scholarly journals Outcomes of Patients with Multiple Myeloma Who Received VRD Induction, Autologous Hematopoietic Cell Transplantation and Lenalidomide Maintenance

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-15
Author(s):  
Mahmoud R. Gaballa ◽  
Taha Al-Juhaishi ◽  
Qaiser Bashir ◽  
Samer A. Srour ◽  
Neeraj Saini ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Advisory Board ◽  
Research Support ◽  
Advisory Committees ◽  
Grant Support ◽  
Standard Risk ◽  
Autologous Hematopoietic Cell Transplantation

Background: Recent clinical trials have shown a steady improvement in the outcomes of patients with multiple myeloma (MM), especially in those who have received induction with bortezomib, lenalidomide, and dexamethasone (VRD), followed by autologous hematopoietic cell transplantation (Auto-HCT) and lenalidomide maintenance (Attal et al. 2017, Joseph et al. 2020). Here, we report our center's outcomes of MM patients who received VRD induction, followed by Auto-HCT and maintenance therapy incorporating lenalidomide. Methods: In this single-center retrospective analysis, eligible patients received an auto-HCT between June 2007 and November 2015. We excluded patients who received induction regimens other than VRD or did not receive lenalidomide-based maintenance therapy. Primary endpoints were progression-free survival (PFS) and overall survival (OS), which were estimated by using the Kaplan-Meier method. We performed multivariate Cox regression analysis to evaluate the impact of several important variables, including age, sex, race, immunoglobulin subtype, light chain, ISS, cytogenetic risk, conditioning regimen, post-transplant therapy, and best final response, on PFS and OS. Results: We identified 303 patients who fulfilled the eligibility criteria for this study. Table 1 and 2 summarize patient demographics, disease characteristics, therapies and responses. Sixty-two patients (20.5%) had high risk cytogenetics defined as del17p, t(4;14), t(14;16), and 1q21 gain. 132 (43.6%), 72 (23.8%), and 55 (18.2%) patients had ISS stages I, II, and III, respectively. Overall response rate (ORR) at time of Auto-HCT was 93.4% (sCR 7.6%, CR 4%, VGPR 41.3%, and PR 40.6 %). Importantly, ORR after auto-HCT and maintenance therapy was 99.7% (sCR 40.3%, CR 12.5%, VGPR 33.7%, and PR 13.2%). With a median follow up of 45 months (range: 11 - 113 months), the median PFS was 62 months (95% confidence interval (CI) 48- 76 months) and 4-year PFS was 58% (Fig 1). Median OS has not been reached and 4-year OS was 88% (Fig 1). Patients with high-risk cytogenetics had median PFS and OS of 31 months (95% CI 25- 37 months) and 76 months (95% CI 44-108 months), respectively. In contrast, in patients with standard-risk cytogenetics, the median PFS and OS were 73 months (95% CI 62- 84 months) and not reached, respectively (P<0.001; Fig 2). On multivariate analysis, standard-risk cytogenetics (P<0.001- HR 0.349, P=0.001- HR 0.278) and the final best response of >VGPR (P<0.001 - HR 0.439, P=0.001 - HR 0.306) were associated with significantly better PFS and OS, respectively. Conclusions: These results provide further evidence that VRD induction followed by Auto-HCT and lenalidomide-based maintenance is associated with excellent outcomes in MM, especially in patients with standard-risk cytogenetics. Disclosures Bashir: KITE: Other: Advisory Board; Celgene: Research Funding; StemLine: Research Funding; Amgen: Other: Advisory Board; Purdue: Other: Advisory Board; Takeda: Other: Advisory Board, Research Funding; Acrotech: Research Funding. Nieto:Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Affimed: Consultancy, Other: Grant Support; Secura Bio: Other: Grant Support. Lee:Daiichi Sankyo: Research Funding; Sanofi: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Genentech: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Regeneron: Research Funding; Genentech: Consultancy; Amgen: Consultancy, Research Funding. Patel:Celgene: Consultancy, Research Funding; Nektar: Consultancy, Research Funding; Cellectis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Precision Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding. Kebriaei:Amgen: Other: Research Support; Kite: Other: Served on advisory board; Novartis: Other: Served on advisory board; Jazz: Consultancy; Pfizer: Other: Served on advisory board; Ziopharm: Other: Research Support. Thomas:Pharmacyclics: Other: Advisory Boards; X4 Pharma: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Xencor: Research Funding; BMS: Research Funding. Orlowski:Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees. Champlin:Takeda: Patents & Royalties; Genzyme: Speakers Bureau; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy; Actinium: Consultancy; Johnson and Johnson: Consultancy; Omeros: Consultancy. Qazilbash:Bioline: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Bioclinica: Consultancy; Angiocrine: Research Funding.

scholarly journals High-Dose Chemotherapy (HDC) with Autologous Stem-Cell Transplant (ASCT) with Consolidative Radiation Therapy (RT) for Relapsed or Refractory (R/R) Primary Mediastinal B-Cell Lymphoma (PMBCL): 20-Year Experience at MD Anderson Cancer Center (MDACC)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Neeraj Saini ◽  
Junsheng Ma ◽  
Melissa Timmons ◽  
Amin M. Alousi ◽  
Paolo Anderlini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
Older Age ◽  
Long Term Results ◽  
Cell Transplant ◽  
Research Support ◽  
Advisory Committees ◽  
Grant Support

