectations for response and tolerability (Jain, et. al. ASH 2016). Based on that, and the benefit of higher doses of cytarabine in younger patients (UK-MRC AML, Willemze JCO 2014), we investigated a higher dose of araC in combination with cladribine and idarubicin (CLIA2). Methods Non-APL, non-core binding factor AML pts 18-65 yrs of age with adequate organ function were enrolled in 1 of 3 cohorts: de novo AML, secondary AML (s-AML), or relapsed/refractory AML (R/R). Induction was cladribine 5 mg/m2 IV over 30 minutes on days 1-5, followed by araC 2g/m2 IV on days 1-5, and idarubicin 10 mg/m2 IV days 1-3. Consolidation consisted of up to 5 more cycles of CLIA2 for 3 days instead of 5. Dose-adjustments were allowed for age and PS. Sorafenib or midostaurin was added for pts with FLT3 mutations which occurred in 35% of pts on this study. Prophylactic intrathecal therapy was offered to higher risk pts at count nadir during cycle 1. Mutation profiling was performed using next generation sequencing prior to starting therapy. Results 65 patients were enrolled, with a median age of 47 yrs (range, 24-65): 37 pts (57%) in the frontline, 12 (19%) pts in the s-AML, and 16 (25%) in the R/R cohorts. Pt characteristics and outcomes by cohort are outlined in Table 1. The most commonly detected mutations at baseline were TET2 (45%), DNMT3a (37%), FLT3 (35%), ASXL1 (28%), and NPM1 (28%). Of 35 evaluable pts in the frontline cohort, 31 responded (ORR=89%) with 27 CR (77%) and 4 CRi (11%). Among the responders, 61% were negative for minimal residual disease (MRD [-]) by multiparameter flow cytometry. In the s-AML cohort, 10 pts were evaluable with an ORR of 60% (6/10) with 5 CR (50%) and 1 CRp (10%); 4 (67%) were MRD [-]. In the R/R cohort, 14 pts, previously treated with a median of 1 (1-4) prior therapy were evaluable for response. There were 7 CR (50%), 1 CRi (7%), for ORR of 57%; and 63% were MRD [-]. The median OS was not reached in the frontline and s-AML cohorts with median follow up of 5.2 and 11.5, months, respectively. In the R/R cohort, the median follow up was 4.7 months and median OS was 6.7 months [Figure.1]. Relapse-free survival was not reached in frontline and salvage cohort, and was 9.1 months in s-AML with median follow up of 5.2, 3.9, and 3.5 months in frontline, s-AML, and salvage cohorts, respectively [Figure.2]. The regimen was well tolerated. The most common ≥ grade 3 possibly-related non-hematologic adverse events were fever/infection (38), bleeding (2), and abnormal liver function test (3). Conclusion The 3-drug combination with a higher dose of araC, CLIA2, is safe and effective in younger pts with AML. Compared to our prior experience in pts with s-AML, using higher dose of cytarabine in CLIA2 for this cohort seems to have the highest impact. This trend however was also seen in the salvage and frontline cohorts when compared to the results from CLIA1. Response rates for pts in the newly-diagnosed AML, s-AML, and in the salvage settings are promising and should be explored further in larger studies and compared to current standard regimens. Disclosures Ravandi: Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Sunesis: Honoraria; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Abbvie: Research Funding. Konopleva:Stemline Therapeutics: Research Funding. Daver:Otsuka: Consultancy; Novartis: Consultancy; Incyte: Research Funding; Kiromic: Research Funding; Daiichi-Sankyo: Research Funding; Incyte: Consultancy; Novartis: Research Funding; ImmunoGen: Consultancy; Alexion: Consultancy; Sunesis: Consultancy; Pfizer: Research Funding; Pfizer: Consultancy; Karyopharm: Consultancy; Sunesis: Research Funding; BMS: Research Funding; ARIAD: Research Funding; Karyopharm: Research Funding. DiNardo:Bayer: Honoraria; Karyopharm: Honoraria; Abbvie: Honoraria; Celgene: Honoraria; Medimmune: Honoraria; Agios: Consultancy. Bose:Constellation Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Research Funding; Celgene Corporation: Honoraria, Research Funding; CTI BioPharma: Research Funding; Pfizer, Inc.: Research Funding. Andreeff:SentiBio: Equity Ownership; Jazz Pharma: Consultancy; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Astra Zeneca: Research Funding; Oncolyze: Equity Ownership; Celgene: Consultancy; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Reata: Equity Ownership; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer . Pemmaraju:abbvie: Research Funding; cellectis: Research Funding; samus: Research Funding; SagerStrong Foundation: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; Affymetrix: Research Funding; celgene: Consultancy, Honoraria. Jabbour:novartis: Research Funding. Cortes:novartis: Research Funding. Kadia:Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Celgene: Research Funding; Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding.

