Comparison of Clinical Outcomes Among Patients with Relapsed/Refractory Follicular Lymphoma Treated with Tisagenlecleucel in the Elara Trial Versus a Real-World External Control Arm of Patients Treated with Standard of Care

Abstract Introduction: In the single-arm phase 2 ELARA trial (NCT03568461), tisagenlecleucel demonstrated efficacy and favorable safety profile in patients with relapsed/refractory (r/r) follicular lymphoma (FL) after ≥ 2 lines of prior therapy, including in high-risk sub-populations (Schuster, et al. ASCO 2021). To contextualize these results, we performed a retrospective non-interventional study to compare the efficacy of tisagenlecleucel seen in the single-arm ELARA trial with the standard-of-care (SoC) using individual patient-level data from the US Flatiron Health Research Database (FHRD). FHRD is a database derived from electronic health records from over 280 cancer clinics. The objective was to assess the effect of prescribing tisagenlecleucel vs SoC in patients who participated in ELARA. Methods: Individual patient-level data from FHRD were used to create an external control arm to carry out an indirect comparison with the ELARA trial. Eligible inclusion and exclusion criteria from ELARA were applied to the external control arm. A single eligible line was selected using propensity scores when patients were qualified at multiple lines. Key prognostic factors including age, race, gender, number of prior treatment lines, group stage at initial FL diagnosis, number of months between initial FL diagnosis and indication of index treatment, double refractoriness, and disease progression within 24 months were included in a propensity score model to reduce confounding due to systematic differences in ELARA patients from FHRD patients at baseline for the selected line. Weighting by odds of receiving tisagenlecleucel was used to estimate the average treatment effect on progression-free survival (PFS), overall survival (OS), time to next treatment (TTNT), overall response rate (ORR), and complete response rate (CRR). The rates and difference in rates were calculated for CRR and ORR. Kaplan-Meier (KM) analysis and Cox proportional hazards model were used to analyze all time-to-event endpoints. 95% confidence interval (CI) was calculated using bootstrapping. Data from the first 24 months after enrollment in ELARA or after treatment in FHRD were used for the follow-up period in the time to event endpoints, as few patients in ELARA trial had > 24 month data (Figure). Results were reported based on the post-weighting sample by incorporating a weight factor in the above analyses. A series of sensitivity analyses were conducted to assess the robustness of the primary analysis. Results: As of Mar 29, 2021, 98 patients were enrolled in the ELARA trial, of which 97 were included in this indirect comparison (median follow-up, 15 months). In the FHRD cohort (data cut-off, Jun 30, 2020), 98 patients with ≥ 3 treatment lines who met the ELARA eligibility were included (median follow-up, 14 months in the post-weighted sample) (Table 1). In the ELARA vs FHRD cohorts, after applying weighting by odds, the ORR was 85.6% vs 58.1%, and the CRR was 69.1% vs 17.7%. The difference in CRR (51.4%; 95% CI: 21.2, 68.8) was clinically meaningful (Table 2). The median TTNT or death was not reached in the ELARA cohort and was 19.0 months in the FHRD cohort after weighting (HR = 0.34 [95% CI: 0.15, 0.78]) (Table 2). The median OS was not reached for both ELARA and FHRD cohorts in the first 24-month period. KM estimate of OS at 12 months was 96.6% in the ELARA cohort and 84.5% in the FHRD cohort, post weighting. The estimated 59% risk reduction was in favor of tisagenlecleucel over SoC (hazard ratio [HR] = 0.41 [95% CI: 0.11, 1.47]) (Table 2). The median PFS was not reached in the ELARA cohort and was 9.9 months in the FHRD cohort, after weighting. In the ELARA vs FHRD cohorts, the 12-month PFS was 73.2% vs 41.8%, with a HR of 0.45 indicating a 55% reduction in the risk of progression and death with tisagenlecleucel vs SoC. The median PFS considering new anti-cancer therapy as an event was not reached for ELARA and was 9.9 months for FHRD; the estimated probability of being progression-free at 12 months was 70.5% in the ELARA cohort and 39.4% in the FHRD cohort (Table 2). Sensitivity analyses results were consistent with that of primary analysis. Conclusion: In the weighted analyses with adjustment for baseline prognostic factors, there was a consistent trend towards greater CRR, TTNT, OS and PFS in favor of tisagenlecleucel vs SoC in patients with r/r FL. These results support the clinically meaningful treatment benefit of tisagenlecleucel observed in the ELARA trial. Figure 1 Figure 1. Disclosures Hao: Novartis: Current Employment. Hsu: Novartis: Consultancy. Parzynski: Novartis: Consultancy. Lobetti Bodoni: Spouse: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Spouse: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Spouse: Celgene: Honoraria; Spouse: Harlcok Healthcare: Current holder of individual stocks in a privately-held company; Spouse: Takeda: Consultancy, Honoraria, Speakers Bureau; Spouse: NHS: Ended employment in the past 24 months; Spouse: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spouse: F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; Gilead: Other: Travel sponsorship in June 2019; Novartis: Current Employment, Current equity holder in publicly-traded company. Degtyarev: Novartis: Current Employment, Current equity holder in publicly-traded company. Hampson: Novartis: Current Employment. Masood: Novartis: Current Employment, Current holder of stock options in a privately-held company. Wu: Novartis: Consultancy. OffLabel Disclosure: Tisagenlecleucel (Kymriah) an autologous CD19-directed CAR-T-cell therapy, has been approved for children and young adults with relapsed/refractory (r/r) acute lymphoblastic leukemia and, adults with r/r diffuse large B-cell lymphoma.

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Utilization of External Control Arm to Contextualize Clinical Efficacy of Tisagenlecleucel Treated Among Patients with Relapsed/Refractory Follicular Lymphoma from the Single-Arm Elara Trial

Blood ◽

10.1182/blood-2021-152685 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4506-4506

Author(s):

Yanni Hao ◽

Wei-Chun Hsu ◽

Craig S Parzynski ◽

C Lobetti Bodoni ◽

Lisa Hampson ◽

...

