Outcomes of Single Versus Tandem Hematopoietic Stem Cell Autologous Transplant in High-Risk Myeloma Patients: A Single-Center Experience

Abstract Introduction: Over the past decade, significant advances in the treatment strategy of newly diagnosed multiple myeloma patients (NDMM) have challenged the initial management strategy in transplant-eligible (TE) patients. The value of a single autologous stem cell transplant (ASCT) is established in standard-risk myeloma; however, the role for tandem ASCT reveals conflicting results, especially in patients with high-risk cytogenetic (HR) features. HR changes include at least one of the cytogenetic lesions: t(4;14), t(14;16), t(14;20), del17p, 1q amp +, 1q amp + del 1p. Subgroup analyses of HR patients in the EMN02 study suggest benefits with tandem ASCT. Methods: We retrospectively reviewed our single centre ASCT experience in TE NDMM patients with HR from London, Canada, from January 1, 2007, to April 30, 2021 with the primary objective to compare single versus tandem ASCT for patients with high-risk MM. Secondary objectives include progression-free survival (PFS), overall survival (OS) and the effect of maintenance therapy on survival. OS and PFS were estimated using the Kaplan-Meier method. We also applied univariate and multivariate cox regression to assess the effects of age, hemoglobin, and creatinine on survival. Results: 155 NDMM received at least one ASCT between January 1, 2007 to April 30, 2021. 61/155 (39.3%) patients had HR disease. T(4:14) was seen in 19/61 (31.1%) patients; t(14:16) in 9/61 (9.8%) patients; del 17p in 20/61 (32.7%) patients, 1q amp in 36/61 (59.0%) patients and 1p del + 1q amp in 8/61 (13.1%). Patients with more than one abnormality was seen in 22/61 (36.0%) patients. In this high-risk group, the most common induction regimen consisted of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in 58/61 patients (95.0%). 34 (55.7%) patients received single ASCT and 27 (44.2%) patients received tandem ASCT. 18/34 (52.9%) single ASCT patients and 15/27 (55.5%) tandem ASCT patients received maintenance therapy. Maintenance therapy included single-agent lenalidomide (imid) in 14/61 (22.9%); single-agent bortezomib or ixazomib (proteasome inhibitor (PI)) in 8/61 (13.1%), and; imid + PI combination in 11/61(18.0%). Baseline characteristics are summarized in Table 1. Single versus tandem ASCT in HR patients revealed no statistically significant PFS difference at 60 months (p=0.3). Maintenance therapy demonstrated a substantial improvement in PFS regardless of the number of ASCT (single ASCT HR=0.1687, 95% CI range 0.05-0.52, p<0.001) tandem ASCT (HR=0.1319, 95% CI range 0.01-0.96, p=0.019). PFS was similar in patients who did not receive maintenance in tandem ASCT (20 months) or single ASCT (19 months) (p=0.57). At the 60-month follow-up, the median PFS for high-risk patients without maintenance was 18.8 months. In contrast, the PFS for patients on maintenance was not reached (HR=0.1446, 95% CI range 0.05-0.38, p<0.001). There was no difference in OS (p=0.38) with or without maintenance therapy. When comparing single-agent vs. combination strategy with maintenance, there was no PFS (p=0.47) or OS (p=0.68) difference between strategies. All patients were progression-free in those who received any maintenance at 60 months. Conclusion: In our single centre experience, single vs. tandem ASCT in TE NDMM with HR disease did not contribute to long-term survival outcomes, but the presence of any maintenance therapy had a more considerable impact on PFS. Our data does show a longer progression-free survival compared to previous published data, which is likely due to our sample size. Figure 1 Figure 1. Disclosures Lam: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; SeaGen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Phua: Amgen: Honoraria; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Louzada: Amgen: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Janssen: Honoraria.

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Outcomes of Tandem Hematopoietic Stem Cell Autologous Transplant in High-Risk Myeloma Patients: A Single-Center Experience

Blood ◽

10.1182/blood-2021-153321 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4901-4901

Author(s):

Shona Philip ◽

Selay Lam ◽

Chai Wye Phua ◽

Martha L Louzada ◽

Anargyros Xenocostas ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Partial Response ◽