Download Full-text

Real World Outcomes of Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma Who Are Ineligible for Autologous Stem Cell Transplantation and Receive Commercially-Available Salvage Therapy

Blood ◽

10.1182/blood-2019-128815 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2893-2893

Author(s):

Emily C. Ayers ◽

David J Margolis ◽

Phyllis A. Gimotty ◽

Daniel J. Landsburg

Keyword(s):

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Standard Of Care ◽

Current Therapy ◽

High Dose ◽

Cell Of Origin ◽

Advisory Committees ◽

Ecog Ps

Introduction: Salvage immunochemotherapy (IC) followed by high-dose chemotherapy with autologous stem cell transplantation (autoSCT) is standard-of-care second-line therapy (2L) for patients with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) deemed fit for autoSCT as per the CORAL study (J Clin Oncol. 2010 Sep 20;28(27):4184-90). Optimal therapeutic management of patients with R/R DLBCL who are autoSCT-ineligible is unknown. Here we describe the real-world outcomes of patients with R/R DLBCL who receive palliative intent 2L therapy in community and academic settings and do not receive autoSCT. Methods: This analysis includes de-identified patients from the nationwide Flatiron Health electronic health record-derived database with a histologic diagnosis of DLBCL and R/R disease after frontline IC who do not undergo autoSCT and receive treatment with either bendamustine-based therapy, gemcitabine-based therapy, lenalidomide, or ibrutinib. Patients receiving rituximab/ifosfamide/carboplatin/etoposide (R-ICE) and high-dose cytarabine-containing second-line therapies were excluded. Event free survival (EFS) was defined as the interval between the start of current therapy and start of subsequent therapy if needed, last follow-up on current therapy, or death on therapy. Overall survival (OS) was defined as the time between start of current therapy and death or last follow-up while alive. Results: A total of 250 patients were eligible for inclusion in 2L. Eight patients received autoSCT after gemcitabine therapy and were excluded from this analysis. Clinicopathologic characteristics at time of diagnosis include 56% male, 87% age >60, 55% ECOG performance status >1, 87% stage III-IV disease, 78% IPI >2, 56% germinal center (GCB) of those with cell of origin testing performed, 9% cMYC rearrangement positive when tested, and 29% transformed from indolent disease. A total of 106, 78, 36, and 22 patients received bendamustine, gemcitabine, lenalidomide, and ibrutinib, respectively. For all patients, median EFS was 5.1 months and median OS was 14.3 months in 2L. Median EFS was 7.6, 2.4, 9.1, and 4.2 months, and median OS was 16.0, 9.4, 16.3, and 11 months for bendamustine, gemcitabine, lenalidomide, and ibrutinib in 2L, respectively. Patients receiving bendamustine and lenalidomide demonstrated significantly improved EFS compared to those receiving gemcitabine (p=0.001 and 0.01, respectively), see Figure 1. We observed no difference in EFS (p=0.40) or OS (p=0.89) between lenalidomide and bendamustine in 2L. Univariate analysis demonstrated receipt of gemcitabine, ECOG PS>1, and IPI >2 to have statistically significant increased hazard for treatment failure and ECOG PS>1 to have an increased hazard for death in 2L relative to the reference group. Multivariate analysis demonstrated receipt of gemcitabine (HR 1.57, p=0.03 95% CI: 1.04 - 2.37) and ECOG PS>1 (HR 1.61, p=0.02 95% CI: 1.09-2.38) were associated with an increased hazard for treatment failure in 2L. Median EFS for patients on lenalidomide was 6.7 and 8 months (p=0.26), and median OS was 13.9 and 12.2 months (p =0.48) for patients with nonGCB and GCB cell of origin, respectively. Conclusions: For patients with R/R DLBCL treated with palliative therapy in the 2L, bendamustine- and lenalidomide-based therapies resulted in significantly longer EFS compared to gemcitabine therapy. Although we cannot exclude the possibility that some patients received gemcitabine in 2L with the original intent to proceed with autoSCT, this does not contest our results as this therapy remains inferior to bendamustine and lenalidomide even if given to a potentially more fit patient population. Analysis shows no difference in outcomes by cell of origin if receiving lenalidomide in 2L. These findings may serve as benchmarks for outcomes following receipt of these therapies in the non-investigational setting and suggest both bendamustine and lenalidomide may be considered reasonable standard-of-care therapies for patients unfit for autoSCT in the 2L setting. Figure 1 Disclosures Landsburg: Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Triphase: Research Funding; Takeda: Research Funding; Takeda: Research Funding. OffLabel Disclosure: Outcomes with lenalidomide and ibrutinib in patients with relapsed/refractory DLBCL will be discussed.