Keyword(s):

Performance Assessment ◽

Board Of Directors ◽

Real World ◽

Indirect Comparison ◽

External Control ◽

Target Trial ◽

Publicly Traded ◽

Eligibility Criteria ◽

Advisory Committees

Abstract Introduction: While randomized clinical trials (RCT) remain the gold standard for evaluating the safety and efficacy of treatments, interest in the use of external control arm (ECA) has grown when randomization is either infeasible or unethical (Friends of Cancer Research 2019). ECAs can provide contextual evidence to support regulatory approval in such situations. Single arm trials in patients with relapsed/refractory follicular lymphoma (FL) is one example due to the rarity of the disease and lack of standardized treatment in this patient population. The target trial framework (Hernán and Robins 2016) can be used to emulate a hypothetical RCT that ideally would have been performed to estimate the relative efficacy of treatment of interest when non-interventional studies were used to supplement single arm trials. We present an ECA in order to contextualize the efficacy of tisagenlecleucel in the single arm Phase 2 ELARA trial with evidence on standard of care (SOC) derived from the Flatiron Health Research Database (FHRD). Methods: Key components of the target trial include objective, population, treatment assignment, endpoints, start of follow-up period, performed comparison and causal effect of interest. These components were specified collaboratively with clinical and statistical input. The ECA was constructed by applying key eligibility criteria from the ELARA trial to FHRD. Key endpoints including real-world progression and real-world response of the target trial were identified and curated for ECA for comparison with ELARA by reviewing clinically relevant aspects for the population/disease of interest, understanding routine documentation practices of oncology healthcare professionals at both the system level (e.g., across various hematologic and oncologic diseases) as well as at the disease specific level (e.g., NHL), and extracting from the electronic health record (EHR) specific measurements of interest. A performance assessment was conducted to confirm the comparability of real-world and trial endpoints. Methods utilizing propensity scores were used to select a single line of therapy for patients from FHRD, ameliorate the impact of measured confounding and facilitate accurate estimation of the primary causal estimand. Feedback on the proposed indirect comparison was sought a priori from the European Medicines Agency (EMA). Upon feedback from EMA, the ECA was constructed and the causal estimand of interest was assessed. Results: The target trial is defined in Table 1. Feasible eligibility criteria from ELARA were applied to FHRD. Briefly, the ECA included patients diagnosed with FL who had at least two prior lines of therapy, including an anti-CD20 and alkylating agent and had not received a clinical study drug, anti-CD19, gene therapy or allogeneic hematopoietic stem cell transplant. Patients were aged at least 18 years at time of treatment and had at least 3 months of follow up. Some criteria from the trial could not be implemented. Endpoints included real-world response (rwR) and real-world progression (rwP). rwR was defined as the treating clinician's assessment of radiological response based on the assessment of the burden of FL disease over the course of treatment with a given regimen. rwP was defined as an evaluation by the treating clinician of progression in FL disease after systemic treatment. The performance assessment confirmed that the rwR/rwP data can be reliably captured and that the scan frequency for rwR is similar to ELARA. EMA acknowledged the limitations associated with the use of this ECA for indirect comparison including limited sample size, inability to match on certain inclusion/exclusion criteria, impact of missing data, potential misalignment on endpoint definition and unmeasured confounders. However, EMA recognized the usefulness of the ECA in contextualizing the efficacy of tisagenlecleucel in the current therapeutic landscape provided statistical analyses were used to address the limitations as far as possible. Detail results of this indirect comparison are included in a separate ASH abstract. Conclusion: Noting the limitations, an ECA constructed using EHR was considered useful to supplement and contextualize the clinical efficacy of tisagenlecleucel vs SOC from a single arm clinical trial using propensity score based methodologies to account for confounders. Figure 1 Figure 1. Disclosures Hao: Novartis: Current Employment. Hsu: Novartis: Consultancy. Parzynski: Novartis: Consultancy. Lobetti Bodoni: Novartis: Current Employment, Current equity holder in publicly-traded company; Gilead: Other: Travel sponsorship in June 2019; Spouse: F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; Spouse: NHS: Ended employment in the past 24 months; Spouse: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spouse: Takeda: Consultancy, Honoraria, Speakers Bureau; Spouse: Harlcok Healthcare: Current holder of individual stocks in a privately-held company; Spouse: Celgene: Honoraria; Spouse: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Spouse: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hampson: Novartis: Current Employment. Masood: Novartis: Current Employment, Current holder of stock options in a privately-held company. Rhodes: Novartis: Consultancy. Wu: Novartis: Consultancy. OffLabel Disclosure: Tisagenlecleucel (Kymriah) an autologous CD19- directed CAR-T-cell therapy, has been approved for children and young adults with relapsed/refractory (r/r) acute lymphoblastic leukemia and, adults with r/r diffuse large B-cell lymphoma.

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Blinatumomab in Children with Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia (R/R-ALL): Final Results of 110 Patients Treated in an Expanded Access Study (RIALTO)

Blood ◽

10.1182/blood-2020-141336 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 24-25

Author(s):