Maintenance Therapy ◽

Board Of Directors ◽

Progression Free Survival ◽

Single Center ◽

Advisory Committees ◽

Free Survival ◽

Risk Patients

Abstract Introduction: Studies have demonstrated that multiple myeloma (MM) is a clinically, genetically complex and heterogeneous disease. Cytogenetic alterations identify high-risk patients in MM and are associated with a poor prognosis. They include at least one of the following at diagnosis: t(4;14), t(14;16), t(14;20), del(17p), 1q amp and 1q amp + del(1p). Autologous stem cell transplantation (ASCT) and the development of novel agents have considerably increased the median survival of MM patients. Patients with high-risk cytogenetics are associated with worse survival, and studies have shown improvement in progression-free survival with tandem ASCT when compared to single ASCT. Methods: This is a retrospective single-center study evaluating MM patients with high-risk cytogenetics at our center who have undergone a tandem autologous transplant from January 1, 2017, to December 31, 2020. Primary objective was overall response rates (ORR) and relapse rates. Secondary objectives looked at progression-free survival (PFS), overall survival (OS) using the Kaplan-Meier method. Results: From January 1, 2017, to December 31, 2020, 25 high-risk patients underwent tandem ASCT. Key patient characteristics are shown in table 1. Translocation (4:14) was seen in 8/25 (32%) patients; t(14:16) in 5/25 (20%) patients; del17p in 7/25 (28%), 1q amp in 8/25 (32%) patients, del1p + 1q amp in 5/25 (20%) patients. In terms of double hit and triple hit disease, 9/25 (36%) patients had two high risk changes and 3/25 (12%) with had three high risk changes. ISS staging wise, 5/25 (20%) patients were ISS stage I, 5/25 (20%) patients ISS stage 2 and 9/25 (36%) patients were ISS stage 3. The most common induction regimen consisted of cyclophosphamide, bortezomib, and dexamethasone (CyBorD). One patient each transitioned to daratumumab, lenalidomide and dexamethasone and PAD/CVD due to poor response. Maintenance therapy was given to 21/25 (84%) tandem ASCT patients with 5 (20%) patients receiving lenalidomide, 4 (16%) patients receiving proteasome inhibitor and 12 (48%) patients received dual maintenance. In terms of response, we recorded CR (complete response) vs VGPR (very good partial response) vs PR (partial response) after induction, 2-3 months after ASCT #1, 2-3 months after ASCT #2, 12 months after ASCT #2, and 12 months after maintenance. Following induction, 16 patients had achieved VGPR, and 9 of patients had achieved PR. After ASCT #1, 5 (55.5%) PR patients deepened their response to a VGPR. 1-3 months post ASCT #2, 3 (33.3%) PR patients deepened to a VGPR, and 2 (12.5%) VGPR patients achieved CR. 12 months after ASCT #2, 2 of the previous VGPR patients (12.5%) achieved CR, and 1 PR (11.1%) patient achieved VGPR. At the median follow-up time of 60 months, 44% of patients had relapsed. 1 patient relapsed within 1-3 months post ASCT#1. Nine other patients relapsed post ASCT #2 and maintenance except one patient who relapsed at time of ASCT #2. Univariable analysis identified hemoglobin as a statistically significant association with risk of progression or death. All patients who received any maintenance after tandem transplant were progression-free at 60 months (p<0.001). Conclusion: In our retrospective study, results suggest that tandem ASCT allows for deepening of responses. Together with maintenance therapy, this contributes to the durability of further PFS prolongation in high-risk MM patients. Figure 1 Figure 1. Disclosures Lam: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: 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; SeaGen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees. Phua: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Amgen: Honoraria. Louzada: Amgen: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Janssen: Honoraria.

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Evomela® Significantly Increases the Risk of Engraftment Syndrome in Patients with Multiple Myeloma Treated with Autologous Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-132114 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3316-3316 ◽

Cited By ~ 1

Author(s):

Marshall McKenna ◽

Phyllis McKiernan ◽

David S. Siegel ◽

Scott D. Rowley ◽

Noa Biran ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Engraftment Syndrome ◽

Equity Ownership

Background: Evomela, a Melphalan bioequivalent, was approved by the FDA in 2016 for high-dose conditioning treatment prior to hematopoietic stem cell transplantation for multiple myeloma (MM). Evomela has increased solubility and stability compared to traditional Melphalan which requires propylene glycol, a stabilizing agent. A retrospective review (Miller et al. 2019) showed that there was no difference in outcomes or short term morbidity in autologous stem cell transplant (ASCT) recipients conditioned with either Melphalan or Evomela. There was, however, an increased incidence of C. difficile-negative diarrhea in the Evomela group. Engraftment syndrome (ES) is a well characterized, although poorly understood, conglomerate of symptoms occurring in the autologous peri-engraftment period. We have previously demonstrated (McKiernan et al. 2017) that patients with ES have an adverse overall outcome. This study aims to evaluate the effect of Evomela conditioning on patients with MM receiving ASCT. Methods: Our study cohort included 644 patients with MM who received ASCT between January 2008 and December 2018. Evomela conditioning was administered to all patients treated on or after September 4, 2016, defining the Melphalan and Evomela cohorts. ES was defined as diarrhea, rash, non-infectious fever, hepatic dysfunction, pulmonary infiltrates, or encephalopathy not attributed to other causes from 3 days prior to 15 days post engraftment. High-risk disease (HRD) was defined as del 17p, 1q gain, t(4;14), t(14;16), t(14;20) by FISH, monosomy 13, del 13q or hypodiploidy by standard cytogenetics, or high-risk gene expression profiling. Response criteria from the International Myeloma Working Group was used to determine response. Progression free survival (PFS) and overall survival (OS) probabilities were estimated using log rank or Wilcoxon tests. Cox hazard regression model was examined for factors influencing ES. Results: Of the 644 patients, 78 were conditioned with Evomela and 554 were conditioned with Melphalan. Thirty five percent of the total patient population had HRD, 234 (36%) were age 65 or older, and 369 (57%) were males. A total of 197 (30%) patients developed ES with 171 (87%) receiving treatment with corticosteroids. Conditioning with Evomela was associated with a significantly higher incidence of ES 15 days post ASCT compared to Melphalan (40.3% vs 24.8%, p=0.0006). Multivariate analysis showed that patients conditioned with Evomela were 60% more likely (HR-1.597, 95% CI, 1.116-2.285, p=0.0105) to develop ES than traditional Melphalan. Across both cohorts, higher median CD34+ stem cell doses (5.22 vs 5.85 x 10e6/kg, p=0.0026) were protective against ES. Age greater than 65 was associated with increased 15 day post ASCT incidence of ES (HR-1.903, 95% CI, 1.435-2.523, p=<0.0001). There was no PFS (p=0.2996) or OS (p=0.2778) difference between the Evomela group and the Melphalan group. There was a trend towards decreased OS (p=0.0914) among patients with ES, but it was not statistically significant. There was no statistically significant progression difference between ES and non-ES groups (p=0.9739). Conclusion: Patients conditioned with Evomela are significantly more likely to develop ES than patients conditioned with traditional Melphalan. We were not able to show any survival or progression-free survival advantage for patients treated with Evomela. We would caution the use of Evomela in patients with other risk factors for ES. More studies are needed to further understand the differences between Melphalan and Evomela. Disclosures Siegel: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Biran:Merck: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Goldberg:Bristol-Myers Squibb: Consultancy; COTA: Equity Ownership; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership. Goy:Hackensack University Medical Center, RCCA: Employment; Takeda: Other: Grants outside of the submitted work; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; University of Nebraska: Research Funding; Hakensackumc: Research Funding.