Download Full-text

EARLY Results of TOTAL Therapy 7 (TT7): High Response Rates of NEWLY Diagnosed High Risk Myeloma to Daratumumab

Blood ◽

10.1182/blood-2019-131887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4569-4569 ◽

Cited By ~ 1

Author(s):

Frits van Rhee ◽

Sharmilan Thanendrarajan ◽

Carolina D. Schinke ◽

Jeffery R. Sawyer ◽

Adam Rosenthal ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Response Rates ◽

Newly Diagnosed ◽

Advisory Committees ◽

Early Results ◽

Research Grant

Background. The TT approach has significantly improved the outcome of multiple myeloma (MM) by combining new drugs with a regimen that comprises induction, tandem autologous stem cell transplantation (ASCT), consolidation and maintenance. However, a group of 15% of patients with high risk multiple myeloma (HRMM) have derived little benefit despite similar response rates to induction chemotherapy and ASCT when compared to low risk MM. The poor outcome of HRMM is explained by early relapse post ASCT resulting in a short progression free survival (PFS) with only 15-20% of patients surviving long-term. Daratumumab (Dara) is a human IgG1k anti-CD38 monoclonal antibody that has shown favorable results in early single-arm studies and more recently in phase III studies for relapsed/refractory and newly diagnosed MM. In TT7, we introduced Dara during all phases of therapy, including immune consolidation early post ASCT, to improve responses rate and PFS in HRMM. Methods. Patients had newly diagnosed HRMM as defined by high risk cytogenetic abnormalities, presence of extramedullary disease, >3 focal lesions on CT-PET, elevated LDH due to MM, or ISS II/III with cytogenetic abnormality. Dara (16mg/kgx1) was added to induction with KTD-PACE (carfilzomib, thalidomide, dexamethasone; and four-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide). Conditioning for tandem autologous stem cell transplantation (ASCT) was with fractionated melphalan (50mg/m2x4) (fMEL) based on prior observations that patients with adverse cytogenetics fare better with fMEL rather than single high dose MEL200mg/m2.In the inter tandem ASCT period immunological consolidation with Dara (16mg/kg) alone for 2 doses was followed by Dara (16mg/kg) on day 1 combined with K (36mg/m2) and D (20mg) weekly for 2 cycles. DaraKD was administered to avoid treatment free periods allowing for myeloma regrowth. The 2nd ASCT was followed by further immunological consolidation with Dara (16mg/k) for 2 doses, and maintenance therapy for 3 yrs with 3-months block of alternating Dara-KD (dara 16mg/kg day 1; K 36mg/m2 and dex 20mg weekly) and Dara-lenalidomide (R)D (dara 16mg/kg day 1; R 15mg day 1-21 q28 and D 20mg weekly). Results. TT7 enrolled 43 patients thus far. The median follow-up was 11 months (range: 1-22). The median age was 61 yrs (range 44-73). Sixteen patients were ≥65 yrs (37.2%). A mean of 29.4x106 CD34+ cells/kg (range: 4.6-86.4) were collected. 36 patients completed ASCT #1 (83.7%) and 18 (41.9%) ASCT #2, whilst 14 patients have proceeded to the maintenance phase. R-ISS II/III or metaphase cytogenetic abnormalities were present in 85.1 and 58.1% of patients, respectively. Elevated LDH or >3FL on CT-PET were noted in 30 and 41.8%. The 1-yr cumulative incidence estimates for reaching VGPR and PR were 87 and 83%, respectively. A CR or sCR was achieved in 68 and 46%. The 1-yr estimates of PFS and OS were 91.6 and 87.2%. 40 subjects are alive, whilst 5 progressed on study therapy and 3 subsequently died. 38 patients are progression free at the time of reporting. Dara was well-tolerated and no subjects discontinued therapy due to dara-related side effects. The CR and sCR rates compared favorably to the predecessor HRMM TT5 protocol where CR and sCR rates were 59 and 27%. Conclusion. The early results of TT7 point to increased response rates of HRMM to a dara-based TT regimen with especially higher rates of CR and sCR. Longer follow-up is required to determine if these early results translate into superior PFS and OS. Figure Disclosures van Rhee: Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy. Walker:Celgene: Research Funding. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding.

Download Full-text

Safety and Efficacy of Midostaurin in Combination with High-Dose Daunorubicin in 7+3 Induction for Acute Myeloid Leukemia with FLT3 Mutation

Blood ◽

10.1182/blood-2019-129331 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3896-3896

Author(s):

Yehuda E. Deutsch ◽

Robert Wilkinson ◽

Amanda Brahim ◽

Stephanie Boisclair ◽

Jose Sandoval-Sus ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Cancer Center ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Safety And Efficacy ◽