Background Most PMBCL pts are cured with frontline chemoimmunotherapy ± RT. Data are scant regarding the role of HDC/ASCT for R/R PMBCL, and the benefit of RT administered peri-HDC/ASCT. Our institutional approach has focused on developing potentially more active HDC regimens, and on consideration of post-ASCT consolidation RT, especially for pts who had not achieved a CR at the time of HDC. Methods We retrospectively analyzed all patients (pts) with R/R PMBCL treated with HDC/ASCT at MDACC between 01/01/2000-12/31/2019. All pts underwent similar standard pre-SCT evaluation and met eligibility criteria as per our institutional guidelines. Response assessment differed over time and included CT and gallium scan (N=9) and PET/CT (N=49). Cox proportional hazards regression models evaluated the associations of the specific HDC regimen and clinical covariates of interest with EFS and OS. Results 58 pts received HDC/ASCT with BEAM-rituximab (N=36) or rituximab/gemcitabine/busulfan/melphalan ± vorinostat (R-GemBuMel) (n=22) (Table 1). The R-GemBuMel group included more pts pretreated with >2 lines of therapy than the R-BEAM group (55% vs. 28%, p=0.025), had fewer pts in CR (41% vs. 69%, P=0.01) and more pts in PD/SD at ASCT (32% vs. 3%, P=0.01). Prior RT at a median 44 (36-48) Gy was administered to 29 pts (20 R-BEAM, 9 R-GemBuMel, P=0.27). Nineteen pts (89% not in CR at SCT) who had not previously received full doses of RT received post-SCT RT (6 after BEAM, 13 after R-GemBuMel, P<0.001) at median 40 Gy (36-48). There were 2 treatment-related deaths in the R-BEAM arm, none in the R-GemBuMel arm. At median follow-up of 69.1 months (interquartile range, 36.5-85.2), the EFS rates were 57.6% (overall), 67.6% (R-GemBuMel) and 52.7% (R-BEAM) (Figure 1a). Their respective OS rates were 69.3%, 81.1% and 63.9% (Figure 1b). On multivariable Cox regression analyses, R-GemBuMel (vs. R-BEAM) (HR=0.29, p=0.05), and 1 organ involved (vs. >1) (HR 0.28, p=0.009) were associated with improved EFS, whereas older age (HR= 1.08 per year above median, p=0.005), refractory disease (SD/PD) at SCT (vs. CR/PR) (HR 5.44, p=0.01) correlated with worse EFS. Likewise, R-GemBuMel (HR= 0.16, p=0.03) and 1 organ involved (HR=0.17, p=0.004) significantly resulted in improved OS, whereas older age (HR= 1.11, p=0.002), and refractory (SD/PD) disease at SCT (HR= 21.27, p=0.001) correlated with worse OS. Neither sex nor disease status (primary refractory vs. relapse) nor No. prior lines (2 vs. >2) nor pre-SCT RT nor post-SCT RT correlated significantly with EFS or OS. Conclusions HDC/ASCT for R/R PMBCL pts, with post-SCT RT for pts with active disease at SCT, results in favorable long-term results. R-GemBuMel ± vorinostat seems to improve EFS and OS compared to R-BEAM. Disclosures Alousi: Incyte: Honoraria, Research Funding; Therakos: Research Funding; Alexion: Honoraria. Hosing:NKARTA Inc.: Consultancy. Kebriaei:Amgen: Other: Research Support; Ziopharm: Other: Research Support; Kite: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Jazz: Consultancy; Novartis: Other: Served on advisory board. Popat:Bayer: Research Funding; Novartis: Research Funding. Qazilbash:Angiocrine: Research Funding; Bioline: Research Funding; Janssen: Research Funding; Bioclinica: Consultancy; Amgen: Research Funding. Shpall:Zelluna: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Licensing Agreement. Champlin:Takeda: Patents & Royalties; Genzyme: Speakers Bureau; Cytonus: Consultancy; Omeros: Consultancy; Actinium: Consultancy; Johnson and Johnson: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees. Nieto:Affimed: Consultancy, Other: Grant Support; Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Secura Bio: Other: Grant Support.

scholarly journals Panobinostat As a Maintenance Therapy after Autologous Hematopoietic Cell Transplantation for Patients with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3189-3189
Author(s):  
Taiga Nishihori ◽  
Rachid Baz ◽  
Leonel Ochoa ◽  
Omar Alexis Castaneda Puglianini ◽  
Kenneth H. Shain ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Advisory Committees ◽  
Autologous Hct ◽  
Autologous Hematopoietic Cell Transplantation

Background: Autologous hematopoietic cell transplantation (HCT) followed by maintenance therapy with an immunomodulatory agent or a proteasome inhibitor remains an important strategy for upfront treatment in multiple myeloma (MM) with progression-free survival (PFS) and overall survival (OS) advantage. We designed a two-arm, open-label prospective study to examine the safety and tolerability of two different dosing schedules of an oral pan-histone deacetylase inhibitor, panobinostat (pano) as an alternative maintenance therapy option in patients with MM (NCT02722941). Methods: A total of 30 MM patients who underwent autologous HCT within the preceding 90 to 180 days were enrolled at Moffitt Cancer Center using a sequential alternating allocation to starting dose of either Cohort A: 20 mg PO 3/week, q 2 weeks on a 28-day cycle, or Cohort B: 10 mg PO daily for 7 days, q 2 weeks on a 28-day cycle, for 12 cycles. Dose level -1 was cohort A: 15 mg 3/week; and cohort B: 10 mg 4/week. Patients with clinically significant cardiac diseases, bradycardia, QTc > 470 msec, bifascicular block were ineligible. EKG was performed on pre- and post-dose on day 1 & 5 of cycle 1, and pre-dose on day 1 of cycles 2-4. Relative dose intensity (RDI), a ratio of amount of drug actually delivered in mg over the amount of planned dose in mg, was calculated to evaluate the treatment feasibility as a surrogate measure. Results: The median age of the entire cohort was 60 (range, 40-73) years with a male/female = 18/12. Disease characteristics are summarized in the Table. Patients initiated pano maintenance at a median of 131 (range 91 - 178) days after autologous HCT. As of 8/1/2019, 16 patients (8 in each cohort) completed full 12 cycles of pano. The RDI for the entire cohort, cohort A, and cohort B was 94.1% (33,750mg/35,860, 98% (16,350mg/16,680mg), and 90.7% (17,400mg/19,180mg), respectively. One patient in cohort A had dose reduction, and 6 patients in cohort B had dose reductions with cytopenias (43%) and GI toxicities (43%) being the most common reasons. No patients required dose modifications due to QT prolongation thus far. There were 3 possibly treatment-associated serious adverse events (pneumonia=2; colitis=1) but all patients successfully resumed pano. Three patients progressed while on pano maintenance. No mortality has been observed thus far. Ten patients are still on pano treatment. The median follow-up is 11 (range, 1-29) months. Conclusions: RDI is 90% overall and panobinostat as a single oral maintenance agent either at 20 mg three times per week or 10 mg po daily for 7 days on alternating weeks appears to be overall well tolerated. There were more dose reductions required in the 10 mg starting dose (cohort B). Panobinostat is a safe alternative for maintenance therapy after autologous HCT. Longer follow-up is needed to confirm the utility of this approach and updated results will be presented at the meeting. Disclosures Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Baz:Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shain:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy. Brayer:Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Locke:Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Alsina:Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau. OffLabel Disclosure: Panobinostat single agent maintenance therapy after autologous hematopoietic cell transplantation for multiple myeloma

scholarly journals African-Americans Multiple-Myeloma Patients Undergoing Upfront Autologous Stem Cell Transplant Have Similar Survival Outcomes Compared to Whites: A Propensity-Score Matched Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Neeraj Saini ◽  
Junsheng Ma ◽  
Qaiser Bashir ◽  
Ruby Delgado ◽  
Gabriela Rondon ◽  
...  
Keyword(s):  
Propensity Score ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Survival Outcomes ◽  
Cell Transplant ◽  
Research Support ◽  
Advisory Committees ◽  
Propensity Score Matching Analysis ◽  
Grant Support