Franco Locatelli ◽

Gerhard Zugmaier ◽

Noemi Mergen ◽

Peter Bader ◽

Sima Jeha ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Final Analysis ◽

Publicly Traded ◽

Primary Analysis ◽

Advisory Committees ◽

Grade 3

Introduction: The open-label, expanded access study (RIALTO) demonstrated that blinatumomab is efficacious with a manageable safety profile in children with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). Blinatumomab is a BiTE® (bispecific T-cell engager) immuno-oncology therapy that activates cytotoxic T cells to kill target B cells. Here, findings from the final analysis of RIALTO are presented (NCT02187354). Methods: Enrolled in the study were children >28 days and <18 years of age with R/R CD19+ BCP-ALL (defined as ≥2 relapses, relapse after allogeneic hematopoietic stem cell transplant [alloHSCT], or refractory to prior treatments) and ≥5% blasts or <5% blasts but with minimal residual disease (MRD) level ≥10−3. Blinatumomab was given as continuous infusion in a 6-week cycle (4 weeks on and 2 weeks off) for up to 5 cycles and safety follow-up visit 30 days post-treatment. Patients with <25% blasts were dosed at 15 µg/m2/day, whereas those with ≥25% blasts were dosed at 5 µg/m2/day (days 1-7 of cycle 1) followed by dose increase to 15 µg/m2/day. Primary endpoint was incidence of treatment-emergent (TE) and treatment-related (TR) adverse events (AEs). Secondary endpoints included complete response (CR; <5% blasts) and MRD response (<10−4 blasts by PCR or flow-cytometry) in the first 2 cycles, relapse-free survival (RFS), overall survival (OS), and alloHSCT rate after blinatumomab treatment. Results: As of the data cutoff date (January 10, 2020) for the final analysis, demographics and baseline characteristics of 110 patients enrolled (median age, 8.5 years [95% CI 0.4-17.0]), 61% had <50% blasts at baseline, and 11% had <5% blasts (n=12; with MRD ≥10−3) remain unchanged compared with the primary analysis (Table 1). For best treatment response within the first 2 cycles, results are comparable to that of the primary analysis. Among 110 patients, overall CR rate was 62.7% (n= 69). Of 98 patients with ≥5% blasts at baseline, 59% (n=58) achieved CR; of them, 79% (n=46) achieved an MRD response and 62% (n=39) proceeded to HSCT. The 2 patients with t(17;19) achieved CR with an MRD response. Of the 4 patients with germline trisomy 21 (Down syndrome), 3 achieved CR with an MRD response Among the 12 patients with <5% blasts but with MRD ≥10−3 at baseline, 92% (n=11) achieved CR and MRD response; 75% (n=9) proceeded to HSCT (Table 2). Of the 5 patients who had received prior blinatumomab , 4 achieved CR. Of 110 patients treated with blinatumomab, median OS (95% CI) was 14.6 (11-24.5) months with median follow-up time of 18.2 months, which increased by 1.5 months compared with that reported in the primary analysis, with 29.9% of patients still surviving at month 24. Median RFS (95% CI) remains unchanged at 8.5 months (4.7-14.0), with a median follow-up time of 11.5 months in patients who achieved CR; 38% of patients relapsed and 9% died. RFS was more favorable for patients who received HSCT post blinatumomab (70%) than for those who did not (30%) at month 12, respectively, which is consistent with the results from primary analysis. Among patients who had HSCT prior to blinatumomab (n= 45), median OS (95%) was 16.6 (7.1-NE) months vs 14.6 (10.9-24.5) months in patients without HSCT prior to blinatumomab (n= 65). Compared with the primary analysis, 5 additional patients received HSCT after achieving CR in the final analysis. Median OS among patients in CR after HSCT by MRD responders vs MRD non-responders was NE at 15-month analysis (Figure). Safety results in the final analysis were consistent with those reported in the primary analysis. Of 110 patients, 99% experienced TEAEs, with 65% being grade ≥3 (see Table 3 for details). TRAEs were reported in 74% of patients; 26% were grade ≥3 and 19% were deemed serious. Details on grade ≥3 TRAEs are shown in Table 3. The 9 fatal AEs, unrelated to blinatumomab, occurred due to relapse and progressive nature of the disease (Table 3). Conclusions: Overall, the safety and efficacy results from the final analysis are consistent with those reported in the primary analysis as no new safety signals were observed. These findings strengthen the observation that blinatumomab demonstrates durable efficacy and is a suitable treatment option in children with R/R BCP-ALL. Table 1. Disclosures Locatelli: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceeutical: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zugmaier:Amgen: Current Employment, Other: Personal Fees ; 20190300609: Patents & Royalties: Licensed patient . Mergen:Amgen: Current Employment, Current equity holder in publicly-traded company. Bader:Medac: Patents & Royalties, Research Funding; Amgen: Consultancy, Speakers Bureau; Neovii: Research Funding; Celgene: Consultancy; Novartis: Consultancy, Speakers Bureau; Riemser: Research Funding. Schlegel:bluebird bio: Honoraria. Bourquin:Servier: Other: Travel Support. Handgretinger:Amgen: Honoraria. Brethon:Amgen: Other: invitation to meetings, remunerations for oral presentations, advices for the record of Blinatumomab in pediatrics in France. Rössig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Pfizer: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Kormany:Amgen: Current Employment, Current equity holder in publicly-traded company. Viswagnachar:IQVIA: Current Employment.

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Progression-Free Survival Outcomes By Response Status for Bortezomib, Melphalan, and Prednisone with or without Daratumumab in Newly Diagnosed Multiple Myeloma: Pooled Subgroup Analysis of Octans and Alcyone

Blood ◽

10.1182/blood-2021-148937 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1648-1648

Author(s):

Jianxiang Wang ◽

Weijun Fu ◽

Soo-Mee Bang ◽

Honghui Huang ◽

Kihyun Kim ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Publicly Traded ◽