Acute Myeloid

Introduction: Acute myeloid leukemia (AML) is a heterogeneous disease with varied outcomes dependent on patient cytogenetic and mutational status. Thirty percent of adults with newly diagnosed AML have a mutation in the fms-related tyrosine kinase 3 (FLT3) gene. Midostaurin is a small molecule inhibitor that acts on multiple receptor tyrosine kinases, including FLT3. The RATIFY trial showed improved overall survival (OS) and event-free survival in patients treated with daunorubicin and cytarabine (7+3) plus midostaurin (Stone et al, NEJM 2017). In this trial, a dose of daunorubicin 60 mg/m2 was administered. High dose (HD) 90 mg/m2 daunorubicin significantly improved the rate of complete remission and overall survival, including in patients with FLT3-ITD (Luskin et al, Blood 2016). HD daunorubicin has also been shown to be more effective than idarubicin in patients with FLT3-ITD AML (Lee et al, J Clin Oncol 2017). This data raises the question of whether the combination of midostaurin and HD daunorubicin would further improve outcomes of FLT3 mutated AML patients, while maintaining a tolerable safety profile. The objective of this study is to describe the safety and efficacy endpoints of FLT3 mutated AML patients treated with HD daunorubicin plus midostaurin as part of induction therapy. Methods: We retrospectively reviewed clinical and molecular data of patients at Memorial Healthcare System, Moffitt Cancer Center, and Sylvester Cancer Center with newly diagnosed FLT3 mutated AML treated from May 1st, 2017 to July 1st, 2019. Clinical data was abstracted in accordance with institutional review board approved protocol. All patients were induced with HD daunorubicin 90 mg/m2 on days 1-3, cytarabine 100 mg/m2 on days 1-7, and midostaurin 50 mg PO twice daily on days 8-21. Growth factor and antimicrobial support were used per institutional guidelines. Demographics were analyzed using descriptive statistics. OS was analyzed using Kaplan Meier method. Other efficacy outcomes were CR, CRi (assessed according to the European Leukemia Network Criteria for AML), proportion of patients needing re-induction, and proportion of patients who underwent hematopoietic stem cell transplant (HSCT). Safety outcomes were adverse events (AEs) and early (30- and 60-day) mortality. Results: Twenty-six patients were included in the final analysis. Patient characteristics are outlined in TABLE 1. All patients were FLT3 mutated, as confirmed with molecular studies. The FLT3 subtype was ITD (high) in 3 patients, ITD (low) in 16 patients, TKD in 5 patients, and both in 2 patients. Seventy-seven percent of patients achieved a CR/CRi after one induction cycle, and 96.2% attained CR after two induction cycles. Median time to ANC and platelet recovery was 28 and 26 days, respectively. One patient died during the first 60 days, due to Enterococcus sepsis. The most common non-hematological AEs were nausea (77%), diarrhea (62%), mucositis (58%), rash (54%), and increased ALT (54%). Cumulative incidence of relapse in the cohort was 28% (n=7). Four patients relapsed pre-transplant and achieved CR2 with additional therapy. All 7 of these patients had co-occurring mutations of various types. Of the 20 patients who were considered transplant eligible, 13 (65%) underwent HSCT and 4 (20%) are pending transplant. Of the 13 transplanted patients, 3 experienced relapse post-transplant. After a median follow up of 14.5 months, median OS has not been reached. Conclusion: In our multi-center experience, induction with HD daunorubicin, cytarabine, and midostaurin is clinically effective and seems to be well tolerated. Short term mortality was low and AEs were manageable, with no unexpected safety signals. Also, CR/CRi rates were higher than previously reported, suggesting that the combination of HD daunorubicin and midostaurin may improve the outcomes of patients with FLT3 mutated AML. Future analyses with larger patient samples and longer follow up are warranted to further evaluate long-term safety and efficacy for this regimen. Figure Disclosures Sandoval-Sus: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Bradley:AbbVie: Other: Advisory Board. Talati:Agios: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding.

Download Full-text

Reduced-Intensity Induction with Dasatinib Vs. Hypercvad + 2nd Generation TKIs with MRD-Guided Follow-up Therapy Leads to Comparable Rates of MRD-Negative Remission While Reducing Transfusions and Neutropenia in Ph+ ALL

Blood ◽

10.1182/blood-2020-141264 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-44

Author(s):

Jonathan Webster ◽

Hua-Ling Tsai ◽

Eric Gehrie ◽

Tania Jain ◽

Christopher S. Hourigan ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Treatment Initiation ◽