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Brentuximab Vedotin As Consolidation Therapy Post Hematopoietic Stem Cell Transplantation for Patients with Relapsed or Refractory Hodgkin Lymphoma: A Real World Analysis of the Colombian Experience

Blood ◽

10.1182/blood-2019-129295 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5275-5275

Author(s):

Bonell Patiño ◽

Cristina Acon-Solano ◽

Mario Pereira ◽

Leonardo Enciso-Olivera ◽

Diana Otero-de la Hoz ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Retrospective Cohort ◽

Progression Free Survival ◽

Brentuximab Vedotin ◽

Advisory Committees ◽

Free Survival

Introduction: High-dose chemotherapy followed by autologous stem-cell transplantation (auto-HCT) is standard of care for patients with relapsed or primary refractory classical Hodgkin lymphoma (cHL). Brentuximab vedotin (BV) consolidation after auto-HCT improves progression-free survival of cHL patients with primary refractory disease and high risk for relapse as seen in the AETHERA trial. There are no published reports of BV consolidation post auto-HCT in cHL patients treated in developing countries. The aim of this study is to determine the clinical outcomes and safety of BV consolidation after auto-HSCT in a cohort of Colombian patients with relapsed or refractory (R/R) cHL. Methods: A retrospective cohort study was conducted at ten tertiary referral centers in five cities in Colombia. Data from patients with R/R cHL who underwent auto-HCT followed by BV consolidation was collected and analyzed. Descriptive statistics were used to analyze patient's demographic characteristics. The Kaplan-Meier method was used to assess overall survival (OS) and progression-free survival (PFS) rates and log-rank test was used to compare survival between groups. All data were analyzed by R Studio software. Results: Fifty-three patients with a confirmed diagnosis of cHL were included, 49,1% were women. Median of age at auto-HCT was 29 years (range 17 - 66). The most frequently used frontline regimen was ABVD 90,6%. Median number of treatment lines including auto-HCT was 3 (range 2 to 7). 83% of patients had BV consolidation after 1stAUtoHCT and 17% after 2 auto-HCT. The most common high-risk feature before auto-HCT was primary refractory cHL (54,7%). Responses were determined by Lugano criteria. However, unconfirmed complete responses (uCR) per 2007 IWC criteria were used due to lack of PET-CT availability of evaluation in some centers, where CT scan were used. The overall rate (ORR) before auto-HCT was 94,4% with complete response (CR) in 28,3%, uCR 20,8% and partial response (PR) in 45,3% of patients. The ORR after auto-HCT was 90,5% with CR in 52,8%, uCR in 22,6%, and PR 15,1%. Table1. A total of 531 BV cycles were administered as post auto-HCT consolidation with a median of 11 cycles (range 1-16). A median of 23 days between each cycle was documented (range 7-210 days). The most common grade 3-4 toxicities were peripheral neuropathy (18,8%), fatigue (9,4%), weight loss (5,6%). OS at 132 months was 92,5% (CI95%: 4,9 - NR) (Figure A), and the median PFS was not reached (CI 95%: 36.5 months - Not reached) with 75,5% PFS at 132 months, with a mean of follow-up of 23,5 months (Range: 4,2 - 133,2 months) (Figure B). There was a trend towards worse PFS in patients treated with ≥ 3 regimens before auto-HCT Median: 38.7 months, (CI 95%: 36.5 - NA) Vs. 2 lines: Median: NR (CI 95%: 4,2-NR) P= 0.4.(Figure C). Also patients that required a second transplant followed by BV consolidation had a worse PFS, compared to the ones that underwent BV consolidation post first auto-HCT: median: 13.6 months (CI 95%: 6.7- NR)Vs. median: NR (CI95%: 38,7 - NR) respectively p=0,009 (Figure D). Twelve patients relapsed and 4 patients died form disease progression. Conclusions: BV consolidation after auto-HCT in high-risk R/R cHL patients treated in a developing country setting seems to be a safe and effective treatment. Although OS and PFS were slightly superior to the ones reported in the AETHERA trial, the mean of follow-up in our analysis is shorter. Another shortcoming of our analysis are the inherit limitation of a retrospective cohort. These retrospective results need to be assessed in prospective trials that specifically includes Latin-American with high-risk patients with R/R cHL. Disclosures Patiño: Amgen: Speakers Bureau. Enciso-Olivera:Takeda: Speakers Bureau. Otero-de la Hoz:Takeda: Speakers Bureau. Martínez Cordero:Takeda: Speakers Bureau. Karduss:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Abello:Takeda: Other: Participation in advisory board meeting. Sandoval-Sus:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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A Phase II Single Arm Study of Nivolumab As Maintenance Therapy after Autologous Stem Cell Transplantation in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression

Blood ◽

10.1182/blood-2021-148139 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2455-2455

Author(s):

Carlos Bachier ◽

Henning Schade ◽

Behyar Zoghi ◽

Aravind Ramakrishnan ◽

Nirav N. Shah

Keyword(s):

Stem Cell ◽

High Risk ◽

Maintenance Therapy ◽

Board Of Directors ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Residual Disease ◽