Background: Since the introduction of novel anti-myeloma agents, multiple studies have shown disparate survival outcomes among African American (AA) patients compared to whites with multiple myeloma (MM). Limited access to novel therapies and autologous hematopoietic stem cell transplant (auto-HCT) has been considered partly responsible for the lower survival outcomes in AA, but other disease-related features may also contribute to this disparity. We hypothesize that patients receiving ASCT would have equal healthcare access, which may nullify the impact of disparate access to novel drugs and healthcare facilities. To test this hypothesis, we compared survival outcomes of AA and whites with MM who underwent upfront ASCT at our center through propensity score matching analysis. Methods and patients: A total of 705 MM patients, including AA and whites, who underwent auto-HCT at our institution from 2007 to 2015. By using 1:1 propensity-matching, we identified 251 patients, 125 AA and 126 whites. Clinical response, relapse, and progression were defined by the International Myeloma Working Group criteria. Results: Table 1 includes the baseline characteristics of the matched doublets. Patients in the two groups were well matched for age at auto-HCT, ISS stage, serum creatinine, induction, response to induction, consolidation, preparative regimen, and maintenance therapy. The median follow-up for the matched cohort was 71.5 (interquartile range: 51.6-90.3) months. The overall response rate (CR+VGPR+PR) after auto-HCT was 95.2% (119/125 patients)) and 98.4% (123/125 patients) in the AA and the white group, respectively (p = 0.289). Thirty-four (27.2%) patients achieved a CR in each group. Sixty (48.0%) and 62 (49.6%) patients achieved a VGPR in the AA and the white group, respectively. The median PFS for the AA and the white group was 44.6 (95%CI: 35.5 - 54.7) and 51.0 (95%CI: 38.3 - 63.9) months, respectively (p = 0.763, stratified log-rank test). The 4-year PFS in the AA and the white group was 48% (95%CI: 39.3 - 57.8) and 51.2% (95%CI: 43.0 - 61.0), respectively (Fig. 1). The 4-year OS in the AA and the white group was 78.5% (95%CI: 71.5 - 86.2) and 80.9% (95%CI: 74.1 - 88.2), respectively (Fig. 2). Conclusions: In this propensity score matching analysis of MM patients who underwent an auto-HCT at our institution, we showed that AA patients had similar response rates, PFS, and OS as white patients Disclosures Bashir: KITE: Other: Advisory Board; Amgen: Other: Advisory Board; Purdue: Other: Advisory Board; Celgene: Research Funding; StemLine: Research Funding; Takeda: Other: Advisory Board, Research Funding; Acrotech: Research Funding. Popat:Bayer: Research Funding; Novartis: Research Funding. Hosing:NKARTA Inc.: Consultancy. Nieto:Secura Bio: Other: Grant Support; Affimed: Consultancy, Other: Grant Support; Astra Zeneca: Other: Grant Support; Novartis: Other: Grant Support. Kebriaei:Amgen: Other: Research Support; Ziopharm: Other: Research Support; Novartis: Other: Served on advisory board; Jazz: Consultancy; Kite: Other: Served on advisory board; Pfizer: Other: Served on advisory board. Alousi:Incyte: Honoraria, Research Funding; Therakos: Research Funding; Alexion: Honoraria. Mehta:Kadmon: Research Funding; Incyte: Research Funding; CSL Behring: Research Funding. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Thomas:Genentech: Research Funding; BMS: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Advisory Boards; X4 Pharma: Research Funding; Xencor: Research Funding. Lee:Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy; Regeneron: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Consultancy; Amgen: Consultancy, Research Funding. Patel:Janssen: Consultancy, Research Funding; Oncopeptides: Consultancy; Nektar: Consultancy, Research Funding; Precision Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Cellectis: Research Funding; Celgene: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Poseida: Research Funding. Orlowski:Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; STATinMED Research: Consultancy. Champlin:Actinium: Consultancy; Johnson and Johnson: Consultancy; Cytonus: Consultancy; Omeros: Consultancy; Genzyme: Speakers Bureau; DKMS America: Membership on an entity's Board of Directors or advisory committees; Takeda: Patents & Royalties. Qazilbash:Bioclinica: Consultancy; Angiocrine: Research Funding; Amgen: Research Funding; Bioline: Research Funding; Janssen: Research Funding.

scholarly journals Bortezomib, Lenalidomide and Dexamethasone (VRD) Followed By Autologous Stem Cell Transplant for Newly Diagnosed Multiple Myeloma; The Mayo Clinic Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2147-2147
Author(s):  
M Hasib Sidiqi ◽  
Mohammed A Aljama ◽  
Angela Dispenzieri ◽  
Eli Muchtar ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
High Risk ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Mayo Clinic ◽  
Research Funding ◽  
Advisory Committees ◽  
Post Transplant ◽  
Standard Risk

