Immune Reconstitution and Long-Term Outcomes Following Allo-HCT with TLI-ATG and Post-Transplant Rituximab

Post-transplant, prophylactic rituximab has been associated with low incidence of chronic graft-versus host disease (cGVHD) by significantly reducing B-cell allogeneic immunity. However, the long-term effects of B-cell depletion on immune reconstitution and the long-term overall survival (OS) and incidence of cGVHD remain unknown. We describe 35 patients with mantle cell lymphoma (MCL; n = 13) or high-risk chronic lymphocytic leukemia (CLL; n = 22) treated with allogeneic hematopoietic cell transplantation (HCT) with total lymphocyte irradiation/anti-thymocyte globumin (TLI-ATG) conditioning and prophylactic rituximab. The median follow up time was 9.9 years. As a comparison group, we analyzed 43 patients of various histologies transplanted during the same time period who received TLI-ATG conditioning but no prophylactic rituximab. Overall survival and progression-free survival (PFS) at 8 years for CLL were 54.5% and 22.7%, respectively; for MCL patients 8-year OS and PFS were 53.8% and 23.1%, respectively. The 8-year cumulative incidence of cGHVD and freedom from immunosuppression for all patients treated with prophylactic rituximab were 22.8% and 65.7%, respectively, compared to 34.9% and 48.8% for the comparison group. To assess B-cell alloimmunity, we examined formation of antibodies targeting Y-chromosome encoded protein (HY Abs) in male patients receiving grafts from female donors (F à M). At 3 years post-HCT, 20% of F à M patients receiving rituximab had formed HY Abs compared to 78% of F à M patients in the comparison group (p = 0.04). At 10 year follow up, only 33% of F à M patients who received rituximab had formed HY Abs. B-cell alloimmunity was also assessed by development of antibodies to common infectious antigens. At 3 years post-HCT, patients who received rituximab had significantly lower tetanus (3.29 vs 3.74 fold, p = .017) and EBV (3.36 vs 3.76 fold; p = 0.045) titers than patients who did not. At 10-year follow up, tetanus and EBV titers patients who received rituximab had not significantly changed. Importantly, patients who received prophylactic rituximab had significantly lower IgG levels at both 3 years (498 vs 843 mg/dL, p = 0.009) and 5 years (357 vs 724 mg/dL, p = 0.041) post-HCT. For patients receiving prophylactic rituximab, at 10 years post-transplant, the median IgG was 603, and 20% of patients had IgG < 400 mg/dL. More patients receiving rituximab required intravenous immunoglobulin (IVIG) supplementation than patients not receiving rituximab (62.9% vs 32.6%, p = 0.01). Of the patients who required IVIG, patients receiving rituximab did so for a longer amount of time (median duration of use 3.9 vs 0.6 years, p = 0.002). Despite decreased IgG levels, use of rituximab was not associated with a significant increase in hospitalizations for infectious etiologies or febrile neutropenia. Rituximab treatment after allogeneic transplantation provides significantly decreased incidence of chronic GVHD and reduction in B cell alloimmunity, but associates with prolonged hypogammaglobulinemia without increased infection risk. Figure Disclosures Miklos: Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees.

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Final Overall Survival Results of a Randomized Trial Comparing Bortezomib Plus Pegylated Liposomal Doxorubicin with Bortezomib Alone in Subjects with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.3448.3448 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3448-3448

Author(s):

Robert Z. Orlowski ◽

Arnon Nagler ◽

Pieter Sonneveld ◽

Joan Bladé ◽

Roman Hajek ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Pharmaceutical Research ◽