Primary Analysis ◽

Advisory Committees ◽

Once Daily ◽

Free Survival ◽

Asian Patients

Abstract Introduction: Daratumumab is a human IgGκ monoclonal antibody that targets CD38 with a direct on-tumor and immunomodulatory mechanism of action. In the primary analysis (median follow-up, 16.5 months) of the global phase 3 ALCYONE trial, daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) significantly improved progression-free survival (PFS) versus VMP alone in patients with newly diagnosed multiple myeloma (NDMM) who were ineligible for transplant (median PFS, not reached vs 18.1 months; hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.38-0.65; P<0.001). In the primary analysis (median follow-up, 12.3 months) of the phase 3 OCTANS trial, D-VMP significantly prolonged PFS versus VMP in transplant-ineligible Asian patients with NDMM (median PFS, not reached vs 18.2 months; HR, 0.43; 95% CI, 0.24-0.77; P=0.0033). Here, we present a pooled subgroup analysis of PFS stratified by best response in Asian and global patients from the OCTANS and ALCYONE studies, respectively. Methods: Eligible patients in OCTANS and ALCYONE were ≥18 years of age, were diagnosed with NDMM, and were not eligible for autologous stem cell transplant due to age (≥65 years) or comorbidities. All patients received up to 9 cycles (42-days) of bortezomib (1.3 mg/m 2; subcutaneous) twice weekly on Weeks 1, 2, 4, and 5 of Cycle 1 and once weekly on Weeks 1, 2, 4, and 5 of Cycles 2 to 9; melphalan (9 mg/m 2; oral) once daily on Days 1 to 4 of each cycle; prednisone (60 mg/m 2; oral) once daily on Days 1 to 4 of each cycle. For patients in the D-VMP group, daratumumab (16 mg/kg, intravenous) was administered once weekly in Cycle 1, once every 3 weeks in Cycles 2 to 9, and once every 4 weeks thereafter until disease progression or unacceptable toxicity. Response over time (at 6, 12, 18, 24, 54 weeks) and disease progression were assessed by a validated computer algorithm in accordance with the IMWG criteria. Minimal residual disease (MRD) negativity (10 -5) was assessed by multi-parameter flow cytometry in OCTANS and by next-generation sequencing in ALCYONE. Results: In the OCTANS study, 220 Asian patients were randomized (D-VMP, n=146; VMP, n=74); in the ALCYONE study, 706 global patients were randomized (D-VMP, n=350; VMP, n=356). Median age in OCTANS was 69 (range, 57-84) years and 71 (range 40-93) years in ALCYONE. Patients were pooled from both studies (D-VMP, n=496; VMP, n=430). D-VMP increased the rate of complete response or better (≥CR; 10.2% vs 5.6%) and the rate of very good partial response or better (≥VGPR; 58.5% vs 38.1%) versus VMP after 18 weeks of treatment (Figure A). Responses deepened over time among patients in both the D-VMP and VMP groups, as shown by the ≥CR rate (D-VMP, 38.8%; VMP, 21.6%) and the ≥VGPR rate (D-VMP, 74.0%; VMP, 50.7%) at 54 weeks. At a median follow-up of 12.3 months for OCTANS and 16.5 months for ALCYONE, among patients who achieved a VGPR (D-VMP: n=145 [29.2%]; VMP: n=109 [25.3%]), the median PFS was not reached in the D-VMP group versus 19.9 months in the VMP group (HR, 0.61; 95% CI, 0.36-1.00; P=0.0499; Figure B). All patients who achieved ≥CR with or without MRD negativity (10 -5) demonstrated prolonged PFS, regardless of treatment (≥CR: HR, 1.54; 95% CI, 0.65-3.65; P=0.3210; ≥CR+MRD negativity: HR, 0.67; 95% CI, 0.13-3.40; P=0.6225; Figure B); however, more patients treated with D-VMP achieved this level of response (≥CR: D-VMP , n=212 [42.7%]; VMP, n=100 [23.3%]; ≥CR+MRD negativity: D-VMP, n=116 [23.4%]; VMP, n=27 [6.3%]; Figure B). Conclusion: In a pooled analysis of OCTANS and ALCYONE, more patients with transplant-ineligible NDMM achieved deeper responses with D-VMP versus VMP. More patients treated with D-VMP achieved ≥CR with or without MRD negativity compared with those treated with VMP alone, leading to prolonged PFS regardless of treatment. These results support the use of daratumumab in addition to VMP in transplant-ineligible Asian patients with NDMM. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding. Kim: BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Li: Suzhou Zelgen Biopharmaceuticals Co.,Ltd.: Honoraria. Chim: Janssen, Takeda & Amgen: Other: received sponsorship for overseas meetings. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria; Clínica Universidad de Navarra: Current Employment. Liberati: abbvie, amgen, archigen, beigene, BMS, celgene, DR REDDY'S LABORATORIES SPA, fibrogen, glaxo, Janssen, Karyopharm, Morphosys, Novartis, Onconova, Oncopeptides ab, Roche, Sanophi, Secura Bio, Takeda, Verastem,: Research Funding. Takamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; SRL: Consultancy; Adaptive Biotechnologies, Eisai: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Dimopoulos: BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Wroblewski: Janssen: Current Employment, Current equity holder in publicly-traded company. Carson: Janssen: Current Employment. Qi: Janssen: Current Employment, Current equity holder in publicly-traded company. Wang: Janssen: Current Employment. Song: Janssen: Current Employment. Jia: Janssen: Current Employment. Yang: Janssen: Current Employment, Current equity holder in publicly-traded company. Liu: Janssen: Ended employment in the past 24 months. Li: Janssen: Current Employment. Zhang: Janssen: Current Employment.

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Evolving Unmet Need in Patients Refractory to Lenalidomide: Overview of the Clinical Trials in Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2020-142642 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 22-23

Author(s):

Maria-Victoria Mateos ◽

Rohan Medhekar ◽

Istvan Majer ◽

Mehmet Turgut

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Literature Review ◽

Board Of Directors ◽

Unmet Need ◽

Publicly Traded ◽

First Line ◽

Advisory Committees ◽

Line Of Therapy

Introduction: The majority of newly diagnosed multiple myeloma (NDMM) patients are currently treated with lenalidomide-based regimens as their first line of therapy. This trend is likely to continue in the coming years. Typically, lenalidomide is administered until disease progression and has significantly contributed to better outcomes in these patients. However, most patients relapse, and prognosis worsens with each relapse. The choice of optimal treatment for patients who relapse while receiving lenalidomide as first line of therapy is unclear. Moreau et al (Blood Cancer J. 9, 38 [2019]) concluded that there is limited data on approved combinations for treating these patients and are restricted by the low number of lenalidomide-refractory patients enrolled in the pivotal trials. Results from the ongoing clinical trials of the combination of carfilzomib and anti-CD38 antibodies were not available at the time of the Moreau et al publication. The aim of this targeted literature review was to include this new data and to summarize currently available evidence on progression-free survival (PFS) for the treatment of RRMM patients who progressed on lenalidomide-based regimens. Methods: A targeted literature review was conducted to identify registrational clinical trials in patients with RRMM reporting PFS outcomes. PubMed, congress proceedings, and product labels were searched between Jan 2014 to July 2020. In addition to PFS, demographic, disease characteristics and treatment history were extracted for the trial populations to contextualize potential variations in study outcomes. The regimens studied in these trials were classified as lenalidomide-based, proteasome inhibitor (PI)-based and pomalidomide-based. Number of prior lines of therapy, prior exposure and refractoriness to lenalidomide and bortezomib were reported. Results: Twelve registrational trials were identified based on the search criteria (Table 1). Most pivotal trials assessing lenalidomide-based regimens (POLLUX, ELOQUENT-II, TOURMALINE-MM1) except the ASPIRE trial excluded patients who were refractory to lenalidomide. Trials evaluating PI-based regimens (e.g., CANDOR) or pomalidomide-based regimens (e.g., OPTIMISMM) included these patients, with more recent studies enrolling a larger proportion. Percentage of lenalidomide-exposed (and lenalidomide refractory) ranged from 40% (32%) in CANDOR to 98% (90%) in ELOQUENT III. These studies also enrolled a larger proportion of patients who were bortezomib-exposed, although most of these patients were at first relapse, with the exception of ELOQUENT III and ICARIA where most patients were at third relapse. Among lenalidomide-refractory patients, the median-PFS (mPFS) observed for the pomalidomide-based regimens ranged from 9.5 to 10.1 months and that observed for PI-based regimens ranged from 4.9 to 25.7 months. PFS in the lenalidomide-refractory subgroup was considerably shorter than in the ITT population. The mPFS for patients receiving carfilzomib/daratumumab/dexamethasone (KDd; CANDOR) and isatuximab/carfilzomib/dexamethasone (IsaKd; IKEMA) was not reached at median follow-up of 16.9 and 20.7 months respectively. While the mPFS for (KDd) for lenalidomide-refractory patients in CANDOR trial was not yet reached at median follow up of 16.9 months; the mPFS of 25.7 months for KDd in the MMY-1001 trial appears to be the longest among the assessed regimens. Conclusion: Patients refractory to lenalidomide have shorter PFS and represent a population with high unmet need. This targeted literature review suggests that the PI-based KDd regimen provides longer PFS compared to other lenalidomide-sparing regimens in lenalidomide-refractory populations. Heterogeneity across trial populations may limit the comparability of these treatments. Disclosures Mateos: Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; GlaxoSmithKline: Consultancy. Medhekar:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Majer:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company.