Abstract We retrospectively reviewed all patients receiving bortezomib, lenalidomide and dexamethasone induction followed by autologous stem cell transplantation (ASCT) within 12 months of diagnosis for multiple myeloma at the Mayo Clinic. 243 patients treated between January 2010 and April of 2017 were included in the study. Median age was 61 (interquartile range, 55-67) with 62% of patients being male. High risk cytogenetic abnormalities (HRA) were present in 34% of patients. 166 (68%) patients received some form of maintenance/other therapy post transplant (no maintenance (NM, n=77), lenalidomide maintenance (LM, n=108), bortezomib maintenance (BM, n=39) and other therapy (OT, n=19)). Overall response rate was 99% with complete response (CR) rate of 42% and 62% at day 100 and time of best response post transplant respectively. The four cohorts categorized by post transplant therapy were well matched for age, gender and ISS stage. HRA were more common amongst patients receiving bortezomib maintenance or other therapy post transplant (NM 18% vs LM 22% vs BM 68% vs OT 79%, p<0.0001). Two year and five year overall survival rates were 90% and 67% respectively with an estimated median overall survival (OS) and progression free survival (PFS) of 96 months and 28 months respectively for the whole cohort. OS was not significantly different when stratified by post-transplant therapy (Median OS 96 months for NM vs not reached for LM vs 62 months for BM vs not reached for OT, p=0.61), however post-transplant therapy was predictive of PFS (median PFS 23 months for NM vs 34 months for LM vs 28 months for BM vs 76 months for OT, p=0.01). High risk cytogenetics was associated with a worse OS but not PFS when compared to patients with standard risk (median OS: not reached for standard risk vs 60 months for HRA, p=0.0006; median PFS: 27 months for standard risk vs 22 months for HRA, p=0.70). In patients that did not receive maintenance therapy presence of HRA was a strong predictor of OS and PFS (median OS: not reached for standard risk vs 36 months for HRA, p<0.0001; median PFS: 24 months for standard risk vs 7 months for HRA, p<0.0001). Patients receiving maintenance therapy appeared to have a similar PFS and OS irrespective of cytogenetics (median OS: not reached for standard risk vs 62 months for HRA, p=0.14; median PFS: 35 months for standard risk vs 34 months for HRA, p=0.79).On multivariable analysis ISS stage III and achieving CR/stringent CR predicted PFS whilst the only independent predictors of OS were presence of HRA and achieving CR/stringent CR. The combination of bortezomib, lenalidomide and dexamethasone followed by ASCT is a highly effective regimen producing deep and durable responses in many patients. Maintenance therapy in this cohort may overcome the poor prognostic impact of high risk cytogenetic abnormalities. Table Table. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gertz:Abbvie: Consultancy; Apellis: Consultancy; annexon: Consultancy; Medscape: Consultancy; celgene: Consultancy; Prothena: Honoraria; spectrum: Consultancy, Honoraria; Amgen: Consultancy; janssen: Consultancy; Ionis: Honoraria; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy.

Clinical Impact of Cytokine Release Syndrome on Outcomes of Peripheral Blood Stem Cell Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Salman Otoukesh ◽  
Hany Elmariah ◽  
Dongyun Yang ◽  
Sally Mokhtari ◽  
Madiha Siraj ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Multivariable Analysis ◽  
Advisory Board ◽  
Board Meeting ◽  
Advisory Committees ◽  
Gvhd Prophylaxis ◽  
Haploidentical Hematopoietic Cell Transplantation ◽  
Grade 3

Peripheral blood stem cell (PBSC) as a graft source compared to bone marrow has been reported to result in lower risk of relapse after haploidentical hematopoietic cell transplantation (haplo-HCT) with use of post-transplant cyclophosphamide (PTCy) as a graft-versus-host-disease (GvHD) prophylaxis. However, cytokine release syndrome (CRS) is a common complication of this platform that can affect the outcomes of patients after PBSC haplo-HCT. CRS occurs due to rapid activation and proliferation of alloreactive donor T cells resulting in the elevated secretion of inflammatory cytokines. In this study, we sought to examine the risk factors for CRS and the effect of CRS severity on outcomes of PBSC haplo-HCT. We identified total of 271 consecutive patients with hematological malignancies who received their first PBSC haplo-HCT with PTCy-based GVHD prophylaxis at City of Hope (n=157) or Moffitt (n=114) Cancer Centers between 2014 and 2019. The median patient age at HCT was 54 years (INQ range, 37-64) for the entire cohort and 48% of the patients had HCT-CI ³3. Close to 70% of the study cohort had acute leukemia and 33% of all patients had high/very high-risk disease risk index. Myeloablative conditioning was used in 52% of the cases and 81% of all HCT recipients were CMV seropositive. The median donor age at HCT was 33 years (INQ range, 26-43). The HLA -A, -B, -C, -DRB1, -DQB1, or -DPB1 mismatch between the recipient and the donor in the GVH direction was 5/10 in 51%, 4/10 in 29% and £3/10 in 20% of cases. Offspring donors were used in 54% of the patients, sibling donors in 35%, and parent/other relative donors in 11%. Female donors to male recipients were used in only 22% of patients. The median infused CD34 dose was 5.25 x106 cells/kg (range, 2.3-22.4x106) and the CD3 dose was 2.48x108 cells/kg (range, 0.002-8.88 x108). CRS of any grade by ASTCT criteria was observed in 92% of study patients within first 7 days of HCT: 54% had grade 1, 39% grade 2, and 5.2% grade 3-4. Infused cell doses of CD34 &gt;5x106 cells/kg and of CD3 &gt;2.5x108 cells/kg had no significant effect on grade 3-4 CRS. On multivariable analysis, the use of reduced-intensity conditioning (RIC) was associated with increased grade 2-4 CRS (HR = 1.6, 95% CI: 1.11.-2.33, p=0.01) and grade 3-4 CRS (HR = 14.7, 95% CI: 1.97-109.5, p=0.009) compared with the myeloablative conditioning. Donor 5/10 HLA-mismatch was also associated with increased grade 2-4 CRS (HR = 1.5, 95% CI: 1.05-2.18; p=0.03) and grade 3-4 CRS (HR = 3.50, 95% CI: 1.00-12.32; p=0.05) compared with £4/10 HLA-mismatch. Non-relapse mortality (NRM) at day 100, and 1-year overall survival (OS) by CRS severity is shown in Figure. Comparing with the grade 0-1 CRS in multivariable analysis (Table), increase in CRS severity was associated with lower probability of neutrophil engraftment (HR = 0.9 for grade 2 and HR = 0.4 for grade 3-4; p=0.03). Increased CRS severity as compared to the grade 0-1 was also predictive of higher risks of NRM (HR = 1.6, 95% CI: 0.95-2.79 for grade 2 and HR = 6.6, 95% CI: 3.12-13.78 for grade 3-4; p&lt;0.001), lower disease-free survival (DFS; HR = 1.3 for grade 2 and HR = 4.5 for grade 3-4; p&lt;0.001) and lower OS (HR = 1.2 for grade 2 and HR = 4.1 for grade 3-4; p&lt;0.001) after HCT. We observed no association between CRS severity and risk of relapse or the incidence and severity of acute GvHD after transplant. We conclude that CRS is a common complication after PB haplo-HCT/PTCy. CRS severity is associated with post-HCT outcomes with grade 3-4 CRS associated with the highest risk of NRM and overall mortality after HCT. Infused CD34 or CD3 cell doses effect on CRS is unclear. RIC and higher degree of HLA-mismatch are predictive of higher-grade CRS. Identification of modifiable risk factors can help to mitigate the risk for serious CRS and subsequent mortality after PB haplo-HCT/PTCy. Figure 1 Disclosures Nishihori: Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Pidala:CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nakamura:Merck: Other: advisory board meeting; Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; NapaJen Pharma: Consultancy. Al Malki:Rigel Pharma: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Neximmune: Consultancy. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Outcomes of Total Body Irradiation- Versus Chemotherapy-Based Myeloablative Conditioning Regimen in Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide for Acute Lymphoblastic Leukemia: ALWP of the EBMT Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 320-320 ◽  
Author(s):  
Bhagirathbhai Dholaria ◽  
Myriam Labopin ◽  
Emanuele Angelucci ◽  
Johanna Tischer ◽  
Mutlu Arat ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Disease Status ◽  
Advisory Board ◽  
Hematopoietic Cell ◽  
Advisory Committees