Refractory Disease ◽

Advisory Committees ◽

Extranodal Disease

Abstract Introduction: Autologous stem cell transplants (ASCT) are standard of care for patients with primary refractory or recurrent Hodgkin lymphoma (HL). While transplant results in cure for some patients, others relapse and succumb from their disease. Studies have found high expression of programmed death ligand 1 (PD-L1) in HL cells. The anti-PD-1 monoclonal antibody, nivolumab, has been safe and efficacious in the treatment of relapsed, refractory HL (Ansell et al. 2015). We evaluated the safety and efficacy of nivolumab maintenance therapy post-ASCT in high risk for relapse Hodgkin disease. Methods: Patients with HL with high risk of residual disease following ASCT ( high risk defined as refractory disease, relapse <12 months, or relapse ≥12 months with extranodal disease after frontline therapy) received nivolumab (240 mg IV every 2 weeks) starting 45-180 days post-transplant for a maximum of 6 months of treatment. Patients were followed for AEs through 100 days after the last dose of drug. PET-CT response assessments were performed 1-3 month, 6 month, and 12 month post-ASCT. The primary objective was to evaluate the safety and tolerability of nivolumab as maintenance therapy early after ASCT. The secondary objective was to evaluate progression-free survival (PFS) at 12 months post-transplant. Results: To date, 37 patients were enrolled; median age 36 years; 25 patients (68%) male. The median number of prior systemic regimens was 2 (range 2-4). 25 patients (68%) had relapsed disease, and 12 patients (32%) had primary refractory disease. 18 patients (49%) had extranodal disease at relapse, 6 patients (16%) had B-symptoms at relapse, and 11 patients (30%) had residual disease after salvage, including 10 patients (27%) of whom had 2-3 prior salvage therapies. 22 patients (60%) had received prior brentuximab, and 3 patients (8%) had received prior nivolumab or pembrolizumab. 36 patients received ASCT and 1 patient received tandem ASCT. At the time of data cutoff, 28 patients (76%) had discontinued nivolumab treatment, 22 patients (60%) because they had completed the 6-month treatment course, 4 patients (11%) due to an adverse event (AE) (1 patient each with pain, pneumonitis, rhabdomyolysis, or hypothyroidism), and 2 patients (5%) due to disease progression. The median duration of treatment was 22.1 weeks. 17 patients (46%) experienced a treatment-related AE (TRAE), of which 5 patients (14%) experienced a ≥Grade 3 TRAE. The most common (≥5%) TRAEs were diarrhea, fatigue, bone pain, neutrophil count decreased, pruritus, rash, and vomiting. 2 patients experienced a treatment-related serious AE (pneumonitis, rhabdomyolysis). There were no treatment-related deaths. With a median follow up of 9.2 months, the median PFS and overall survival (OS) have not been reached. The 6 month PFS is 92.1% and the 12-month OS is 100%. There were no differences in OS when stratified based on prior treatment. Conclusions: The use of nivolumab maintenance early after ASCT is safe and tolerable in this high risk patient population. Early efficacy data is promising, but data need to mature to determine the 12 month PFS. Figure 1 Figure 1. Disclosures Bachier: CRISPR: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Shah: Umoja: Consultancy; Incyte: Consultancy; Legend: Consultancy; Kite: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy.

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Tandem Autologous Hematopoietic Stem Cell Transplants (AuHCT) with or without Maintenance Therapy (auto-auto) Versus Single AuHCT Followed by HLA Matched Sibling Non- Myeloablative Allogeneic HCT (auto-allo) for Patients with Standard Risk (SR) Multiple Myeloma (MM): Results From the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 Trial

Blood ◽

10.1182/blood.v116.21.41.41 ◽

2010 ◽

Vol 116 (21) ◽

pp. 41-41 ◽

Cited By ~ 3

Author(s):

Amrita Krishnan ◽

Marcelo C Pasquini ◽

Marian Ewell ◽

Edward A. Stadtmauer ◽

Edwin P Alyea ◽

...

Keyword(s):

Maintenance Therapy ◽

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Response Rates ◽

Advisory Committees ◽

Free Survival ◽

Allogeneic Hct ◽

Matched Sibling

Abstract Abstract 41 AuHCT improves survival in patients with MM, but disease relapse and progression remain a challenge. Both tandem AuHCT and post transplant maintenance therapy improve progression-free survival (PFS). Alternatively, allogeneic HCT has the potential to reduce disease progression through a graft-versus-myeloma effect. Use of nonmyeloablative conditioning regimens allows the latter approach to be used with reduced treatment-related mortality (TRM). BMT CTN 0102 was a multicenter phase III trial that biologically assigned patients with MM to auto-auto using melphalan 200mg/m2 (MEL 200) conditioning or an auto-allo approach using MEL 200 followed by alloHCT with 2 Gy total body irradiation. Graft-versus-disease (GVHD) prophylaxis was cyclosporine and mycophenolate mofetil. The primary endpoint was 3-year progression free survival (PFS). Between December 2003 and March 2007, 710 patients from 43 US centers were enrolled. Patients were assigned to the auto-allo arm based on availability of an HLA-matched sibling donor at time of enrollment. Patients in the auto-auto arm were further randomized to thalidomide and dexamethasone (Thal-Dex) for 1 year or observation (obs). Among 625 patients with SR MM (absence of chromosome 13 deletion by metaphase karyotyping and β-2 microglobulin ≤ 4mg/L), 436 were assigned to auto-auto (217 Thal-Dex, 219 obs) and 189 to auto-allo. Compliance with Thal-Dex was poor, with 84% of patients not completing prescribed therapy. PFS and overall survival (OS) between the Thal-Dex and obs cohorts were equal and these arms were pooled for the primary analysis. The auto-auto and auto-allo groups differed in age (median 55y vs. 52y, p =0.01) and time between first and second transplants (median 98d vs 105d, p =0.02), but were otherwise balanced. Complete and near complete (CR+nCR) response rates at study entry were 24% for both groups. Three-year PFS was 46% and 43% (p=0.67) and 3-year OS was 80% and 77 % (p=0.19) for the auto-auto and auto-allo groups, respectively. Corresponding probabilities for 3-year progression/relapse were 50% and 46% (p=0.8) and for 3-year TRM were 4% and 11% (p=0.04). Among auto-allo patients, probabilities of grade III-IV acute and chronic GVHD were 9% and 47%, respectively. Eighty-two percent of patients in each arm received the assigned second transplant. Among 522 patients who received their second transplant, 3-year PFS was 47% and 44% (p=0.89) with auto-auto and auto-allo, respectively. Disease response rates at day 56 after second HCT were: 50% very good partial response (VGPR) or better and 40% CR+nCR in the auto-auto group; and 49% (VGPR or better, p=0.8) and 48% (CR+nCR,p=0.12) in the auto-allo group. In conclusion, there were no differences in 3-year PFS and OS between patients receiving auto-auto or auto-allo. Potential benefits of graft-versus-myeloma to reduce disease progression or relapse were offset by increased TRM. Thal-Dex maintenance did not improve PFS or OS, likely due to poor tolerability of this regimen. At 3 years, the auto-allo approach for SR MM had no added benefit compared to tandem AuHCT. Disclosures: Krishnan: Celgene: Speakers Bureau. Stadtmauer:Celgene: Speakers Bureau. Comenzo:Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Elan Pharmaceuticals: Consultancy; Genzyme: Research Funding; Celgene: Research Funding; Ortho: Research Funding. Hari:Celgene: Research Funding. Qazilbash:Celgene: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Giralt:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