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Final Analysis of a Randomized Comparison of ABVD Chemotherapy with a Strategy That Includes Radiation Therapy (RT) in Patients with Limited-Stage Hodgkin Lymphoma (HL): NCIC CTG/ECOG HD.6

Blood ◽

10.1182/blood.v118.21.590.590 ◽

2011 ◽

Vol 118 (21) ◽

pp. 590-590 ◽

Cited By ~ 1

Author(s):

Ralph M. Meyer ◽

Mary Gospodarowicz ◽

Joseph M. Connors ◽

Robert G Pearcey ◽

Woodrow A Wells ◽

...

Keyword(s):

High Risk ◽

Disease Progression ◽

Board Of Directors ◽

Final Analysis ◽

Primary Analysis ◽

Advisory Committees ◽

Limited Stage ◽

Risk Patients ◽

Single Modality

Abstract Abstract 590FN2 Background: The NCIC CTG / ECOG HD.6 trial is based on the hypothesis that for patients with limited-stage HL, treatment with single-modality ABVD provides comparable disease control, is associated with a reduced incidence of deaths due to late treatment effects and thus might improve long-term survival in comparison with treatment that includes extended-field RT. In this randomized controlled phase III trial, our primary objective was to compare the 12-yr overall survivals (OS) of limited-stage HL patients treated with ABVD alone with those receiving therapy that includes RT. Secondary outcomes include freedom from disease progression (FFDP), in which those dying prior to disease progression are censored, and event-free survival (EFS), in which the first of disease progression or death is considered an event. In 2005, we published 5-yr outcomes (median follow-up 4.2 yrs [Meyer, J Clin Oncol]). We now report results of the final analysis. Methods: Eligible patients had non-bulky clinical stage I-IIA HL; patients with subdiaphragmatic disease were eligible if disease was confined to the iliac, inguinal and/or femoral regions. Prior to randomization, patients were stratified into low and high-risk categories; low-risk patients had all of lymphocyte predominant or nodular sclerosis histology, age < 40 yrs, ESR < 50, and involvement of 3 or fewer disease-site regions; all others were high-risk. Patients randomized to therapy that includes RT received single-modality subtotal nodal irradiation (STNI) if low-risk and combined-modality ABVD (2 cycles) plus STNI if high-risk. All patients randomized to the experimental arm received single-modality ABVD (4 cycles); those not demonstrating a complete remission with restaging after 2 cycles received 6 cycles. Between March 1994 and April 2002, 405 patients were entered; 399 were eligible and included in the primary analysis (modified intent–to-treat [ITT]). The clinical cut-off date for follow-up was 2010/DEC/31 and the database was locked on 2011/JUL/15. All P-values are 2-sided. Results: The median duration of follow-up is 11.3 yrs. The OS was superior in patients randomized to ABVD (P=.04; HR=0.5; 12-yr estimates 94% vs. 87%). In comparison with patients randomized to therapy that includes RT, FFDP trended to being inferior in patients randomized to ABVD (P=.07; HR=1.82; 12-yr estimates 88% vs. 92%); no differences in EFS were detected (P=.5; HR=0.87; 12-yr estimates 86% vs. 80%). Sensitivity analyses included a true ITT evaluating all randomized patients and adding data obtained between the clinical cut-off and data-lock dates; results were robust and yielded similar findings. Causes of death in ABVD vs. RT-arm patients (N = 12 vs. 24) included HL or early treatment complication (6 vs. 4), second cancers (4 vs. 9), and other (2 vs. 11). Analysis of high-risk patients allocated to ABVD (N=137) vs. ABVD+STNI (N=139) showed similar respective results to the primary analysis: in comparison with those randomized to RT, OS was superior in the ABVD arm (12-yr estimates 92% vs. 81%; HR=.47; P=.04), FFDP was inferior (12-yr estimates 87% vs. 94%; HR=3.03; P=.01) and no differences in EFS were detected (12-yr estimates 84% vs. 78%; HR=.87; P=.6). Late-effects trended to being less frequent in ABVD patients, including second cancers (6.1% vs. 10.8%) and cardiac events (9.7% vs. 14.8%). Conclusions: We conclude that in patients with limited-stage HL, ABVD improves OS as compared with treatment that includes STNI, including combined modality therapy, because it is associated with fewer deaths from causes other than HL. The HD.6 trial hypothesis was thus confirmed. With respect to modern RT approaches, the implications of our results are: i) at 12 years, 88% of patients are disease-free and more than 90% are alive when initially treated with ABVD alone; ii) limitations exist in using FFDP as a proxy measure for OS when late treatment effects may occur; and, iii) when treatment strategies have competing risks, long-term follow-up provides crucial insights into the interpretations of best therapy. Disclosures: Connors: Seattle Genetics: Consultancy, Research Funding. Horning:Genentech: Employment, Equity Ownership. Crump:Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Johnson & Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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.