Background The intensity of a conditioning regimen has significant impact on outcomes of allogeneic hematopoietic cell transplantation in acute leukemia. In acute lymphoblastic leukemia (ALL) patients undergoing matched donor transplant, total body irradiation (TBI)- based myeloablative conditioning (MAC) regimen was associated with improved leukemia free survival (LFS) compared to chemotherapy (CT)-based MAC (Eder S. et al. 2017). Haploidentical hematopoietic cell transplantation(haplo-HCT) with post-transplant cyclophosphamide (PTCy) has emerged as a safe alternative in absence of a matched donor. The optimal MAC in haplo-HCT setting is yet to be defined. We studied the outcomes of TBI- vs. CT-based MAC in ALL patients undergoing haplo-HCT and reported to the Acute Leukemia Working Party of the EBMT. Methods The study included 427 ALL (B-ALL-75%) patients, that underwent haplo-HCT with PTCy during the years 2010-2018, following TBI- (n=188, 44%) or CT- (n=239, 56%) based MAC. Regimen intensity was defined by EBMT criteria and cases with busulfan dose &lt;9 mg/kg or TBI dose ≤6 Gy were excluded. All disease status were included (CR1=208, CR2+=135; advanced=84). Ninety-one (27%) patients had Philadelphia+ disease. Graft source was bone marrow in 229 (54%) patients. Fludarabine-TBI (72%) and thiotepa-busulfan-fludarabine (65%) were the most common TBI and CT-based regimens, respectively. Cyclosporin with mycophenolate was used as GVHD prophylaxis in 64% of patients. The patients, disease, and transplant related characteristics were similar in both cohorts. Median patient age was 32 yrs and the median follow ups for TBI and CT cohort were 20.7 (IQR-11.7-35.3) and 26.2 (IQR-10.2-41) months, respectively. Results In univariate analysis, day 100 incidences of acute GVHD II-IV and III-VI were 38% vs. 30% (p-0.07) and 19% vs. 13% (p-0.14) for TBI and CT cohort, respectively. Two-year overall and severe chronic GVHD incidences were 34% vs. 30% (p-0.51) and 17% vs. 12% (p-0.18) for TBI and CT cohort, respectively. Graft failure was reported in 6 (3%) and 19 (8%)(p-0.09) patients who received TBI and CT-based MAC, respectively. Death from veno-occlusive disease was reported in 4 (5%) TBI patients and 8 (7%) CT patients. There was no difference in reported deaths due to infection (28%) or interstitial pneumonitis (4%) among study cohorts. In multivariate analysis, TBI was associated with significant improvement in nonrelapse mortality (NRM) [HR=0.51, 95% CI:0.32-0.83, p&lt;0.01] and LFS [HR=0.71, 95% CI:0.52-0.97, p-0.03] and higher incidence of aGVHD II-IV [HR=1.5, 95% CI:1.02-2.19, p-0.04]. Finally, relapse incidence (RI), acute GVHD (aGVHD) III-IV, OS and GVHD free relapse free survival (GRFS) did not differ between the groups. Two-year NRM, LFS and OS of TBI and CT cohort were 21% vs. 31% (p&lt;0.01); 45% vs. 37% (p-0.05) and 51% vs. 47% (p-0.18), respectively (Figure 1). Other factors negatively impacting OS were disease status (CR2, HR=1.69, p-0.01 or advance, HR=2.62, p&lt;0.01) and use of peripheral blood as graft source (HR=1.49, p-0.02). Interestingly, peripheral blood graft source also negatively impacted LFS (HR=1.44, p-0.02), aGVHD II-IV (HR=1.58, p-0.02 and GRFS (HR=1.54, p&lt;0.01). Philadelphia+ disease was associated with reduced RI (HR=0.39, p-0.01) but had no impact on LFS (HR=0.80, p-0.29) or OS (HR=0.81, p-0.34)(Table 1). In a subgroup univariate analysis of patients &lt;40 yrs old, TBI was associated with reduced 2-year NRM (19% vs. 28%, p-0.04) without impacting other outcome measures. In patients with pre-HCT disease status CR2 or advance disease, improvement in 2-year NRM (22% vs. 36%, p-0.02) was observed with TBI but no interaction was seen with other endpoints. Conclusions TBI based MAC resulted in significant reduction of NRM, translating into a better LFS without impacting aGVHD III-IV, chronic GVHD, RI or OS when compared to CT based MAC. Non-significant difference in OS between TBI and CT cohorts might be related to lower number of events, short follow-up and/or salvage therapies after relapse. These novel findings based on a large cohort of ALL patients, support the use of TBI based MAC and bone marrow graft in haplo-HCT with PTCy. Disclosures Dholaria: Celgene: Honoraria. Labopin:Jazz Pharmaceuticals: Honoraria. Angelucci:Novatis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC. Apperley:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Socie:Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

scholarly journals Safety and Efficacy of Combination Maintenance Therapy with Ixazomib and Lenalidomide in Post-Transplant Myeloma Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4774-4774
Author(s):  
Krina K. Patel ◽  
Jatin J. Shah ◽  
Lei Feng ◽  
Hans C. Lee ◽  
Elisabet E. Manasanch ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Clinical Trials ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Cell Carcinoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Proteasome Inhibitors ◽  
Advisory Board ◽  
Advisory Committees