Phase Iii ◽

Advisory Committees ◽

Grant Support ◽

Johnson Pharmaceutical Research

Abstract Introduction Previous results of an open-label, randomized, controlled, multicenter phase III study (DOXIL-MMY-3001) demonstrated that bortezomib+pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in treating subjects with relapsed or refractory multiple myeloma (MM) whose disease had failed one or more lines of prior therapy. The risk of developing disease progression was significantly reduced by 45% with bortezomib+PLD (median time to progression (TTP) with bortezomib+PLD: 9.3 months, bortezomib: 6.5 months; HR=1.82, 95% confidence interval (CI) [1.41, 2.35]; p=0.000004). In the interim analysis, the 15-month overall survival (OS) rate for bortezomib+PLD was 76% (95% CI [70%, 83%]) compared with 65% (95% CI [58%, 73%]) for bortezomib alone (p=0.03)(Orlowski et al JCO 25: 3892-3901, 2007). A protocol-defined analysis of the final survival data of this study is provided here. Methods Subjects with confirmed MM, ECOG status 0 to 1, platelets ≥75,000/mm3, hemoglobin ≥8.0 g/dL, absolute neutrophils ≥1,000/mm3, and creatinine clearance ≥30 mL/min were randomized to bortezomib (bortezomib 1.3 mg/m2, intravenous, days 1, 4, 8, and 11 of an every 21-day cycle), or bortezomib+PLD (same bortezomib+PLD 30 mg/m2 intravenous on day 4). Randomization was stratified according to serum β2-microglobulin levels (≤2.5, >2.5 and ≤5.5, or >5.5 mg/L) and response to prior treatment (response followed by progression, or primary refractory). The primary endpoint was TTP; secondary efficacy endpoints included overall survival, progression-free survival (PFS) and overall response rate (complete response [CR] + partial response [PR]). Results A total of 646 subjects (bortezomib+PLD: 324; bortezomib: 322) were randomized between December 2004 and March 2006. In the pre-planned interim analysis, the study met its primary and other secondary end points. The study continued for long-term survival follow-up. At the clinical cutoff of 16 May, 2014, for the final survival analysis with a median follow-up of 103 months, 79% of subjects were dead (bortezomib+PLD: 253 [78%]; bortezomib: 257 [80%]), 6% withdrew consent, 4% were lost to follow-up, and 11% were still alive. Median OS in bortezomib+PLD–treated subjects was 33.0 months (95% CI [28.9, 37.1]) versus 30.8 months (95% CI [25.2, 36.5]) in bortezomib-treated subjects (HR=1.05, 95% CI [0.88, 1.25]; p=0.6068). The types of salvage therapies utilized included dexamethasone (49.1%), thalidomide (31.0%), cyclophosphamide (28.5%), melphalan (22.9%), lenalidomide (21.8%), bortezomib (20.4%) and doxorubicin (8.0%), which were well-balanced between the two treatment groups. Conclusion Despite inducing a superior TTP, long-term follow-up revealed that PLD+bortezomib-treatment did not improve the OS compared with bortezomib alone in subjects with relapsed or refractory MM. The inability to confirm the early survival advantage may be due to the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase III trials. Disclosures Orlowski: Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sonneveld:Orthobiotech;: Consultancy. Bladé:Celgene: Grant support, Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Spencer:Hospira: Research Funding. Robak:MorphoSys AG: Research Funding. Dmoszynska:Johnson & Johnson Pharmaceutical Research & Development: Research Funding. Horvath:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Research Funding. Sutherland:OrthoBiotech: Consultancy. Xiu:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Employment, Equity Ownership. Parekh:Johnson & Johnson Pharmaceutical Research & Development: Employment, Equity Ownership. Miguel:Janssen Cilag: Consultancy, Honoraria.

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Sustained Overall Survival Benefit with Lenalidomide Plus Dexamethasone Versus No Treatment in Patients with Smoldering Myeloma at High Risk of Progression to Myeloma: Long Term Analysis

Blood ◽

10.1182/blood.v128.22.3308.3308 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3308-3308 ◽

Cited By ~ 1

Author(s):

Maria-Victoria Mateos ◽

Miguel-T Hernandez ◽

Pilar Giraldo ◽

Javier De La Rubia ◽

Felipe De Arriba ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Confidence Interval ◽

Board Of Directors ◽

Early Treatment ◽

Survival Benefit ◽

Research Funding ◽

Advisory Committees

Abstract Background: For patients with smoldering multiple myeloma (SMM), the standard of care is observation. However, high-risk patients may benefit from early intervention. Methods: In this phase 3 trial, 119 patients with high-risk SMM were randomized to treatment or observation. The high risk populationwas defined by the presence of both PC_ 10% and MC_ 3g/dl or ifonly one criterion was present, patients must have a proportionof aPC within the total PCBM compartment by immunophenotypingof 95% plus immunoparesis. Patients in the treatment group received nine 4-week induction cycles (lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone at a dose of 20 mg per day on days 1 to 4 and days 12 to 15), followed by maintenance (lenalidomide at a dose of 10 mg per day on days 1 to 21 of each 28-day cycle) up to 2 years. The primary end point was time to progression (TTP) to myeloma. Secondary end points were overall survival (OS), response rate and safety. Results: After a median follow-up of 75 months (range: 57-100), there was a 57% reduction in the risk of death for the early treatment with lenalidomide-dexamethasone versus not treatment (hazard ratio, 0.43; 95% confidence interval, 0.2 to 0.9; P=0.02). Median overall survival has not been reached in either group, but 86% and 62% of patients are alive at 6 years in the early treatment and observation arms, respectively (Figure 1). The benefit in TTP is also highly sustained (hazard ratio: 0.24 (95% confidence interval, 0.14 to 0.41; P<0.0001). Progression to MM occurred in 53 out of the 62 patients (86%) in the abstention arm while only 22 out of 57 patients (38%) in the len-dex arm. At the time of progression patients received optimized treatments: bortezomib-based combinations were administered to thirteen out of 22 patients (59%) in the len-dex arm and to 23 out of 53 patients (43%) in the observation arm; lenalidomide-based combinations to 3 out of 22 patients (14%) in the experimental and to 8 out of 53 patients (15%) in the control arm; two out of 22 patients in the len-dex arm (9%) received bortezomib plus immunomodulatory agents whilst 16 out of 53 patients (30%) in the observation group received this combination; four out of 22 patients (18%) and six out of 53 patients (11%) in the len-dex and observation groups, respectively, were treated with chemotherapy; four patients (18%) in the experimental arm and 15 (28%) in the observation groups received an ASCT. Most patients responded to rescue therapies in both arms, resulting in overall response rates of 78% (17/22) and 86% (45/53) in the experimental and control arm, respectively. We compared survival from start of subsequent therapy in the patients population who progressed to active disease; the outcome was similar in both arms: at 6 years, 62% (16/22) of the patients in the len-dex arm remain alive and 49% (31/53) in the observation arm (P=0.50; Fig. 2C). The survival benefit observed was independent of the classification model used for defining high risk SMM ( Mayo Clinic and Spanish model) Conclusion: This long term follow-up analysis confirms that early treatment with lenalidomide-dexamethasone for high-risk SMM translates into a significant benefit in TTP but also in a sustained significant prolongation of the OS. The early exposure to lenalidomide-dexamethasone does not induce more resistant relapses. Figure 1 Figure 1. Disclosures Mateos: Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria. De La Rubia:Amgen, Bristol Myers, Celgene, Janssen: Consultancy. Paiva:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding. Oriol:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Tandem Autologous-Autologous Vs. Autologous-Allogeneic Transplantation for Newly Diagnosed Multiple Myeloma: Pooled Analysis of 1,338 Patients from Four Trials with Long-Term Follow up