Advisory Board ◽

High Dose ◽

Allogeneic Bone ◽

Advisory Committees ◽

2Nd Generation ◽

Reduced Intensity

Background: Reduced-intensity induction (RII) with imatinib yields comparable outcomes to HyperCVAD with imatinib with fewer induction deaths and an improved CR rate in Ph+ ALL (Chalandon. Blood. 2015). Dasatinib with steroids also produces excellent responses with little toxicity (Foa. Blood. 2011). Allogeneic bone marrow transplant (AlloBMT) remains the goal of therapy in Ph+ ALL based on contemporary trials with TKIs demonstrating improved survival in patients transplanted in CR1, and we have shown that transplant following induction with dasatinib yields better outcomes than with imatinib. Thus we implemented RII with dasatinib for the treatment of Ph+ ALL and compared to patients who received HyperCVAD with a 2nd generation TKI. Methods: Patients with newly diagnosed Ph+ ALL admitted to Johns Hopkins Hospital from September 2017-June 2020 underwent a 4-week RII with: vincristine 2 mg/d weekly, dexamethasone 40 mg PO weekly on days 1 and 2, and dasatinib 100 mg PO daily. CNS prophylaxis with IT MTX was given on day 8. Dexamethasone and vincristine were reduced by 50% for patients over age 70. Filgrastim was started on day 15 for patients without ANC recovery. Patients who received HyperCVAD with dose adjustments for age (Rausch et al. Cancer. 2020) from July 2011-June 2020 were included for comparison. Dasatinib 100 mg PO daily or nilotinib 400 mg PO BID were given with HyperCVAD at the discretion of the treating physician. Rituximab 375 mg/m^2 on days 1 and 8 was given based on CD20 status. Subsequent therapy after induction was not specifically mandated. Results: 21 patients received RII and 24 received HyperCVAD. The cohorts were comparable in terms of gender (38.1% female vs. 50%, p=0.55), age (median 49.8 vs. 50.3, p=0.33), age >60 (33.3% vs. 29.2%, p>0.99), median WBC at diagnosis (19 vs. 23.5, p=0.56), and the presence of decompensated DIC (fibrinogen <150) prior to treatment initiation (4.8% vs. 8.3%, p>0.99). Among the patients treated with HyperCVAD, 15 received dasatinib (62.5%) and 9 received nilotinib (37.5%). Rituximab use was balanced between the cohorts (61.9% vs. 58.3%, p>0.99). Table 1 compares the time to ANC recovery >500, transfusion requirements within 30 days of chemotherapy initiation, rates of decompensated DIC following treatment initiation, and the duration of inpatient hospitalization for induction. While the rates of decompensated DIC were similar in each cohort, patients treated with RII required fewer platelet and pRBC transfusions. ANC recovery was faster following RII, and only 5 patients (23.8%) received growth factor support. All patients achieved a hematologic response. There was one induction death with HyperCVAD (4.2%). Most patients received a subsequent cycle of high-dose (HD) MTX and Ara-C with TKI (76.2% following RII and 91.7% following HyperCVAD). The remaining patients treated with RII subsequently received HD MTX (14.2%) or blinatumomab (9.5%) with TKI due to co-morbidities. Among those patients treated with HD MTX and Ara-C, blinatumomab was given with TKI to 6 patients (37.5%) who initially received RII and 1 patient (4.5%) after HyperCVAD (p=0.03) due to persistent MRD. As shown in Figure 1, the incidence of MRD-negativity by multi-color flow cytometry (MFC) with a sensitivity of 10-4 at day 120 after treatment initiation was similar for RII (85.4%, 95% CI 64.8-97.1) versus HyperCVAD (86.7%, 95% CI 69.8-96.6). Among patients subsequently treated with HD MTX and Ara-C, 62.5% proceeded to alloBMT after RII with an additional 12.5% currently undergoing transplant evaluation, while 86.4% proceeded to alloBMT after HyperCVAD. The 1-year RFS and OS following RII were 87.9% (95% CI 59.6-96.8) and 100% compared to 87.5% (95% CI 66.1-95.8) and 95.8% (95% CI 73.9-99.4) following HyperCVAD. Conclusion: RII with dasatinib results in fewer transfusions and less myelosuppression compared to HyperCVAD with a 2nd generation TKI. More patients treated with RII received blinatumomab following high-dose MTX and Ara-C, but the rates of MRD-negativity were comparable between the two regimens. Thus RII with dasatinib followed by MRD-guided follow-up therapy facilitates MRD negative remissions with less toxicity than HyperCVAD. The vast majority of fit patients were able to proceed to alloBMT following either regimen. Transplant outcomes following dasatinib with induction are presented in our concurrent abstract demonstrating a 5-year RFS of 83% (95% CI 59.8-93.5). Disclosures Webster: Amgen: Consultancy; Pfizer: Consultancy. Jain:Bristol Myer Squibb: Other: for advisory board participation; CareDx: Other: Advisory Board; Takeda: Consultancy, Honoraria. Dalton:AbbVie: Research Funding; Eli Lilly: Research Funding. DeZern:Abbvie: Consultancy; Astex: Research Funding; Celgene: Consultancy, Honoraria; MEI: Consultancy. Gojo:Genentech: Research Funding; Amphivena: Research Funding; Merck: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Bolanos-Meade:Incyte: Other: DSMB Fees. Luznik:WindMil Therapeutics: Patents & Royalties: Patent holder; AbbVie: Consultancy; Merck: Research Funding, Speakers Bureau; Genentech: Research Funding. Ali:Celgene: Membership on an entity's Board of Directors or advisory committees. Borrello:Celgene: Research Funding; Aduro: Patents & Royalties; WindMIL Therapeutics: Other: Founder , Research Funding. Wagner-Johnston:ADC Therapeutics, Regeneron, CALIB-R, Verastem: Membership on an entity's Board of Directors or advisory committees. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: 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. Levis:Menarini: Honoraria; Amgen: Honoraria; Daiichi-Sankyo: Honoraria; FujiFilm: Honoraria, Research Funding; Astellas: Honoraria, Research Funding.