Abstract Backrground: Several randomized controlled clinical trials have demonstrated improved outcomes for newly diagnosed multiple myeloma (NDMM) patients who were treated with lenalidomide as maintenance therapy after autologous stem cell transplant (ASCT). Proteasome inhibitors have demonstrated clinical benefit in myeloma patients when used as part of induction and maintenance regimens, and the combination of proteasome inhibitors and lenalidomide in induction regimens has produced strong clinical responses. In this study, the addition of ixazomib to lenalidomide maintenance post-ASCT in NDMM patients was evaluated. Methods: Patients (n=64) were started on maintenance therapy with lenalidomide and ixazomib within 60-180 days of stem cell infusion. Each cycle was defined as 28 days with lenalidomide starting at 10 mg/day orally for 28 days with the option to increase the dose to 15 mg after 3 cycles. Ixazomib was provided at 3 mg (n=48 patients) or 4 mg (n=16 patients) orally on days 1, 8, and 15 of each 28-day cycle. However, ixazomib dose was reduced to 3 mg in all patients based on toxicity observed in other clinical trials of ixazomib at that time. The primary endpoint measured was progression-free survival (PFS), which was defined as the time between ASCT and disease progression or death, whichever occurred first. Results: A total of 64 patients were enrolled on this study between December 4, 2012, and May 13, 2015. Of these patients, 41 (64.06%) were 60 years of age or older and 42 (65.63%) were male. Fourteen patients had high-risk cytogenetic features (+1q21, Del17p, t(14:16), t(4:14)), 50 patients had standard cytogenetic risk features (t(11:14), t(6:14), hyperdiploidy, normal) and 9 patients had International Staging System stage 3 disease. Median PFS (mPFS) for all patients was 73.3 months and has not been reached for those with ISS stage 1 disease. mPFS for ISS Stage 3 disease and high-risk cytogenetic subgroups was 33.8 and 25.4 months, respectively. Twenty-two patients had progressive disease, while 21 patients continue to receive dual maintenance. Response rates deepened over time from baseline post-ASCT for 39 patients. The complete response (CR)/stringent CR rate was 42.9% and median overall survival was not reached with a median follow-up of 62 months (range 25.4 - 82.1 months). Thirty-one patients (48%) had improvement from their baseline response after maintenance therapy: 6 patients improved from PR to VGPR; 7 from PR to stringent CR (sCR)/CR; 16 from VGPR to sCR/CR; 1 from SD to CR; and 1 patient improved from SD to VGPR. The median time to response in the 31 patients with improved response to maintenance therapy was 10.9 months (range, 0.9 to 51.3 months). Minimal residual disease (MRD) was evaluated by multicolor flow cytometry (10^-5) in 21 patients by bone marrow biopsy; 8 patients were MRD-positive. The most common grade 3/4 adverse events (AEs) included neutropenia (46.9%), leukopenia (20.3%), thrombocytopenia (15.6%), lung infections (26.6%), diarrhea and maculopapular rash (12.5% each). Secondary primary malignancies occurred in 9 patients; these included squamous cell carcinoma of the skin (n=4), basal cell carcinoma of the skin (n=1), squamous cell carcinoma and basal cell carcinoma of the skin (n=1), hepatocellular carcinoma (n=1), melanoma (n=1) and leukemia (n=1). AEs led to dose reductions in ixazomib and lenalidomide in 20 and 31 patients, respectively. Discontinuation of ixazomib due to AEs occurred in 4 patients. Grade 1/2 neuropathy occurred in 22 patients and led to reduction or discontinuation of ixazomib in 2 patients. Conclusion: Addition of ixazomib to lenalidomide maintenance in myeloma patients demonstrated a better than expected PFS compared with what has been reported in studies of lenalidomide alone, and was both safe and tolerable. These results indicate a significant clinical benefit, especially for standard risk patients. Figure 1 Figure 1. Disclosures Patel: Oncopeptides: Consultancy; Pfizer: Consultancy; Janssen: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Lee: GlaxoSmithKline: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Regeneron: Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Oncopetides: Consultancy; Amgen: Consultancy, Research Funding; Karyopharm: Consultancy; Legend Biotech: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; Genentech: Consultancy. Thomas: BeiGene: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Ascentage Pharma: Research Funding; X4 Pharma: Research Funding; Genentech: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Qazilbash: NexImmune: Research Funding; Angiocrine: Research Funding; Amgen: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; Oncopeptides: Other: Advisory Board; Janssen: Research Funding; Biolline: Research Funding. Orlowski: Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees.

Outcomes in Patients with AL (Light-Chain) Cardiac Amyloidosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-13
Author(s):  
Jeremy L. Ramdial ◽  
Mahmoud R. Gaballa ◽  
Taha Al-Juhaishi ◽  
Qaiser Bashir ◽  
Samer A. Srour ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Staging System ◽  
Advisory Board ◽  
High Dose ◽  
Advisory Committees ◽  
Grant Support ◽  
Organ Response ◽  
High Dose Melphalan