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High Risk Diffuse Large B Cell Lymphoma: A Comparison of Aggressive Subtypes Treated with Dose Adjusted Chemotherapy-the University of Texas MD Anderson Experience

Blood ◽

10.1182/blood.v128.22.106.106 ◽

2016 ◽

Vol 128 (22) ◽

pp. 106-106 ◽

Cited By ~ 3

Author(s):

Vishwanath Sathyanarayanan ◽

Yasuhiro Oki ◽

Amir K Issa ◽

Mohamed Amin Ahmed ◽

Mansoor Noorani ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Time To Event ◽

Advisory Committees ◽

Free Survival ◽

Large B Cell Lymphoma ◽

Md Anderson

Abstract Background: Diffuse large B cell lymphoma (DLBCL) is the most common type of non Hodgkin lymphoma (NHL).Nearly 50% of high-risk DLBCL patients are not cured with standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP). High risk DLBCL may be defined as double hit lymphoma (DHL, translocation of MYC and BCL2 or BCL6), double expressor lymphoma (DEL, over expression of MYC and BCL2), high risk international prognostic index (IPI) of 3-5, high Ki-67, and non-germinal center subtype (non-GCB). The majority of DHL cases occur in the GCB subtype, as opposed to the majority of DEL cases which occur in non-GCB. Hence we sought to compare different high risk subsets treated with dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and rituximab (DA) EPOCH-R. In single arm phase II clinical trials, dose adjusted (DA) EPOCH-R has shown promising results, with potential greater efficacy in the GCB subtype in subset analyses (Wilson et al, Hematologica 2012). A randomized phase III study comparing RCHOP with (DA) EPOCH-R in newly diagnosed DLBCL has completed accrual, with highly anticipated results due in late 2016. Methods: We conducted a retrospective reviewof all consecutive, newly diagnosed DLBCL patients treated with (DA) EPOCH-R at MD Anderson Cancer Center from 2010 to 2014. Eligible patients were 18 years or greater, had high-risk DLBCL as determined by the treating physician, and had available data of treatment and response. The cell of origin subtype was determined by immunohistochemistry using Hans algorithm, and MYC and BCL2 positivity were defined as BCL2 positive in at least 70% and MYC positive in at least 40% of cells. DHL was defined as rearrangement of MYC and BCL2 or BCL6 by fluorescent in situ hybridization. The objectives were to analyze demographic, prognostic, and treatment variables in comparison with clinical response and survival outcomes in three sub groups which included 1. DHL (GCB) 2. DLBCL without MYC and BCL2 expression (GCB), and 3. DEL (GCB and non GCB). Complete response (CR), overall survival (OS) and progression free survival (PFS) were calculated using standard methods. Statistical analysis was done using Fishers exact test or Chi-square test / Kruskal-Wallis test. Kaplan-Meier method was used for time-to-event analysis including overall survival and progression free survival. The Log-rank test was used to evaluate the difference in time-to-event endpoints between patient groups. Results: We identified 233 high risk DLBCL patients treated with (DA) EPOCH-R. After filtering the data to identify patients which were included in our three groups, we identified 22 patients with DHL (GCB), 46 patients with non DEL (GCB), and 16 with DEL. The demographic features and outcomes are mentioned in the table 1 below. The DHL group had more frequent bone marrow (BM) involvement, and the DHL and DEL groups were more frequently age >60 years and high IPI in comparison to the non DEL GCB group. The CR rate, OS and PFS at 1 year were not significantly different between these three groups. Figure 1 highlights the OS (A) and PFS (B) results of each group. Conclusions: (DA) EPOCH-R is highly effective in patients with subsets of patients with high-risk DLBCL and may be able to overcome prognostic factors which have been shown to be adverse with RCHOP therapy. The results of this retrospective study suggest that OS in DHL, DEL and non DEL (GCB) are not statistically different. Hence, intensive chemotherapy with (DA) EPOCH-R could be considered as a frontline treatment option for patients with high risk DLBCL, pending further confirmation in randomized trials. Disclosures Oki: Novartis: Research Funding. Fowler:Infinity: Consultancy, Research Funding; Roche: Consultancy, Research Funding; TG Therapeutics: Consultancy; Celgene: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Gilead: Research Funding. Wang:Pharmacyclics: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; BeiGene: Research Funding; Kite Pharma: Research Funding; Onyx: Research Funding; Asana BioSciences: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fayad:Seattle Genetics: Consultancy, Research Funding. Westin:ProNAi: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees.