Download Full-text

Second Primary Malignancies in Newly Diagnosed Multiple Myeloma Patients Treated with Lenalidomide: Analysis of Pooled Data in 2459 Patients

Blood ◽

10.1182/blood.v118.21.996.996 ◽

2011 ◽

Vol 118 (21) ◽

pp. 996-996 ◽

Cited By ~ 2

Author(s):

Antonio Palumbo ◽

Alessandra Larocca ◽

Sonja Zweegman ◽

Giulia Lupparelli ◽

Agostina Siniscalchi ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Alkylating Agents ◽

Second Primary ◽

High Dose ◽

Second Primary Malignancy ◽

Primary Malignancy ◽

Advisory Committees ◽

Related Factors

Abstract Abstract 996 Background: The risk of developing a tumor is 2.1% per year of life in the general population older than 65 years. In MGUS, the incidence of AML/MDS is increased 8 fold compared with normal population, this observation supports a role for non-treatment related factors in the causation of AML/MDS in plasma-cell dyscrasias (Blood, July 27,2011). In multiple myeloma (MM) patients, the risk of second primary malignancy (SPM) is influenced by age and the use of alkylating agents. Methods: We examined SPM incidence rates (IRs) per 100 person-years in 2459 newly diagnosed MM patients, enrolled in 9 experimental trials of the European Myeloma Network (RVMM EMN 01, RVMM EMN 441, RVMM PI 026, RVMM PI 302, RVMM PI 209, GIMEMA MM 03 05, GIMEMA MM 04 05, GISMM 2001, HOVON 87). 287 patients received cyclophosphamide-lenalidomide-corticosteroids (CRC), 685 melphalan-prednisone-lenalidomide (MPR), 484 high-dose melphalan followed by lenalidomide maintenance (MEL200-R), 164 melphalan-prednisone (MP), 328 MP-thalidomide (MPT), 257 MP-bortezomib (MPV), 254 MP-bortezomib-thalidomide (VMPT). This post hoc analysis was restricted on pooled data from 1798 patients with at least 1 year of follow-up. Results: As of March 2011 cut-off, median follow-up was 28 months. Median age was 69 years, 49% of patients were aged 65–74 years, and 19% aged ≥75 years. Total cases of SPMs were 30/1798 (IR 0.72), including 8 hematologic (acute leukemia) and 22 solid cancers (gastrointestinal, lung, breast, skin, gynecologic). No cases of SPMs were reported in patients receiving cyclophosphamide and lenalidomide. SPM: second primary malignancy; CRC: cyclophosphamide-lenalidomide-corticosteroids; MPR: melphalan-prednisone-lenalidomide; MEL200-R: high-dose melphalan followed by lenalidomide maintenance; MP: melphalan-prednisone; MPT: MP-thalidomide; MPV: MP-bortezomib; VMPT: MP-bortezomib-thalidomide In patients receiving lenalidomide and alkylating agents (CRC/MPR/MEL200-R), the cumulative incidence of death for MM and diagnosis of SPMs at 3 years was 13.8% and 2.0%, respectively. In patients not receiving lenalidomide (MP/MPT/MPV/VMPT), the cumulative incidence of death and SPMs at 3 years was 26.1% and 1.1%, respectively. In the analysis restricted to Italian patients treated with lenalidomide and alkylating agents, we report 11 cases of SPMs. This figure is lower than the 15.6 cases expected from the age/sex adjusted incidence derived form the Italian Cancer Registry, with a standardized incidence ratio of 0.70. Conclusions: SPM incidence was lower than expected in all treatment groups. At present, the benefits of continuous therapy with lenalidomide outweigh the potential risk of SPMs. Longer follow-up is needed to definitively assess the risk of SPMs in patients receiving lenalidomide with alkylating agents. With the limitation of a short follow-up, the numbers currently support a role for non-treatment related factors as causes of SPMs. Updated data will be presented at the meeting. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Amgen: Honoraria. Larocca:Janssen-Cilag: Honoraria. Zweegman:Celgene: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding. Musto:Celgene: Consultancy, Honoraria, Research Funding. Lokhorst:Celgene: Consultancy; Genmab: Consultancy. Ria:celgene: Consultancy. Patriarca:Celgene: Honoraria; Schering-Plough: Honoraria. Bringhen:Celgene: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Merck Sharp & Dhome: Membership on an entity's Board of Directors or advisory committees. Hajek:Merk: payment for educational presentation; celgene: Honoraria; Janssen-Cilag: Honoraria. Spencer:Janssen: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sonneveld:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Clinical, Metabolic and Molecular Responses After 4 Courses of R-DHAP and After Autologous Stem Cell Transplantation for Untreated Mantle Cell Lymphoma Patients Included in the LyMa Trial, a Lysa Study

Blood ◽

10.1182/blood.v120.21.152.152 ◽

2012 ◽

Vol 120 (21) ◽

pp. 152-152 ◽

Cited By ~ 8

Author(s):