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Real-World Outcomes for Standard-of-Care Treatments in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2021-146250 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4075-4075

Author(s):

Michel Delforge ◽

Marie-Christiane Vekemans ◽

Sébastien Anguille ◽

Julien Depaus ◽

Nathalie Meuleman ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Retrospective Chart Review ◽

Standard Of Care ◽

Real World Data ◽

Advisory Committees ◽

Treatment Regimens

Abstract Background: With the advent of immunomodulatory agents (IMiDs), proteasome inhibitors (PIs) and, more recently, anti-CD38 monoclonal antibodies (mAbs), prognosis of patients with multiple myeloma (MM) has improved considerably. Unfortunately, even with these 3 major MM drug classes, most patients ultimately relapse and require further therapy. There remains an incomplete understanding of how patients who have received extensive therapy and with relapsed/refractory multiple myeloma (RRMM) are treated in routine clinical practice, as no standard-of-care exists for these patients, and what the outcomes are in this real-world setting. Objective: This study aims to evaluate the outcomes of patients with triple-class (IMiD, PI and anti-CD38 mAb) and triple-line exposed RRMM using real-world data from patients in Belgium. Methods: A multicenter, observational study, involving 7 non-academic and academic Belgian centers, was conducted based on a retrospective chart review of adult RRMM patients who started subsequent treatment from March 2017 through May 2021 after having received ≥3 lines of therapy including at least an IMiD, a PI, and anti-CD38-directed therapy (tri-exposed). Data were captured in an electronic case report form (Castor EDC). Patients with an ECOG performance status of ≥2, who received prior CAR-T treatment or prior BCMA-targeted therapy, or with a known active or prior history of CNS involvement (or with clinical signs thereof), were excluded. All treatment lines initiated after becoming eligible were used in the analysis. Specifically, all treatment lines for patients meeting the eligibility criteria more than once in their entire follow-up were included as separate observations, with date of treatment initiation as specific baseline for each treatment line. Cox proportional hazards models were fitted to explore the prognostic value with Overall Survival (OS), Progression Free Survival (PFS), and Time to Next Therapy (TTNT). Results: A total of 112 patients with 237 eligible treatment lines were included in the analysis; median follow-up was 16.6 months. In 45% of the initiated treatment lines, patients were refractory to 4 or 5 therapies, 62% had received ≥5 prior lines, 22% had extramedullary disease and in 48% of observations the time to progression in prior line was shorter than 4 months. After patients became tri-exposed, more than 50 unique treatment regimens were initiated, with the following being the most common: carfilzomib + dexamethasone (14%), pomalidomide + dexamethasone + chemotherapy (8%), and ixazomib + lenalidomide + dexamethasone (6%). Additionally, 4% of included observations were exposed to anti-BCMA agents. Overall, the following treatment classes were the most frequently started: PI only (19%), PI + IMiD combinations (17%), and regimens including anti-CD38 antibodies (15%). Median OS was 9.79 months [95% CI: 7.79; 12.22], median PFS was 3.42 months [95% CI: 2.79; 4.27], median TTNT was 3.61 months [95% CI: 3.09; 4.57]. Higher refractory status (p<0.001), being male (p=0.001), older age (p<0.001), shorter duration of prior lines (p<0.001), shorter time to progression in prior line (p=0.025), and higher LDH levels (p<0.002) were prognostic for worse outcomes for both OS (Figure 1) and PFS. Conclusions: This retrospective chart review of patients with tri-exposed RRMM in Belgium shows that real-world outcomes in terms of OS, PFS and TTNT are poor for these patients, with a median OS of <10 months. A wide variety of treatment regimens used in clinical practice confirm the absence of a clear standard-of-care in this patient population. The literature also confirms that these poor outcomes observed in Belgium, for this subset of MM patients, are similar in other countries. These real-world data highlight the high unmet medical need in this patient population and critical need for new and effective treatment options. MD and MCV contributed equally to this work. Figure 1 Figure 1. Disclosures Delforge: Amgen, Celgene, Janssen, Sanofi: Honoraria, Research Funding. Vekemans: Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceutica: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Depaus: Takeda: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy. Meuleman: iTeos Therapeutics: Consultancy. Strens: Realidad bvba: Consultancy. Van Hoorenbeeck: Janssen: Current Employment. Moorkens: Janssen-Cilag: Current Employment. Diels: Janssen: Current Employment. Ghilotti: Janssen-Cilag SpA, Cologno Monzese, Italy: Current Employment. Dalhuisen: Janssen: Current Employment. Vandervennet: Janssen: Current Employment.

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Surveillance Program of Romiplostim Use Connected to Pregnancy

Blood ◽

10.1182/blood-2021-150314 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 585-585

Author(s):

James B Bussel ◽

Nichola Cooper ◽

Tatiana Lawrence ◽

Marc Michel ◽

Emilie Vander Haar ◽

...

Keyword(s):