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Novel Prognostic Scoring System for Autologous Hematopoietic Cell Transplantation (AHCT) in Multiple Myeloma (MM)

Blood ◽

10.1182/blood-2019-126646 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 783-783 ◽

Cited By ~ 2

Author(s):

Binod Dhakal ◽

Raphael Fraser ◽

Zhubin Gahvari ◽

Aric C. Hall ◽

Natalie Scott Callander ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Scoring System ◽

Research Funding ◽

Validation Cohort ◽

Progression Free Survival ◽

Low Risk ◽

Advisory Committees ◽

Final Model ◽

Free Survival

Background: Novel agent induction and AHCT remains the preferred initial therapeutic strategy for transplant-eligible MM patients. Current prognostic tools in MM focus solely on disease-specific factors at diagnosis to determine patient prognosis-International Staging System (ISS) and revised-ISS (R-ISS). A major limitation to both, the ISS and R-ISS, is that they are not specific for HCT-eligible patients and do not take into account other patient factors that may enter into a decision to pursue AHCT. The data used to generate these staging systems were from broad populations with varying upfront treatment strategies and included patients who were ineligible for intensive therapy. Additionally, there is considerable interest in identifying the population that relapses early despite modern induction/AHCT approaches who are candidates for novel approaches for maintenance/consolidation. To address these problems, we used data from the Center for Blood and Marrow Transplant Research (CIBMTR) registry to identify disease-, patient-, and transplantation-specific variables that are associated with progression-free survival (PFS) in patients undergoing upfront AHCT (within 12 months of diagnosis). Methods: We used the outcomes of 2528 MM patients undergoing upfront AHCT from 2008-2017 reported to the CIBMTR. Patients were divided into training and validation sets with a 50% random split. High risk cytogenetics was defined as the presence of one or more of the following: t(4;14), t (14;16), t (14;20), del 13q, del 17p, 1q gain, or 1p deletion. We used a Cox multivariable model to identify factors prognostic of progression free survival (PFS) in a training subset. The regression coefficients of the final model was transformed into a risk score with an appropriate transformation. A weighted score using these factors was assigned to the training cohort (n = 917) and validation cohort (n=897) using subset that had all values that entered the final model. Kaplan-Meier estimates of the individual scores were used to classify patients into risk groups for both cohorts. Results: Baseline characteristics of these patients are shown in Table 1. No cytogenetic abnormality, VRD induction, pre-AHCT bone marrow plasma cells (BMPCs) <10% and 1 line of induction chemotherapy were assigned 0 points. Pre-AHCT BMPCs ≥10% (hazard ratio HR, 1.47; 95% CI, 1.19-1.83), use of ≥2 lines of induction chemotherapy prior to AHCT (HR 1.32; 95% CI 1.06-1.64), standard cytogenetic risk vs. no abnormality (HR 1.41; 95% CI 1.13-1.77) and induction regimens (non-VRD regimens vs. VRD) (HR 1.4, 95% CI 1.17-1.74) were associated with increased hazard of progression and assigned 1 point in the scoring system. Presence of high-risk cytogenetics vs. no abnormality (HR 1.87; 95% CI 1.45-2.42) was assigned 2 points, and the use of thalidomide and dexamethasone (TD) as an induction regimen (HR 2.19; 95% CI 1.48-3.2) was assigned 3 points. A two-category system was created based on the scoring: low risk (0-3) and high risk (4-6). The scoring system was prognostic for PFS when applied to both cohorts. High-risk group was found to have significantly higher risk of progression and/or death compared to low risk in training (HR 2.2; 95% CI 1.74-2.86; p<0.0001) and validation cohort (HR 1.7, 95% CI 1.30-2.22; p=0.0001) respectively (Table 2). The 3-year PFS in the training cohort was 60% (95% CI 56%-64%) in low risk and 27% (95% CI 17%- 36%) in high risk while in the validation cohort was 51% (95% CI 47%-55%) in low risk and 28% (95% CI 16%- 39%) in high risk (Figure 1A and 1B). Conclusions: We describe a prognostic model specifically for patients undergoing upfront AHCT in MM which can identify patients at very high risk for early relapse/progression. These patients should be ideal candidates for studies of immunotherapy or other interventions after AHCT aimed at reducing relapse. Disclosures Dhakal: Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Shah:Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment; Poseida: Research Funding; Indapta Therapeutics: Equity Ownership; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding. Qazilbash:Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Bioclinical: Consultancy; Genzyme: Other: Speaker. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:AbbVie: Consultancy, Honoraria; Cell Vault: Equity Ownership; Sanofi: Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Amgen: Research Funding; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

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A Multi-Institutional Outcomes Analysis of Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Treated with Ibrutinib

Blood ◽

10.1182/blood.v128.22.1115.1115 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1115-1115 ◽

Cited By ~ 1

Author(s):

Allison Marie Winter ◽

Daniel J. Landsburg ◽

Francisco J. Hernandez-Ilizaliturri ◽

Nishitha Reddy ◽

Stephen Smith ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

De Novo ◽

Molecular Subtype ◽

Single Agent ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Free Survival ◽