Background: Cardiac involvement by light chain amyloidosis (AL) is generally associated with an unfavorable outcome. Bortezomib-based induction, and high-dose melphalan followed by autologous hematopoietic stem cell transplantation (auto-HCT) in eligible patients is associated with best long-term outcomes. We report the outcome of cardiac AL patients who underwent auto-HCT at our institution. Methods: We retrospectively reviewed all patients with cardiac AL who received auto-HCT between January 1997 and December 2018 at our institution. Hematologic and cardiac organ responses were evaluated according to the Consensus Guidelines for AL (R Comenzo et al. Leukemia 2012). Revised Mayo staging system was used for cardiac staging (S Kumar et al. JCO 2012). Progression free survival (PFS) and overall survival (OS) were calculated from the date of transplant. Survival was estimated using Kaplan Meier method and compared using log rank test. Cox proportional hazard models were used for adjusted survival analysis. Results: 57 patients were identified and baseline characteristics summarized in Table 1. Thirty eight patients (67%) at diagnosis and 17 (30%) at auto-HCT were evaluable by the revised Mayo staging system. Eleven (19%), 14 (25%), 17 (30%), and 13 (23%) patients had stage 1, 2, 3 and 4 disease, respectively, while the stage was unknown in 2 (3%) patients. Twenty-four (42%) patients received induction with a combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD), 14 (25%) received bortezomib and dexamethasone, and 2 (3%) received other bortezomib-based induction (Table 1). Based on hematologic response criteria, 3 (5%), 15 (27%) and 22 (39%) patients achieved complete response (CR), a very good partial response (VGPR), or partial response (PR) to induction, with an overall response rate (ORR) of 71%. All patients underwent peripheral blood stem cell (PBSC) mobilization with filgrastim, with or without plerixafor. Thirty-nine (68%) patients received melphalan 200mg/m2 and 18 (32%) received melphalan 140mg/m2 as preparative regimen. Nineteen patients (33%) received maintenance therapy post auto-HCT. One-hundred day and 1-year post auto-HCT non-relapse mortality rate was 5% (3 patients). Best post auto-HCT hematologic ORR was 92%, with 19 (34%), 20 (35%), and 13 (23%) patients achieving CR, VGPR and PR, respectively. Based on the consensus guidelines for cardiac response in AL using NT-proBNP or NYHA class, 51 patients (89%) had a cardiac organ response at their last evaluation (Table 2). Median follow up in surviving patients was 32.9 months (range 5.1 - 140.6). The 3-year PFS was 53.5% [95% CI 38.6-68.4%], and 3-year OS was 67.8% [53.9-81.7%]. On univariate analysis, melphalan 200 vs. 140 (p=0.017, HR 0.387 95%CI 0.178- 0.844) was associated with a better PFS, but none of the variables had an impact on PFS or OS on a multivariate Cox regression analysis, perhaps due to a small sample size. Conclusion: In this retrospective analysis we showed that in transplant-eligible patients with advanced cardiac AL, high-dose melphalan and auto-HCT is associated with a low (5%) NRM, an organ response rate of almost 90%, and a 3-year OS of almost 70%. Disclosures Bashir: Takeda: Other: Advisory Board, Research Funding; Acrotech: Research Funding; Celgene: Research Funding; StemLine: Research Funding; KITE: Other: Advisory Board; Purdue: Other: Advisory Board; Amgen: Other: Advisory Board. Nieto:Secura Bio: Other: Grant Support; Astra Zeneca: Other: Grant Support; Novartis: Other: Grant Support; Affimed: Consultancy, Other: Grant Support. Hosing:NKARTA Inc.: Consultancy. Popat:Bayer: Research Funding; Novartis: Research Funding. Lee:Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Genentech: Consultancy; Daiichi Sankyo: Research Funding; Sanofi: Consultancy; Regeneron: Research Funding. Patel:Takeda: Consultancy, Research Funding; Precision Biosciences: Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Janssen: Consultancy, Research Funding; Nektar: Consultancy, Research Funding; Cellectis: Research Funding; Celgene: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Manasanch:Merck: Research Funding; Sanofi: Honoraria; GSK: Honoraria; Takeda: Honoraria; Quest Diagnostics: Research Funding; Adaptive Biotechnologies: Honoraria; JW Pharma: Research Funding; Novartis: Research Funding; BMS: Honoraria; Sanofi: Research Funding. Thomas:X4 Pharma: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Pharmacyclics: Other: Advisory Boards. Kaufman:Karyopharm: Honoraria; Janssen: Research Funding; Bristol Myers Squibb: Research Funding. Orlowski:Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties. Champlin:Takeda: Patents & Royalties; Genzyme: Speakers Bureau; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy; Omeros: Consultancy; Johnson and Johnson: Consultancy; Actinium: Consultancy. Qazilbash:Bioclinica: Consultancy; Amgen: Research Funding; Angiocrine: Research Funding; Bioline: Research Funding; Janssen: Research Funding.

Prognostic Impact of Beta 2 Microglobulin in Patients with Immunoglobulin Light-Chain Amyloidosis Undergoing Autologous Hematopoietic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-21
Author(s):  
Aimaz Afrough ◽  
Samer A. Srour ◽  
Qaiser Bashir ◽  
Neeraj Saini ◽  
Chitra Hosing ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Light Chain ◽  
Research Funding ◽  
Advisory Board ◽  
Immunoglobulin Light Chain ◽  
Research Support ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Immunoglobulin Light Chain Amyloidosis ◽  
Beta 2 Microglobulin