Platelet Count ◽

Ectopic Pregnancy ◽

Board Of Directors ◽

Birth Outcomes ◽

Pregnancy Outcomes ◽

Surveillance Program ◽

Publicly Traded ◽

Advisory Committees ◽

Elective Termination

Abstract Introduction Immune thrombocytopenia (ITP), defined as an isolated low platelet count (<100 × 10 9/L), occurs in approximately 1 in 1000 to 10,000 pregnancies in the United States and is the most common cause of severe thrombocytopenia (platelet count <50 × 10 9/L) detected in the first and second trimesters. Treatment for ITP during pregnancy is limited by the lack of safety evidence for the fetus/infant. The Pregnancy Surveillance Program (PSP) was conducted to collect safety information on pregnancy and fetal outcomes of women exposed to the thrombopoietin receptor agonist romiplostim before conception, during pregnancy, or immediately postpartum. Here, we report pregnancy and birth outcomes as well as adverse events (AEs) for mother and fetus/infant. Methods Pregnancy outcomes data from women of 25 different countries were collected from August 1, 2017-March 15, 2020. Authorization to obtain pregnancy and infant health information as well as follow up with healthcare professionals was obtained from the mothers. One follow-up attempt was made if the mother was unresponsive, and two follow-up attempts were made 6-8 weeks after the mother's estimated date of delivery. Additional follow-ups were conducted when the infant was 6 and 12 months of age. Romiplostim pregnancy exposure cases reported during the data-collection period were entered into the PSP database and reported to global health authorities per local rules and regulations. Abnormal pregnancies were defined as those with at least one serious AE. Birth outcomes included live birth, premature birth, spontaneous abortion, elective termination, and stillbirth. Results Overall, 200 pregnancies were reported, including 11 pregnancies from clinical study sources, and 189 pregnancies from non-trial sources; 188 women were exposed to romiplostim. Two pregnancies were ongoing at the time of data cutoff (March 15, 2020). The median (Q1, Q3) overall duration of romiplostim exposure was 156 (44, 522) days (data available for 56 women), and 28 (7, 60) days during pregnancy (data available for 53 women). Median (Q1, Q3) age for the pregnant women was 30 (27, 33) years. Concomitant medications for ITP were used by 61 (32%) women and included corticosteroids (n=37), immunoglobulins (n=29), and rituximab (n=8). Overall, 43 (23%) women received treatment with romiplostim in the third trimester with median (Q1, Q3) exposure of 21 (7, 63) days. Of the 86 known pregnancy outcomes by trimester exposure (Figure 1), 40 (46.5%) were normal pregnancies with 15% abnormal birth outcomes, and 46 (53.5%) were abnormal pregnancies with 65.2% abnormal birth outcomes; 26 (56.5%) of the abnormal pregnancies were low platelet counts. Three cases of ectopic pregnancy were reported among women receiving romiplostim for ITP prior to conception. In all three women, romiplostim was continued up to, during, and after the ectopic pregnancy. One molar pregnancy was reported in a woman who received romiplostim for chronic ITP for approximately one year before conception. Of the 96 known birth outcomes, 57.3% were normal term, 11.5% were spontaneous abortion, 9.4% were term with complication (inguinal hernia, congenital cytomegalovirus infection, trisomy 8, and single umbilical artery), 9.4% were elective termination, and 12.4% were other outcomes (including 11 premature births, and one stillbirth). Twelve infants (including one case of twins) had thrombocytopenia at birth, of whom nine received immunoglobulins, and three received platelet transfusions. Out of the 12 infants, eight had resolution of thrombocytopenia within a week, and four (including the twins) had no available information about outcomes. No infant had defective immune system development, neoplasm, or bone marrow reticulin formation. One infant was diagnosed with fetal and neonatal alloimmune thrombocytopenia that resolved two months after birth. Among the 12 thrombocytopenic infants, six had good and six had unknown current/discharge health status. Conclusions The available data from the PSP suggested that the risk of adverse birth outcomes was low regardless of the timing of exposure. Additionally, no substantial safety concerns were identified for the mothers, fetuses, and infants due to romiplostim use during pregnancy. The results are complicated, however, by the abnormal pregnancies in women with severe ITP who comprised the majority of cases where romiplostim was used. Figure 1 Figure 1. Disclosures Bussel: UCB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Dova/Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Other: DSMB; Principia/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Momenta/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; UptoDate: Honoraria; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; RallyBio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cooper: Principia and Sanofi: Consultancy; Sanofi and Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations expenses. Lawrence: Amgen Inc: Current Employment, Current equity holder in publicly-traded company. Michel: Amgen: Consultancy; Rigel: Honoraria; Novartis: Consultancy; Argenx: Honoraria; UCB: Honoraria; Alexion: Honoraria. Wang: Amgen Inc: Current Employment, Current equity holder in publicly-traded company. Saad: Amgen: Current Employment, Current equity holder in publicly-traded company.

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

Blood ◽

10.1182/blood-2019-128815 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2893-2893

Author(s):

Emily C. Ayers ◽

David J Margolis ◽

Phyllis A. Gimotty ◽

Daniel J. Landsburg

Keyword(s):

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Standard Of Care ◽

Current Therapy ◽

High Dose ◽

Cell Of Origin ◽

Advisory Committees ◽

Ecog Ps

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

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Vascular and Parenchymal Alterations of the Liver and Liver Surveillance in Patients Who Received Inotuzumab Ozogamicin As the Standard of Care for Relapse/Refractory Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2019-130632 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1343-1343

Author(s):

Giovanni Marconi ◽

Federico Ravaioli ◽

Giovanni Martinelli ◽

Elton Dajti ◽

Maria Chiara Abbenante ◽

...

Keyword(s):