Steven Le Gouill ◽

Mary Callanan ◽

Elizabeth Macintyre ◽

marie-Hélène delfau-Larue ◽

Caroline bodet-Milin ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Response Rates ◽

High Dose ◽

Molecular Response ◽

Advisory Committees ◽

Mantle Cell

Abstract Abstract 152 Mantle cell lymphoma (MCL) is a rare B-cell malignancy characterized by the t(11;14) translocation. The European MCL network has demonstrated that a sequential R-CHOP/R-DHAP chemotherapy regimen prior to autologous stem cell transplantation (ASCT) provides better disease control than R-CHOP (Hermine et al, ASH 2010, abstract 110) and that molecular minimal residual disease (MRD) measured by IGH real-time quantitative polymerase chain reaction (PCR) before and after ASCT is an important prognostic factor to predict progression-free survival (PFS) (Pott et al. Blood. 2010;115(16):3215–23). Indeed, the use of high-dose aracytine upfront before ASCT is now recommended and molecular remission appears to be a major objective for future clinical trials in MCL. It therefore appeared interesting to appreciate response rates combining standard evaluation (Cheson 1999), FDG-PET imaging (Cheson 2007) and PCR techniques after rituximab plus upfront high-dose aracytine (R-DHAP) followed by ASCT. Response rates after 4 courses of R-DHAP were one of the objectives of the LyMa trial (NCT00921414). This trial is a randomized, open-label, phase III study that evaluates the efficacy of rituximab maintenance therapy in MCL patients aged between 18 and 66 years old, undergoing first-line treatment with 4xR-DHAP and exhibiting a response after ASCT (R-BEAM). Patients who do not reach a sufficient partial remission after R-DHAP are planned to receive 4 additional courses of R-CHOP before ASCT. The LyMa trial started in September 2008 and was designed to enroll 299 patients over a 4 years period. To date (August 2012), 295 patients have been included. Herein, we report response rates according to the combination of Cheson 1999 and 2007 criteria plus molecular response rates after 4xR-DHAP and after ASCT for the first 200 enrolled patients (last inclusion in August 2011). Results: One patient withdrew consent and the analysis is therefore on 199 patients. The cohort's median age is 57.2 years (range 29.7–65.7) and 41 patients are female (20%). At diagnosis, simplified MIPI was low in 104 cases (52%), intermediate in 55 (28%) and high in 40 (20%).Twenty-five patients (12.5%) presented with a blastoid variant. The panel of pathologist experts confirmed the diagnosis in all reviewed cases. Among the 199 evaluable patients, 182 (91%) received 4 courses of R-DHAP and 12 patients (all in PR according to Cheson 99 criteria) received 4 additional courses of R-CHOP because of insufficient clinical response after R-DHAP. Among these 12 patients, 5 reached CR/CRu after R-CHOP. Ultimately, 164 patients (82%) proceeded to ASCT (158 after R-DHAP and 6 after RDHAP/R-CHOP) and 154 (77.4%) have been randomized between rituximab maintenance or no maintenance. In an intention-to-treat (ITT) analysis and according to Cheson 1999 criteria, 152 patients (76.3%) reached CR (n=74) or CRu (n=78) after 4 courses of R-DHAP while 25 patients reached PR and 8 presented with SD/Prog. According to Cheson 2007 criteria (n= 170; PET not done in 17 cases and data missing in 12 cases), 129 patients reached CR while 41 patients remained FDG-TEP positive. Response rates according to Cheson 1999 and 2007 criteria for transplanted patients (n=164) were CR (n=109)/CRu (n=45) in 94% and CR in 84.5% (129 patients underwent FDG-PET after ASCT), respectively. Regarding MRD, diagnosis samples were available for 186/199 patients. Forty-one diagnosis samples have not yet been analyzed and 14 proved to be not informative. To date, the molecular response on peripheral blood (PB) after 4 courses of R-DHAP has been assessed in 103 cases and found negative in 80 cases and positive in 22 cases (not evaluable in one case). MRD on bone marrow (BM) after 4 courses of R-DHAP has been measured in 97 cases and found negative in 59 and positive in 36 (not evaluable in one case). After ASCT, PB and BM MRD were found negative in 91 patients (95 samples have been analyzed to date) and 67 (87 samples analyzed), respectively. Thus, in the LyMa trial,CR/CRu rates after only 4 courses of RDHAP, according to Cheson 1999 and 2007 criteria, are very high confirming the major anti-tumoral impact of high-dose aracytine upfront in MCL. In addition, these encouraging results seem to be confirmed at the molecular level strengthening the interest of an MRD-guided management of MCL patients. Results will be updated at the time of the meeting and patients' outcome according to disease status will be presented. Disclosures: Ribrag: Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Sanofi-Aventis: Research Funding; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Ponatinib In Patients (pts) With Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Resistant Or Intolerant To Dasatinib Or Nilotinib, Or With The T315I BCR-ABL Mutation: 2-Year Follow-Up Of The PACE Trial

Blood ◽

10.1182/blood.v122.21.650.650 ◽

2013 ◽

Vol 122 (21) ◽

pp. 650-650 ◽

Cited By ~ 6

Author(s):

Jorge E. Cortes ◽

Dong-Wook Kim ◽

Javier Pinilla-Ibarz ◽

Philipp D le Coutre ◽

Ronald Paquette ◽

...