Background: Risk stratification for Immunoglobulin light chain amyloidosis (AL) has been refined with advances in the understanding of disease biology. Although nonspecific, beta 2 microglobulin (β2M) levels correlate with disease burden and are considered a prognostic marker in several hematologic malignancies. Recently, we and others have shown the association of β2M levels with survival in AL. In this study, we evaluated the role of β2M as a predictor of outcome for high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) in patients with AL. Methods: We identified 175 consecutive patients with AL who received auto-HCT between 2009 and 2019 at our institution. A β2M≥3.5 mg/L, regardless of renal function status was used as a cutoff value. Hematologic and organ responses were evaluated according to the Consensus Guidelines for AL. Revised Mayo staging system was utilized for Cardiac staging. Results: The median age at auto-HCT was 60 years (range, 27 to 77). Of 175 patients, 153 (87%) had a β2M value available, of whom 57 (37%) had a β2M ≥ 3.5 mg/L. There were no significant differences in baseline characteristics between the 2 groups, except for the higher level of LDH, worse renal function, and more patients with renal involvement in the β2M ≥ 3.5 group, and more patients with lambda light chain type in the β2M &lt;3.5 group (Table 1). The median follow-up from auto-HCT was 38 months (range; 1 to 124). One-year non-relapse mortality (NRM) was 2%. The 1-year NRM was 5% (n=3) and 1% (n=1) in patients with β2M≥3.5, and β2M&lt;3.5, respectively (p=0.115). Hematologic CR after auto-HCT was seen in 21 (37%), and 38 (40%) patients with β2M≥3.5 and β2M&lt;3.5, respectively (p=0.864). Organ response (OR) after auto-HCT was seen in 36 (73%), and 65 (71%) patients with β2M≥3.5 and β2M&lt;3.5, respectively (p=1.00). The 3-year progression-free survival (PFS) was 66%, and 74% in patients with β2M≥3.5, and β2M&lt;3.5 (p=0.17) (Figure 1A).The 3-year overall survival (OS) was 73%, ad 89% in patients with β2M≥3.5, and β2M&lt;3.5 (p=0.009) (Figure 1B). On Cox-regression multivariate analysis, cardiac involvement with AL (p=0.043), and β2M≥3.5 (p=0.029) were associated with a shorter OS. Conclusion: In this single-center retrospective analysis, we showed that high serum β2M is associated with shorter OS. β2M may be incorporated as a prognostic marker for AL if these findings are confirmed in larger studies. Disclosures Bashir: Acrotech: Research Funding; StemLine: Research Funding; Celgene: Research Funding; Takeda: Other: Advisory Board, Research Funding; KITE: Other: Advisory Board; Amgen: Other: Advisory Board; Purdue: Other: Advisory Board. Hosing:NKARTA Inc.: Consultancy. Popat:Bayer: Research Funding; Novartis: Research Funding. Kebriaei:Novartis: Other: Served on advisory board; Jazz: Consultancy; Ziopharm: Other: Research Support; Kite: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Amgen: Other: Research Support. Shpall:Takeda: Other: Licensing Agreement; Magenta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Zelluna: Membership on an entity's Board of Directors or advisory committees. Manasanch:Sanofi: Research Funding; Adaptive Biotechnologies: Honoraria; GSK: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Takeda: Honoraria; Quest Diagnostics: Research Funding; Merck: Research Funding; JW Pharma: Research Funding; Novartis: Research Funding. Lee:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Regeneron: Research Funding; Genentech: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Genentech: Consultancy. Kaufman:Janssen: Research Funding; Karyopharm: Honoraria; Bristol Myers Squibb: Research Funding. Patel:Cellectis: Research Funding; Nektar: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Precision Biosciences: Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding. Thomas:BMS: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; X4 Pharma: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Pharmacyclics: Other: Advisory Boards. Orlowski:STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Champlin:Genzyme: Speakers Bureau; Johnson and Johnson: Consultancy; Actinium: Consultancy; Cytonus: Consultancy; Omeros: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Takeda: Patents & Royalties. Qazilbash:Angiocrine: Research Funding; Bioline: Research Funding; Amgen: Research Funding; Bioclinica: Consultancy; Janssen: Research Funding.

Final Results of Phase I/II Trial of the Oral mTOR Inhibitor Everolimus (RAD001) in Combination with Bortezomib and Rituximab (RVR) in Relapsed or Refractory Waldenstrom Macroglobulinemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3081-3081 ◽  
Author(s):  
Irene M. Ghobrial ◽  
Robert Allyn Redd ◽  
Jeffrey Matous ◽  
Philippe Armand ◽  
Erica N Boswell ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Phase I ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Advisory Board ◽  
Advisory Committees

Abstract Background: Waldenstrom Macroglobulinemia is a distinct lymphoplasmacytic lymphoma. Several clinical trials have shown high rates of response in patients with relapsed WM using bortezomib and rituximab combinations. In addition, the TORC1 inhibitor everolimus has previously shown a high response rate of 70% in this patient population. In this trial, we aimed to examine the safety and activity of the combination of everolimus with bortezomib and rituximab (RVR) and to determine whether a deep response can be achieved with a triple combination of targeted therapeutic agents in WM. Methods: The phase I portion of the study evaluated the maximum tolerated dose of everolimus, rituximab combination or RVR combination, while the phase II portion evaluated the depth of responses to the RVR combination. Patients were eligible for this trial if they had relapsed or refractory WM. There was no limit on the number of prior therapies. Patients were required to be ≥18 years old and have measurable and symptomatic disease. For the phase I, patients were assigned to a dose level in the order of study entry. In the dose-escalation scheme, everolimus was given at 5 or 10 mg PO with rituximab, or with bortezomib at 1.3 or 1.6 mg/m2 and rituximab. Rituximab was given at a fixed dose of 375 mg/m2 IV. In the phase II, patients received everolimus 10 mg flat dose PO daily, Bortezomib IV 1.6mg/m2 weekly on days 1, 8, 15 q 28 days and rituximab IV 375 mg/ m2 weekly on days 1, 8, 15 22 q 28 days on cycles 1 and 4 only. Treatment was daily and 4 weeks (28 days) was considered one cycle. Patients received a total of 6 cycles followed by maintenance therapy with everolimus 10 mg PO daily until progression. Dexamethasone was not permitted. Patients were assessed every cycle while on combination therapy, and every 3 months while on maintenance therapy. Patients with stable disease (SD) or responding disease could continue therapy until progression. Results: From April 2010 to July 2013, a total of 46 patients were enrolled on this trial; of these, 23 patients were in the phase I study and 23 patients in the phase II study. The median number of prior treatments was 2 (range 1-9) Prior therapies received included bortezomib-based therapy (26, 56%) and rituximab (45, 98%). Median treatment duration was 10 months (range, 3 weeks to 41 months) for all patients. There were no DLTs observed and no deaths occurred on this study. The most common toxicities in all patients on study were fatigue (29 patients, 63%); anemia and leukopenia (each in 24 patients, 52%); neutropenia (22, 48%); diarrhea (20, 43%); and neuropathy, pneumonitis/pulmonary infiltrates (each in 19 patients, 41%). The overall response rate (ORR) which includes patients with minor response (MR) or better in the phase II study (N=23) was 91% (95% CI, 72-99%) with 1 CR, 1 VGPR, 16 PR, and 3 MR. When all 36 patients on the phase I and phase II studies who received full dose of RVR were combined, the ORR was 89% (95% CI 74 – 97%), with 2 CR, 3 VGPR, 21 PR, and 6 MR. Conclusions: The RVR regimen is safe and well tolerated. RVR led to an overall response rate of 89% with PR or better achieved in 72% making this a highly effective regimen even in patients previously treated with bortezomib and/or rituximab. This study represents one of the first combination efforts of novel agents targeting the PI3K signaling pathway with a proteasome inhibitor. Disclosures Ghobrial: Sanofi: Research Funding; Noxxon: Research Funding; BMS: Advisory board, Advisory board Other, Research Funding; Onyx: Advisory board Other; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bortezomib and everolimus are not approved for WM. Laubach:Novartis: Research Funding; Onyx Pharmaceuticals: Research Funding. Anderson:Celgene: Consultancy; Sanofi-Aventis: Consultancy; Onyx: Consultancy; Acetylon: Scientific Founder, Scientific Founder Other; Oncoprep: Scientific Founder Other; Gilead Sciences: Consultancy.

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