Blood ◽

10.1182/blood-2019-121367 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 259-259 ◽

Cited By ~ 2

Author(s):

Luciano J. Costa ◽

Simona Iacobelli ◽

Marcelo C. Pasquini ◽

Riddhi Modi ◽

Luisa Giaccone ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Pooled Analysis ◽

Advisory Committees ◽

Long Term Follow Up ◽

Risk Of Relapse

Introduction: Tandem autologous transplant (auto- auto) has been studied as a method to increase remission rates and reduce relapse in the upfront therapy of MM. The use of autologous followed by reduced intensity conditioning allogenic transplantation (auto-allo) offers the potential of long-term graft-versus-myeloma (GVM) effect, but with the risk of graft versus host disease and potentially higher non-relapse mortality (NRM). Trials comparing these two strategies relied on availability of HLA-matched sibling donors for arm allocation (biological "randomization") and have yielded conflicting results, in part due to trial size or limited follow up. A pooled analysis of multiple trials with extended follow up provides the best opportunity to compare these two transplant strategies. Methods: We obtained individual patient data from participants of 4 trials comparing auto-auto vs. auto-allo after brief induction therapy, namely BMT CTN 0102 (N=709), NMAM2000 (N=357), PETHEMA/GEM2000 (N=110), and the Torino consortium trial (N=162). In all 4 trials arm allocation was by biological "randomization". Patients were designated high risk if beta-2 microglobulin ≥ 4.0 mg/L at diagnosis or presence of deletion of chromosome 13 by metaphase karyotyping. Time to event outcomes were analyzed by intention to treat, from the time of first autologous transplant. Main outcomes analyzed were overall survival (OS) and progression free survival (PFS). Secondary outcomes analyzed were NRM and risk of relapse, treated as competing risks, and post relapse survival. Results: There were 1,338 patients included in the analysis, 899 in auto-auto and 439 in auto-allo. Median follow up of survivors is 118.5 months. Characteristics of the two arms are displayed in Table 1. Median OS was 78.0 months in auto-auto and 98.3 months in auto-allo (HR= 0.85, P=0.003, Figure 1). OS was 59.8 % vs. 62.3% at 5-years (P=0.37) and 36.4% vs. 44.1% at 10 years (P=0.01) for auto-auto and auto-allo respectively. PFS was also improved in auto-allo (HR= 0.84, P=0.004) with 5-year PFS of 23.4 vs. 30.1% (P=0.01) and 10-year PFS of 14.4% vs. 18.7% (P=0.06). For the 214 high risk patients (125 auto-auto, 89 auto-allo) there was superior 5-year and 10-year PFS with auto-allo, but no difference in OS. Risk of NRM was higher in auto-allo (10 year 8.3% vs. 19.7%, P<0.001), while risk of disease progression was higher in auto-auto (10 year 77.2% vs. 61.6%, P<0.001). There were 685 progressions in auto-auto and 266 in auto-allo. Median post relapse overall survival was 41.5 months in auto-auto and 62.3 months in auto-allo (HR= 0.71, P<0.001, Figure 2). Five years post relapse, 37.0% of patients were alive in auto-auto vs. 51.1% in auto-allo (P<0.001). Conclusion: Long-term follow up using a large pooled dataset of 4 trials indicates durable, long-term disease control with an auto-allo strategy. Despite higher NRM, there was a reduction in the risk of relapse and superior post relapse survival in auto-allo. This supports the hypothesis of a durable GVM effect enhancing myeloma control with subsequent therapies. Disclosures Costa: Janssen: Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding. Pasquini:Pfizer: Consultancy; Medigene: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Kite Pharmaceuticals: Research Funding; BMS: Research Funding. Bladé:Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Schonland:Sanofi: Research Funding; Takeda: Honoraria, Research Funding; Prothena: Honoraria; Medac: Other: Travel grant; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Giralt:Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kite: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Miltenyi: Research Funding; Spectrum Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding. Patriarca:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Stadtmauer:Abbvie: Research Funding; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Celgene: Consultancy; Takeda: Consultancy. Krishnan:Celgene, Janssen, Sanofi, BMS: Consultancy; Sutro BioPharma, zPredicta: Consultancy; Amgen, Takeda: Speakers Bureau; Celgene, Z Predicta: Other: Stock Ownership; Takeda: Research Funding.