Keyword(s):

Board Of Directors ◽

Stock Options ◽

Research Funding ◽

Response Rates ◽

Advisory Committees ◽

Advisory Boards ◽

Common Drug ◽

Heavily Pretreated ◽

History Of

Abstract Background Ponatinib is a potent, oral, pan-BCR-ABL inhibitor with activity against native and mutant forms of BCR-ABL, including the tyrosine kinase inhibitor (TKI)-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally QD) were evaluated in the phase 2, international, open-label clinical trial (PACE) in pts with CML or Ph+ ALL. Methods 449 pts resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled. Five pts (3 CP-CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses only. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 mos for CP-CML, major hematologic response (MaHR) at any time within 6 mos for advanced Ph+ leukemia. Data are as of 1 April 2013, with a median follow-up of 19 (0.1-30) mos, and 18 mos minimum follow-up for pts remaining on study. Results Median age was 59 (18-94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3-28) yrs. Pts were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib, 7% bosutinib; 58% received ≥3 TKIs. In pts previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance, 12% were purely intolerant to dasatinib or nilotinib. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, 23% MaHR or better in advanced Ph+ leukemia. The most common BCR-ABL mutations at baseline were 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44% of pts (Sanger sequencing). At the time of analysis, 46% of pts remained on study (60% CP-CML). The most common reasons for discontinuation: progressive disease (20%), adverse events (AEs; 13%; most common was thrombocytopenia, 4%). Response rates are shown in the table. Response rates were higher in CP-CML T315I vs R/I cohorts, however, a post-hoc multivariate analysis previously showed that T315I was not an independent predictor of MCyR. Other features, especially higher dose intensity and younger age in T315I pts, may explain the higher response rates. In CP-CML, responses were deep and durable; 91%, 91%, and 75% of pts with MCyR, CCyR, or MMR, respectively, were estimated to remain in response at 12 mos; progression-free survival (PFS) and overall survival (OS) were estimated to be 80% (median 27 mos) and 94% at 12 mos, respectively; progression to AP/BP occurred in 3 CP-CML pts , 2 other pts with a history of AP re-entered AP. 49% of AP-CML pts with MaHR were estimated to remain in response at 12 mos (median 12 mos); PFS and OS were estimated to be 56% (median 14 mos) and 84% at 12 mos. 36% of BP-CML pts with MaHR were estimated to remain in response at 12 mos (median 5 mos); PFS and OS were estimated to be 18% (median 4 mos) and 30% (median 7 mos) at 12 mos. 8% of Ph+ ALL pts with MaHR were estimated to remain in MaHR at 12 mos (median 3 mos); PFS and OS were estimated to be 7% (median 3 mos) and 39% (median 8 mos) at 12 mos. The most common drug-related AEs (>30%) were thrombocytopenia (37%), rash (34%), and dry skin (32%). Pancreatitis was the most common drug-related serious AE (5%); it occurred early and was primarily managed with dose modification, 1 pt discontinued. Serious cardiovascular, cerebrovascular, and peripheral vascular AEs occurred in 6%, 3%, and 2% of pts (drug-related: 2%, 1%, 1%). Conclusions Ponatinib has substantial activity in these heavily pretreated Ph+ leukemia pts who have limited available treatment options, with a safety profile reflective of the population. Updated data with a minimum follow-up of 2 yrs will be presented. Disclosures: Cortes: Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim:BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Pinilla-Ibarz:Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. le Coutre:Novartis: Research Funding; Novatis, BMS, Pfizer: Honoraria. Paquette:ARIAD, BMS, Novartis: Consultancy, Honoraria, Speakers Bureau. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Ariad, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees; Novartis, BMS, Teva: Speakers Bureau; Novartis, BMS, Teva, Pfizer, Ariad: Honoraria; Novartis & Bristol Myers Squibb: Research Funding; Novartis, Ariad and Teva: Consultancy. Apperley:Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. DeAngelo:Araid, Novartis, BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani:Ariad, Novartis, BMS: Consultancy; Ariad, Novartis, BMS, Pfizer, Teva: Honoraria, Speakers Bureau. Müller:Novartis, BMS, Ariad: Consultancy, Honoraria; Novartis, BMS: Research Funding. Gambacorti-Passerini:Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Rivera:ARIAD: Employment. Clackson:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Turner:ARIAD: Employment. Haluska:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hochhaus:Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Ariad: Honoraria. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian:ARIAD, Novartis, BMS, Phizer: Research Funding.

Download Full-text