Portal Hypertension ◽

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Lymphoblastic Leukemia ◽

Monitoring Program ◽

Liver Stiffness ◽

Standard Of Care ◽

Advisory Committees ◽

Hematopoietic Stem

Rationale: Inotuzumab ozagomicin (IO) has been linked to an increased incidence of veno-occlusive disease (VOD) and liver alterations. Most VOD events occurred during hematopoietic stem cell (HSCT) transplantation after IO therapy. We have previously described that the measurement of liver stiffness can anticipate the diagnosis of VOD in the context of HSCT. The mechanisms underlying the increased risk of VOD and liver damage in patients receiving IO are not well understood; in the pathogenesis endothelial damage, ozagomicin release and on-target off-tumor effects may be involved. Here, we aimed to assess the effects of IO on the changes of liver, vascular and biochemistry parameters. Methods: Intensive monitoring of the liver was incorporated into the standard of care of patients who received IO for relapsed or refractory (R / R) acute lymphoblastic leukemia (ALL). Upper abdomen ultrasound with Doppler was performed at baseline and at the end of therapy; liver stiffness measurement (LSM) by Fibroscan® (Echosens, Paris, France) at every IO course or at every IO infusion. With the exception of ursodeoxycholic acid, the patients did not receive prophylaxis for VOD. Data was collected after anonymous aggregation, in accordance with GCP and Helsinki declaration. Results are reported as median with interquartile ranges (IQR). Results: At data cut-off, 1st Apr 2019, 16 patient received baseline assessment and at least a post-IO assessment in our monitoring program. In our patent set, median age was 44.5 (IQR 30.7 - 64.0); 12/16 (75 %) patients relapsed after the last treatment and 4/16 (25 %) patients were refractory to the last treatment; patients received a median of 3 (IQR 2 - 3.7) lines before IO; 6/16 (37.5 %) patients undergone HSCT before IO, of which a patient had 1st and 2nd HSCT before IO; 5/16 (31.25 %) undergone HSCT after IO therapy (no patients had second HSCT after IO). Patients received a median of 2 (IQR 2.0 - 3.7) IO administration according to the schedule of the phase 3 trial. The median duration of the therapy was 61.5 days (IQR 43.2 - 114.0) and median progression-free survival in our population was 278.0 days (95% C.I. 264.0 - 292.0). In our patient set, we performed 113 biochemistry determination, 30 liver ultrasounds with Doppler and 116 LSM examination. One patient received a liver biopsy. Among the biochemical exams (AST, ALT, GGT and alkaline phosphatase) only the AST values significantly increased after 1st course of IO (from the median value of 21 U/L to 53 U/L after course 3). Liver ultrasound with Doppler revealed portal hypertension signs in half of the patients during IO monitoring program. Among these patients 7/16 (44%), 3/16 (17%), 5/16 (33.3%) and 3/16 (17%) showed splenomegaly, recanalization of the paraumbilical vein, dilatation of portal vein and ascites, respectively. Median LSM significantly increased from a baseline value of 6 kPa to 7.8 kPa after last post-IO assessment (p-value<0.01). The median increase of LSM values on the baseline after course 1 of IO was 3.3% (0%- 4.9%), after course 2 was 38.3% (26.4% - 45.2%) after course 3 was 43.3% (35.4% - 48.6%) and after course 4 was 56.7 (45.8% - 60.1%), see figure. Eight of the 16 patients (50%) showed an increase in LSM with values comparable to fibrosis higher than 2 (> 7.1 kPa). With a median follow up of 387.5 days (IQR 182.8-524.5) we observed one VOD event (7%); the VOD was graded severe and occurred after HSCT post-IO. Conclusions: Our clinical experience represents the first step to better understand the IO-related liver alterations, as we described the frequency and relevance of quantitative markers. Most of the patients in our set developed ultrasound and/or elastography alteration during IO therapy. Furthermore, these alterations do not seem to correlate with biochemistry. Even if most of the patients had sub-clinical vascular and parenchymal alterations of the liver portal-hypertension related, VOD incidence in our set is comparable with literature. Long-term follow-up results are expected to test whether alterations return or evolve over time. Stratifying the tailored risk liver complications with prospective non-invasive and marker-driven strategies in term of IO dosing and HSCT timing could be a great benefit for patients. * FR and GM contributed to this manuscript equally # AC and CP contributed to this manuscript equally Figure Disclosures Martinelli: Roche: Consultancy; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy. Cavo:janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau. Papayannidis:Amgen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Shire: Honoraria.

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Long-Term Follow-up Study after Lentiviral Hematopoietic Stem/Progenitor Cell Gene Therapy for Wiskott - Aldrich Syndrome

Blood ◽

10.1182/blood-2021-147697 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2934-2934

Author(s):

Alessandra Magnani ◽

Michaela Semeraro ◽

Frédéric ADAM ◽

Claire Booth ◽

Loic Dupre ◽

...

Keyword(s):

Gene Therapy ◽

T Cell ◽

Board Of Directors ◽

Publicly Traded ◽

Cell Compartment ◽

Advisory Committees ◽

Partial Correction ◽

Over Time

Abstract Wiskott Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency associated with thrombocytopenia, eczema, infectious, autoimmune complications, and lymphomas. Patients lacking an HLA-matched donor may benefit from an alternative therapeutic approach based on the infusion of autologous gene corrected CD34+ cells. We previously reported a non-randomised, open-label, phase 1/2 clinical study applying a lentiviral vector based gene therapy (GT) protocol in 7 paediatric patients with severe WAS (score ≥ 3/5) (S. Hacein-Bey Abina et al, JAMA 2015). One patient died 7 months after GT because of pre-existing severe opportunistic infections, as reported. Two additional patients have been treated since that initial report, with a follow-up of at least 4 years. We here present a comprehensive long-term study on 8 patients with a follow-up from 4 to 9 years (median 7.6). The safety and efficacy of the approach is thoroughly investigated, with a particular focus on the correction of thrombocytopenia and auto-immunity. A stable engraftment of genetically and functionally corrected lymphoid and myeloid cells was reached in all patients, with no serious treatment-associated adverse events or concerning clonal expansion. Corrected lymphoid cells displayed a selective advantage over time with increasing vector copy number (VCN) level. In turn, this led to (i) sustained expression of WAS protein (WASp) in the patients' cells and (ii) clinical resolution of severe eczema and susceptibility to recurrent infections. In line with these results, T-cell function was restored after GT, as shown by the recovery of immune synapse assembly and the normalization of naïve T cell numbers. The T-cell compartment was also reconstituted in the patient treated at the age of 30 years, suggesting that GT for WAS is a treatment option in adult patients. In parallel with the robustness of T-cell reconstitution a normalized B-cell compartment was observed after GT, as shown in particular by increasing levels of WASp + switched memory B cells over time and the age-matched levels of KRECs. Five patients out of 8 were able to discontinue Ig replacement therapy while achieving normal post-vaccination antibody titers. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. After GT, a few autoimmune manifestations were observed: the persistence of lower extremity vasculitis (P2, very severe prior to GT), the new occurrence of nephrotic syndrome (P9), and the presence of anti-platelet antibodies (P2, P4, P7). The levels of circulating autoantibodies detected before GT (including ANA and vasculitis-related autoantibodies) normalized after treatment. Following GT, platelets were found to express sub-normal levels of WASp and to only partially augment their size. Platelet function studies indicated a partial correction of the platelet compartment achieved by GT, which may be sufficient to prevent occurrence of the hemorrhagic symptoms typical of WAS. Our results suggest that lentiviral GT provides sustained clinical benefits for patients with WAS. Overall clinical remission was observed in our patients despite very severe disease scores before GT. More efficacious and more reliable transduction protocols and conditioning regimen are likely to further improve outcomes, particularly with regard to platelet recovery, where the advantages of intrinsic correction are less apparent. Disclosures Booth: Orchard Therapeutics: Consultancy, Honoraria; SOBI: Consultancy, Honoraria; Takeda: Honoraria; GSK: Honoraria; Rocket Pharmaceuticals, Inc.: Consultancy. Thrasher: Orchard Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavazzana: Smart Immune: Other: co-founder.

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