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Improved Outcomes for Patients Receiving High-Doses of IL-21 Ex Vivo Expanded NK Cells after Haploidentical Transplantation (haploSCT): Long-Term Follow-up of a Phase 1/2 Clinical Trial with Comparison to CIBMTR Controls

Blood ◽

10.1182/blood-2019-123936 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 700-700

Author(s):

Stefan O. Ciurea ◽

Roland Bassett ◽

Doris Soebbing ◽

Gabriela Rondon ◽

Kai Cao ◽

...

Keyword(s):

Nk Cells ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Advisory Committees ◽

Post Transplant ◽

Long Term Follow Up ◽

High Doses

Background: Disease relapse following allogeneic stem-cell transplantation remains unacceptably high and there is an urgent need for new therapies that decrease relapse rates and improve survival post-transplant. Natural killer (NK) cells have potent antitumor effects, particularly those expended with mb-IL21 from peripheral blood. Preliminary data from a phase-1 dose-escalation study of up to 1x108 NK cells/Kg/dose and multiple dosing yielded promising results and a favorable safety profile (Ciurea SO.Blood.2017;130:18657). This report presents long-term follow-up from a phase-1/2 clinical trial in patients with high-risk myeloid malignancies (AML/MDS/CML) (clinicaltrials.gov NCT01904136) and a comparison with CIBMTR controls. Methods: Patients received conditioning with fludarabine 160 mg/m2, melphalan 140 mg/m2 and 2GyTBI, post-transplant cyclophosphamide-based GVHD prophylaxis and bone marrow graft from a haploidentical donor. Ex vivo expanded NK cells were generated from peripheral blood mononuclear cells of the same donor with a K562 feeder cells expressing mb-IL21 and 41BB and infused fresh on Day-2, and cryopreserved on Day+7 and +28 (up to Day+90). 1x108/Kg/dose was chosen for the phase 2 trial. An independent matched-pair analysis was done using controls from the CIBMTR database stratified by conditioning intensity. Results: 24/26 patients treated to date were evaluable (one short follow-up and one excluded as ineligible). 80% (19/24) of patients received all 3 doses of NK cells. The median age was 45 years (range 18-59), median follow-up was 43.6 months (range 15.1-60.9). Thirteen patients (54%) were females. 5 patients had donor-specific anti-HLA antibodies (DSA). The median HCT-CI was 2 (range 0-8), 12 patients (50%) had HCT-CI>3. 17 patients (72%) had AML/MDS and 7 (28%) advanced CML. Of AML/MDS patients, 10 (59%) had high-risk cytogenetics, 7 (41%) had measurable residual disease, 9 (53%) had intermediate/adverse-risk ELN2017 and 5 (29.4%) had primary induction failure. No infusion reactions or significant adverse events were observed to date. All patients (100%) achieved engraftment after a median of 19 days (range 14-42). The cumulative incidence (CI) of grade 2-4 aGVHD was 29.2% at Day100 and 41.7% at 1-year post-transplant. Only one patient developed severe grade 3-4 aGVHD and one patient had extensive cGVHD. Only one patient relapsed (a patient with DSA who did not receive desensitization prior to transplantation), 1-year CI of relapse was 5.9%. The CI of TRM at 1-year for patients without DSA was 21%. The median overall survival and progression-free survival (PFS) were not reached. The 1-year and 3-year PFS for all patients and patients without DSA was 70.8% and 66.1%, and 79% and 72.9% for patients without DSA, respectively (Figure 1). One-year and 3-years GRFS for all patients and patients without DSA was 70.8% and 66.1%, and 79% and 72.9%, respectively. An independent matched-pair analysis (at least 1:1) was conducted by CIBMTR after the first 18 patients treated on study in 07/2018 with RIC (N=57) or MAC (N=61) controls. The relapse was 1/18 vs 25/57 for RIC (p=0.037) and 15/61 for MAC (p=0.07), while the 1-year PFS was 82% vs 49% for RIC and 64% for MAC (p=0.21) (Figure 1). Updated results of this analysis will be presented at the meeting. Conclusions: Results from this long-term follow-up analysis confirm very low relapse rate and excellent GRFS after haploSCT for patients treated with high-doses of NK cells expanded with mbIL21 stimulation. A prospective multi-center phase 2 BMTCTN study will evaluate the safetly and efficacy of high doses of NK cells for the prevention of relapse in patents with AML/MDS receiving haploSCT. Figure 1 Disclosures Ciurea: Miltenyi: Research Funding; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; MolMed: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees. Bashir:Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding; Imbrium: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Pasquini:Novartis: Research Funding; Kite Pharmaceuticals: Research Funding; BMS: Research Funding; Medigene: Consultancy; Amgen: Consultancy; Pfizer: Consultancy. Lee:Kiadis Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