Large B Cell Lymphoma

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with distinct survival differences according to molecular subtype with superior outcomes in patients with the germinal center B cell-like (GC) subtype as compared to those with the activated B cell-like (ABC) subtype. Efficacy data for single-agent ibrutinib in patients with relapsed/refractory (r/r) DLBCL are limited to a single clinical trial of 80 patients. In that study, higher response rates were observed for r/r ABC-DLBCL compared to GC-DLBCL (37% vs. 5%), when assigned by gene expression profiling (GEP). The response rate of those with unknown/unclassifiable DLBCL was 22%. Despite biologic rationale for selective cytotoxicity of ibrutinib for ABC-DLBCL, it is not clear that such preferential activity will be observed when subtyping based on immunohistochemical (IHC) staining is used, as the correlation with subtype determined by GEP and IHC is imperfect. Furthermore, GEP is time consuming and expensive so IHC is used in clinical practice to differentiate GC from non-GC, the latter of which includes both ABC and unclassifiable DLBCL. We retrospectively analyzed outcomes of patients with r/r DLBCL treated with ibrutinib at a number of large academic medical centers. Methods: We reviewed medical records of all patients with DLBCL treated with ibrutinib at five U.S. tertiary-care cancer centers from 2013 to 2016. We included patients with de novo DLBCL as well as those transformed from indolent lymphoma if the ibrutinib was given for the DLBCL histology. Patients were excluded if they received ibrutinib for ≤ 14 days. Molecular subtype (GC vs non-GC) was determined by local pathology findings and/or the investigator's application of the Hans algorithm. Categorical variables were compared between groups using the Chi-square test. Outcomes were calculated from the date of initiation of ibrutinib. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Thirty five patients met inclusion criteria (27 de novo and 8 transformed DLBCL). The median age at diagnosis was 61 years (range 38-88) with 66% men.By Hans IHC criteria, there were 21 cases of non-GC, 9 GC and 5 were unknown.The median number of treatments prior to ibrutinib was 3 (range 1-8). 30% of patients had undergone prior autologous stem cell transplant. Characteristics including age, gender, transformed versus de novo, relapsed versus refractory, number of prior therapies, and prior use of transplant did not significantly differ between subgroups. The overall response rate (ORR) to ibrutinib was 29% with 4 patients achieving a complete response (CR) and 6 achieving a partial response (PR). When evaluated by subtype assigned by IHC, GC-DLBCL patients had an ORR of 44% and non-GC-DLBCL patients had an ORR of 19%. There was no significant difference in the rates of CR, PR, stable disease, or progressive disease between the subtypes (p=0.185) or between de novo ortransformed disease (P = 0.114). The median progression-free survival (PFS) was comparable for patients with the GC, non-GC, and unknown subtype (3.9, 2.2, and 4.1 months, respectively, P = 0.382, Figure). The median overall survival (OS) was longer for patients with the GC subtype (10.5 months) compared to 5.5 months for patients with the non-GC subtype, and 9.7 months for those with unknown subtype but this difference was not statistically significant (P=0.564). Figure: Progression Free Survival of r/r DLBCL Patients Treated with Ibrutinib, based on Hans Algorithm Subtype Conclusions: Responserates to single agent ibrutinib in the GC and non-GC subtypes of r/r DLBCL do not appear different when using Hans algorithm to assign subtypes. PFS and OS were modest in both groups and not statistically different. In conclusion, until GEP or other molecular technologies such as Nanostring are in more widespread use for routine subtyping of DLBCL, caution is advised when selecting patients for subtype-specific therapy, as clinical outcomes for patients receiving ibrutinib may not differ by cell of origin as determined by IHC. Figure Figure. Disclosures Reddy: celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees; INFINITY: Membership on an entity's Board of Directors or advisory committees. Shadman:Pharmacyclics: Honoraria, Research Funding. Smith:Spectrum: Honoraria; Celgene: Honoraria; Abbvie: Research Funding; Genentech: Honoraria.

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Phase II Trial of Combination of Elotuzumab, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽

10.1182/blood-2018-154 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 154-154 ◽

Cited By ~ 10

Author(s):

Chia-jen Liu ◽

Irene M. Ghobrial ◽

Mark Bustoros ◽

Kaitlen Reyes ◽

Kalvis Hornburg ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Therapeutic Intervention ◽

Research Funding ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Genomic Studies ◽

Equity Ownership

Abstract Background This study aimed to determine the benefit of early therapeutic intervention with the combination of elotuzumab, Lenalidomide, and Dexamethasone in patients with high-risk smoldering multiple myeloma (SMM). ClinicalTrials.gov Identifier: NCT02279394. Aims The overarching objective of this trial is to determine progression free survival to symptomatic multiple myeloma (MM). Furthermore, the study examined whether genomic studies can help in determining patients who would benefit the most from this early therapeutic intervention. Methods Patients enrolled in this study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al, Blood 2014. Patients were administered weekly elotuzumab (10 mg/kg) on days 1, 8, 15, and 22 for the first two 28-day cycles while receiving lenalidomide on days 1-21. For cycles 3-8, patients were administered elotuzumab infusions on days 1, 8, and 15. dexamethasone (40mg) was given on days 1, 8 and 15 to 40 of the 50 enrolled patients. After 8 cycles or best response, patients were given the option to mobilize with either cyclophosphamide or plerixafor and collect stem cells for future transplant. Patients were then allowed to continue on maintenance therapy where they were administered elotuzumab (20 mg/kg) on day 1, in combination with lenalidomide days 1-21 of a 28-day cycle. Bone marrow (BM) samples of 32 patients were obtained before starting therapy for baseline assessment and whole exome sequencing (WES) of plasma cells. Results In total, 50 patients were enrolled on this study from January 2015 and completed accrual in December 2016, with the participation of eight sites. The median age of enrolled patients was 62 years (range, 29-79) with 18 males (36%) and 32 females (64%). Interphase fluorescence in situ hybridization (iFISH) detected high-risk cytogenetics (defined by the presence of 17p deletion, t(4;14), and 1q gain) in 20 patients. The median time to response was 2.8 months (range, 1.8-4.6). The most common toxicities were fatigue (92%), followed by diarrhea (72%), and hyperglycemia (62%). The most common grade 3 or more adverse events were hypophosphatemia (34%), neutropenia (26%), and lymphocyte count decreased (22%). Three patients (6%) had grade 4 hypophosphatemia during treatment. Additionally, grade 4 cholecystitis, cataract, lymphocyte count increase, hyperglycemia, neutropenia, and thrombocytopenia occurred in one patient (2%). Diabetic Ketoacidosis and sepsis led to death in a patient (2%). Stem cell collection was successful in all mobilized patients to date. As of this abstract date, the overall response rate is 84% (41/49). There were 3 complete responses (6%), 18 very good partial responses (37%), 20 partial responses (41%), 5 minimal responses (10%), 3 stable disease (6%), and 2 unevaluable patients. All the study participants except for three have finished treatment and are currently under follow up. None of the patients showed progression to overt MM to date. We continue to collect data for progression free survival. WES was performed on 32 samples at the time of initiation of therapy. Recurrent mutations in the MAPK pathway (KRAS, NRAS) and tumor suppressor gene, TP53, were detected in 40% of the cases (16% and 24%, respectively), while mutations in the NF-KB and plasma cell differentiation pathways were present in 13% of patients. Somatic copy number alterations (SCNAs) were called based on WES: 1q duplication, 13q, 17p, and 1p deletions were identified in 25, 31, 12, and 7% of cases, respectively. Interestingly, in 6 patients, high-risk SCNAs (1q gain and 17p deletion) were not reported in iFISH but were detected by WES. The analysis of these 32 samples showed that patients who are harboring mutations in the DNA repair pathway genes, had modest response to treatment. Finally, we are analyzing the transcriptomic profile of CD138 negative cells, which represent the BM microenvironment cells (immune and stromal cells) to characterize the BM microenvironment at baseline and end of treatment, and thus, elucidate the role of these cells in the differential response to therapy. Conclusion The combination of elotuzumab, lenalidomide, and dexamethasone is well tolerated and demonstrates a high response rate with no progression to overt MM to date. Correlation with genomic studies can help define patients who benefit the most from this early therapeutic intervention. Disclosures Ghobrial: Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy. Bustoros:Dava Oncology: Honoraria. Badros:GSK: Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Research Funding. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Rosenblatt:Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Karyopharm: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Zonder:Celgene: Consultancy, Honoraria; Pharmacyclics: Other: DSMC; Janssen: Honoraria; Takeda: Honoraria; Alnylam: Honoraria; Coelum: Honoraria; BMS: Research Funding. Munshi:OncoPep: Other: Board of director. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; OncoPep: Equity Ownership, Other: Scientific founder; Millennium Takeda: Consultancy; Celgene: Consultancy. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Phase II Multi-Center Trial Of Pentostatin Plus Cyclophosphamide With Ofatumumab (PCO) In Older Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients