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Long-Term Survivorship with Active Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-120152 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1912-1912

Author(s):

Brett Grieb ◽

Jithma Prasad Abeykoon ◽

Saurabh Zanwar ◽

S. Vincent Rajkumar ◽

Martha Q. Lacy ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Short Term ◽

Advisory Committees ◽

Entire Cohort ◽

Long Term Survivors

Abstract Background The survival of patients with multiple myeloma (MM) has improved significantly over the past two decades with the introduction of novel treatment agents. However, MM is still largely considered an incurable malignancy with a relapsing-remitting course. A follow-up of at least 10 years from active disease is required to determine whether a plateau in progression-free survival has been attained. Prior literature has used 10 years as a cutoff for "long-term survivorship". In this study, we have assessed the biological disease characteristics and outcomes of long-term survivors with MM (≥10 years from active disease). Methods All patients with active MM evaluated at the Mayo Clinic, Rochester between January 1, 1999 and July 1, 2008 were included in the study after approval of the Institutional Review Board. Patients with smoldering multiple myeloma were excluded. The overall survival (OS) was calculated from the time of symptomatic disease requiring treatment. Patients were then divided into two cohorts: (1) long-term survivors, which included patients who had an overall survival of at least 10 years; and (2) short-term survivors, which included patients who had an overall survival of less than 5 years from the diagnosis of active MM. The baseline characteristics between these two groups were compared using Wilcoxon, chi-square, and Fisher's exact test as applicable. All time-to-event analyses were performed using the Kaplan-Meier method and the survival curves were compared using Log-Rank test. Results During the time frame of the study, 2,125 patients were identified who fulfilled the diagnostic criteria for active MM. The median follow-up for the entire cohort was 12.6 years (95% CI: 12.5-13.4).The median OS for the entire cohort was 4.4 years (95% CI: 4.2-4.7 years). Three-hundred and ninety nine (18.7%) patients survived at least 10 years whereas 872 patients (41%) survived less than 5 years from the date of initial diagnosis. The median OS was 14.1 years for the long-term survivors (95% CI: 13.9-14.6 years) and 2.1 years for the short-term survivors (95% CI: 1.8-2.2 years). The clinical features at diagnosis comparing long-term survivors and short-term survivors are shown in Table 1. Among long-term survivors (n=399), based on the available data regarding remission and ongoing treatment status, 331 patients were categorized into 6 cohorts (Table 2). The MM specific survival data of these 6 cohorts is depicted in Table 2.Figure 1 shows survival outcomes from the 10-year landmark. Of the 6 cohorts, 38 patients in Cohort 1 and 19 patients in Cohort 2 (total 57; 17% of long term survivors, ~3% of the entire cohort ) have been off therapy for at least 5 years and remain in remission, representing a distinct group of patients with 100% 15-year survival. Conclusion In our large database with prolonged follow-up, long-term survivors appear to have distinct baseline characteristics, but also constitute a heterogenous group of patients with disparate outcomes. A small subset (17% of long-term survivors) was identified that may represent patients closest to being considered as 'operationally cured'. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Teva: Consultancy; spectrum: Consultancy, Honoraria; Medscape: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; Apellis: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; janssen: Consultancy; celgene: Consultancy; Prothena: Honoraria; annexon: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding.

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High Molecular Remission Rate in Pediatric Patients (pts) with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia (r/r ALL) Treated with Blinatumomab: Rialto an Open-Label, Multicenter, Expanded Access Study

Blood ◽

10.1182/blood-2018-99-109855 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1375-1375 ◽

Cited By ~ 3

Author(s):

Franco Locatelli ◽

Gerhard Zugmaier ◽

Peter Bader ◽

Sima Jeha ◽

Paul-Gerhardt Schlegel ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Prior Treatment ◽

Cell Precursor ◽

Advisory Committees ◽

Expanded Access ◽

Grade 3

Abstract Introduction Despite a high cure rate for pediatric ALL, the prognosis for pts who suffer from r/r disease remains poor. Pediatric pts with r/r ALL face multiple lines of therapy, acute and long-term treatment toxicities, and have limited survival. New agents that are able to provide durable disease control and long-term survival with limited toxicity are needed. Blinatumomab (blin) is a bispecific T-cell engaging (BiTE®) antibody construct that redirects CD3+ cytotoxic T cells to lyse CD19+ B cells. We evaluated the safety and efficacy of blin in pediatric pts with B-cell precursor r/r ALL enrolled in an expanded access study initiated in 2014 (NCT02187354). Methods Eligible pts with r/r CD19+ ALL (≥ 2 relapses, relapse after allogeneic hematopoietic stem cell transplant [HSCT], or refractory to prior treatment) were > 28 days to < 18 years of age and had ≥ 5% blasts or < 5% blasts but with a minimal residual disease (MRD) level ≥ 10-3. Prior treatment with blin was allowed if the pt was not blin-refractory or intolerant (study re-enrollment was not allowed). Blin was dosed by continuous infusion (4 weeks on/2 weeks off) for up to 5 cycles: 15 µg/m2/d for pts with ≤ 25% blasts; 5 µg/m2/d on days 1−7 of cycle 1, 15 µg/m2/d thereafter for pts with > 25% blasts. Subsequent therapy, including HSCT, was off protocol and per investigator preference. The primary endpoint was incidence of treatment-emergent (TE) and treatment-related (TR) adverse events (AEs). Secondary endpoints included morphologic complete response (CR; < 5% blasts) and MRD response (< 10-4 leukemic blasts by PCR or flow cytometry) in the first 2 cycles, relapse-free survival (RFS), overall survival (OS), and HSCT rate after blin treatment. Results Of 98 treated pts (median age, 8.5 [range 0.4-17.0] years), 93% were enrolled in Europe, 54% had > 25% blasts at baseline, 41% had ≥ 50% blasts, and 48% had a cytogenetic abnormality. Prior treatments included HSCT (44%), radiotherapy (15%), and blin (4%); 56% of pts had ≥ 2 relapses, 41% had relapsed after HSCT, 14% were primary refractory and 20% were refractory to reinduction therapy. At data cutoff (March 9, 2018), 37 pts were on study. The median number of completed treatment cycles was 2 (range 1-5), with 4 pts completing 5 cycles of blin. Overall, 99% of pts experienced a TEAE, with a rate of 64% for grade ≥ 3. TRAEs were reported in 77% of pts (26% for grade ≥ 3); 21% were deemed serious. The most frequent TEAEs (any grade) included pyrexia (83%), vomiting (27%), headache (24%), and anemia (19%). Among TEAE categories of interest, rates of any grade/grade ≥ 3 were 67%/9% for infusion reactions, 44%/16% for infections, 43%/5% for neurologic events, 40%/31% for cytopenias, 18%/12% for elevated liver enzymes, 16%/2% for cytokine release syndrome, 8%/0% for decreased immunoglobulins, 4%/2% for tumor lysis syndrome, and 1%/0% for capillary leak syndrome. Dose interruption due to a TRAE was required by 19% of pts, and 4% discontinued blin due to a TRAE. There were 9 fatal AEs, all unrelated to blin. In the first 2 cycles of treatment, 60% of all 98 pts achieved CR, 40% achieved CR with full recovery of peripheral blood counts (PBC), and 48% achieved MRD response. Of 2 pts with t(17;19), both achieved CR with full PBC recovery and MRD response; of 4 pts with Down syndrome, 3 achieved CR (2 full PBC recovery) and MRD response; of 4 pts who had received prior blin treatment, 3 achieved CR (3 full PBC recovery) with blin retreatment and 2 achieved MRD response. Among 59 pts who achieved CR within 2 cycles, 27 (46%) proceeded to HSCT; 19 relapsed and 5 died after a median follow-up 5.3 (range, 0.3-13.2) months for a median RFS of 8.5 (95% CI, 2.9-NE) months from the time of CR. Among all 98 pts, median follow-up was 12.2 (range, 0.5-14.1) months; there were 38 deaths (32 disease related), and median OS was 13.0 (95% CI, 9.3-NE) months. Conclusions The safety profile of single-agent blin in this expanded access study was generally consistent with profiles reported in prior controlled trials of blin in pediatric and adult pts with r/r ALL. Blin was active in this pediatric r/r ALL population. Blin induced MRD response in almost half of the pts, including pts with t(17;19) or prior blin treatment. Pts with a lower leukemia burden (< 50% blasts) had a better probability of response to blin vs pts with a higher burden. These data further support blin as a treatment option for pediatric pts with r/r ALL. Table. Table. Disclosures Locatelli: Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zugmaier:Amgen Inc.: Consultancy, Employment, Patents & Royalties: 20170327581, 9688760, 20170122947, 9486475, 20160208001, 9192665, 20150071928, 8840888, 20140227272, 20140228316, 20130323247, 20130287774, 20130287778, 20110262440, 20100112603, 7700299, 20070037228. Bader:Riemser: Research Funding; Neovii: Research Funding; Cellgene: Consultancy; Medac: Patents & Royalties, Research Funding; Novartis: Consultancy, Speakers Bureau. Bourquin:Amgen: Other: Travel Support. Handgretinger:Miltenyi Biotec: Patents & Royalties: Co-patent holder of TcR alpha/beta depletion technologies, Research Funding. Rossig:Genetech: Consultancy; Roche: Consultancy, Honoraria; MorphoSys: Honoraria; Celgene: Consultancy; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Honoraria; EUSA Pharm: Consultancy.