Blood ◽

10.1182/blood.v122.21.4177.4177 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4177-4177 ◽

Cited By ~ 2

Author(s):

Marco Montillo ◽

Davide Rossi ◽

Marina Motta ◽

Giulia Quaresmini ◽

Marianna Rossi ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Progression Free Survival ◽

Clinical Activity ◽

Advisory Committees ◽

Free Survival ◽

Grade 3 ◽

Anti Cd20

Abstract Introduction The seminal phase 3 trial conducted by the German CLL Study Group demonstrated that the addition of the anti-CD20 monoclonal antibody [mAb] rituximab to the FC platform (FCR) improved response rates, progression free survival and also overall survival. However, FCR showed considerable hematologic toxicity, particularly among patients over age 70. Pentostatin demonstrated similar response frequency to other purine analogues in CLL. Furthermore, its relative lack of myelotoxicity has allowed to use it with improved tolerability particularly when administered in combination with myelotoxic agents such as cyclophosphamide. Ofatumumab is a fully human anti-CD20 mAb with clinical activity as a single agent in patients with fludarabine-refractory CLL. Ofatumumab appears to have greater single agent clinical activity than rituximab in patients with previously treated CLL and also has activity in rituximab-refractory patients. Given the reported efficacy of chemo immunotherapy [CIT] in CLL and the activity and toxicity profile of pentostatin combinations, we designed a trial of pentostatin, cyclophosphamide, and Ofatumumab for previously untreated older patients with CLL. Methods Patients with CLL who required therapy (2008 NCI-WG guidelines) aged ≥ 65 years and ECOG PS of 0-2 were enrolled to receive Pentostatin 2 mg/sqm and Cyclophosphamide 600 mg/sqm both as intravenous infusions at day 1 of each 21 day cycle and Ofatumumab administered as intravenous infusions (Cycle 1: 300 mg day 1 and 1000 mg day 2, subsequent cycles: 1000 mg at day 1). Ofatumumab premedication included acetaminophen, antihistamine and glucocorticoid. Treatment duration was of 6 cycles. The primary endpoint was overall response rate (ORR) including detection of minimal residual disease (MRD) and secondary endpoints included, progression-free survival (PFS) overall survival (OS) and safety. Patients 49 patients from 12 centres from the italians regions of Lombardy and Piedmont were included. Baseline demographics were: Median age 72.8 years with 64% aged over 70, among them 32 were males (65%). Disease characteristics in 32 patients evaluable at this point were: 76% Binet stage B and 24% C; 45% of patients had unmutated IGVH, 7 % showed 17p deletions. Results ORR was 93.7% with 41% CR(11)/CR(2) with incomplete marrow recovery [CRi]. All six intended courses of treatment were administered to 30 (94%), and 90% of these patients received full-dose treatment. The reason for discontinuing treatment before completing six courses was myelosuppression occurring in 2 patients. The primary reason for dose reduction was again myelosuppression. Grade ≥3 AEs that occurred from start of treatment until 60 days after the last dose were experienced by 62% of patients receiving PCO with the most common being neutropenia [Total number of patients with at least one Grade 3 or 4 event: 19 patients] while anemia and thrombocytopenia were detected only as grade 1 to 2 in 41% and 25% of cases respectively. Of the grade 1 to 2 toxicities, fever occurred in 2 patients (6%), hypotension occurred in 2 patients (6%), nausea and vomiting occurred in 3 patients (9%), skin rash of grade 1 occurred in 2 patients. Grade 3 infusion-related AEs were reported in 12% of patients. There were no grade 4 toxicities associated with any Ofatumumab infusion. Grade 3 infection was reported in 1 patient (3%) being a pneumonia. No deaths during treatment occurred in these 32 subjects. Conclusion Ofatumumab added to Pentostatin and Cyclophosphamide demonstrated clinically important results and is well tolerated in patients with previously untreated CLL. In this preliminary report the efficacy of this ofatumumab-based CIT compares favorably to the historical rituximab-based CIT using the same chemotherapeutic agents with a more manageable side effect profile in this older population. Further data in a higher number of enrolled patients and including MRD detection will be presented at the Meeting. Disclosures: Montillo: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Rambaldi:Novartis: Honoraria; Sanofi: Honoraria; Italfarmaco: Honoraria.

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