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High Rate of Long Term Complete Remission for Patients with Chronic Lymphocytic Leukemia (CLL) Who Relapse after Allogeneic Stem Cell Transplantation and Receive Salvage with Donor Lymphocyte Infusions (DLI)

Blood ◽

10.1182/blood.v128.22.5860.5860 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5860-5860

Author(s):

Alan P Skarbnik ◽

Mary E DiLorenzo ◽

Tracy Andrews ◽

Phyllis McKiernan ◽

Scott D. Rowley ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Disease Status ◽

Advisory Committees

Abstract Background: Allogeneic stem cell transplantation (SCT) remains the only curative option for CLL, in part due to allogeneic graft-vs-leukemia effect (GVL), which can lead to complete suppression of the CLL clone (Schetelig et al, JCO 2003). Management of post-SCT relapse remains challenging, and DLI has been successfully used as salvage, due to its potential to induce GVL (Delgado et al, Blood 2009). We evaluated outcomes of SCT for patients (pts) with a diagnosis of CLL transplanted at our center. Methods: 36 consecutive pts transplanted between 2004 and 2015 were reviewed. Kaplan Meier survival curves were produced to examine overall survival (OS), time to progression (TTP) and post-DLI survival. Univariate Cox Proportionate hazard models were also estimated to assess the impact of pt characteristics on the risk of survival and progression. Bivariate frequencies with Fisher exact tests, correlation analysis, and independent samples t-tests were performed to test associations across outcomes. Results: Sample was 72% male. Median age at time of SCT was 57 yo (range 42-74). Pts had a median time of 70 months (mos) between diagnosis (Dx) of CLL and SCT. Median follow-up post-SCT was 32 mos (range 1-118). Of the 30 pts with known disease status at the time of SCT, 16.7% were in complete remission (CR), 20% had stable disease (SD), 50% were in partial remission (PR) and 13.3% had progressive disease (PD). Median number of lines of therapy pre-SCT was 3 (range 1-8). Thirteen pts (36%) were refractory to their first line of therapy. 10 pts (27.8%) had del(17p), 11 pts (30.6%) had del(11q) and 8 pts (22.2%) had complex cytogenetics. Most patients (72%) received pre-SCT conditioning with FCR (Khouri et al, Exp Hematol 2004). 16 pts (44.4%) received rATG as part of their conditioning regimen. Graft-vs-host disease (GVHD) prophylaxis consisted of methotrexate and tacrolimus. 20 (55.6%) pts had acute GVHD and 19 (52.8%) had chronic GVHD. 5 (13.8%) pts had grade 3/4 acute GVHD and 1 (2.7%) had extensive chronic GVHD. When comparing pts who received SCT from unrelated donors (MUD, 24 pts) vs sibling donors (sib, 10 pts) there were no differences in rates of GVHD, disease progression or overall survival. Twenty-seven pts (75%) were in CR at first disease evaluation after SCT (CR conversion rate of 58.3%) and 2 pts (5.5%) had PD. On follow-up, another 15 pts (41.7%) presented PD. Median TTP was 14 months, with only 3 pts relapsing after 2 years from SCT. Eight pts who had PD and one patient who had a PR post-SCT received short-term anti-CLL therapy for disease debulking, followed by DLI. Six (66.6%) out of the 9 pts who received DLI achieved CR and are currently alive and in CR. Median follow-up post-DLI was 43 months and median duration of response to DLI was 47 mos (range 6-85 mos). Ultimately, 13 (36.1%) pts died, 8 (22.2%) were lost to follow-up, and 15 (41.7%) were alive at last contact. Disease progression was the most common cause of death (5 pts, 13.9%). Transplant-related mortality (TRM) was 13.9% (3 deaths due to infection, 2 deaths due to chronic GVHD). Only 2 deaths (5.5%) occurred during the first 100 days post-SCT, both due to infection. No deaths occurred due to acute GVHD. Median OS was 84 months. PFS (not accounting for pts who relapsed post-SCT but achieved CR with DLI) was 58% in the first year and 25% at five years. The median PFS was 19 months. Univariate and multivariate analysis of pre-SCT pt characteristics (age, time from Dx to SCT, number of therapies, stage, presence of adenopathy, MUD vs sib donor, cytogenetic abnormalities, ABO mismatch, disease status at SCT) did not show any statistically significant correlation with OS, PFS or GVHD rates. Conclusion: SCT remains the only curative option for CLL. Our experience shows that pts may achieve long-term survival with this approach. TRM was low (13.8%) and rates of acute and chronic GVHD were compatible with previous reports (Sorror et al, JCO 2005; Dreger et al, Blood 2010). Type of donor (MUD vs sib) did not impact outcomes, suggesting that patients without a matched sibling should not be denied transplantation if a MUD is available. Although 47% of the patients eventually progressed after transplantation, 66% of patients who received DLI for salvage were able to achieve CR and remain progression-free for a prolonged period of time, underlining the importance of the GVL effect. Most relapses occurred within the first 2 years post SCT and late relapses were rare. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Skarbnik: Gilead Sciences: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Consultancy; Pharmacyclics: Consultancy. Vesole:Celgene: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau. Goy:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feldman:Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau.

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High Efficacy of Lenalidomide Plus R-CHOP (R2CHOP) Combination in First Line Treatment of Activated B-Cell (ABC) DLBCL Defined Using Gene-Expression Prophyling: A Combined Analysis from Two Phase 2 Trials

Blood ◽

10.1182/blood-2018-99-119495 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2962-2962 ◽

Cited By ~ 1

Author(s):

Alessia Castellino ◽

Annalisa Chiappella ◽

Betsy Laplant ◽

Levy D. Pederson ◽

Giorgio Inghirami ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

International Prognostic Index ◽

Prognostic Index ◽

Phase 2 ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Introduction: Lenalidomide (Len) in association with standard Rituximab-CHOP (R2CHOP21) has been shown to be safe and effective in newly diagnosed Diffuse Large B-cell Lymphomas (DLBCL) [Nowakowski et al. JCO 2014, Vitolo et al. Lancet Oncol 2014]. The addition of lenalidomide appears to benefit primarily patients with non-Germinal Center B-cell (non-GCB) phenotype as determined by immunohistochemistry (IHC). These early results led to currently ongoing randomized trial in ABC subtype of DLBCL, however efficacy of R2CHOP in ABC DLBCL as defined by Gene Expression Prophyling (GEP) has not been reported. In the present combined analysis of two independent phase 2 studies, we report the long-term follow-up (FU) outcome in DLBCL patients treated with R2CHOP, comparing GCB and ABC according to Nanostring Platform. Methods: We included all newly diagnosed histologically-confirmed de-novo DLBCL patients enrolled in two R2CHOP21 phase 2 trials, conducted by Mayo Clinic (MC) and Italian Lymphoma Foundation (FIL). Inclusion criteria in the two trials were similar, main differences included: all age and all International Prognostic Index (IPI) vs age between 60 and 80 years old and IPI >1, in MC vs FIL study, respectively. All pts received R-CHOP21 plus Len at 25 mg/day for 10 days/cycle and 15 mg/day for 14 days/cycle in MC and FIL trial, respectively. Cell of origin (COO) was determined by IHC, according to Hans algorithm, and retrospectively, in patients with available pathological material, by Nanostring, performed according to Scott algorithm and Masque-Soler signature in MC and FIL study, respectively. We analyzed the long-term FU outcome in terms of progression-free survival (PFS), time to progression (TTP), overall survival (OS), comparing between GCB and ABC phenotypes according to GEP. Results: A total of 112 DLBCL pts (63 MC, 49 FIL) were included. Main characteristics were: median age 69 years (y) (range 22-87), male 65 (58%) pts, advanced stage III-IV in 94 (84%), B symptoms in 38 (34%), International Prognostic Index (IPI) intermediate-high/high in 71 (63%). At a median follow-up of 5.1 years (y), 5y-PFS was 63.5%, 5y-TTP 70.1% and 5y-OS 75.4%. A total of 32 relapses were observed, with only 2 cases of Central Nervous System (CNS) relapse. Late relapse occurring beyond 3 years was observed in 4 cases (3 cases with GCB phenotype and one case with missing COO data). In a subgroup analysis by IPI 0-2 vs 3-5 were: 5y-PFS, 5y-TTP and 5y-OS were: 69.0% vs 59.0% (p=0.100), 73.2% vs 67.4% (p=0.285) and 82.3% vs 70.2% (p=0.059), respectively. Regarding for COO defined by IHC, GCB phenotype vs non-GCB were 45 (40%) vs 41 (37%) patients respectively; 26 (23%) patients were not evaluable. 5y-PFS, 5y-TTP and 5y-OS were: 52.8% vs 64.5% (p=0.198), 61.6% vs 69.6% (p=0.444) and 68.6% vs 74.1% (p=0.238) in GCB vs non-GCB, defined by IHC, respectively. Regarding Nanostring analysis, GCB vs ABC vs Unclassified (Uncl) were 31 (46%) vs 22 (32%) vs 15 (22%) respectively; 44 pts were not evaluable. 5y-PFS, 5y-TTP and 5y-OS were: 62.3% vs 70.8% vs 64.2% (p=0.645), 68.1% vs 79.8% vs 64.2% (p=0.662) and 76.0% vs 74.8% vs 79.0% (p=0.658) in GCB vs ABC vs Uncl, defined by Nanostring, respectively (Table1, Fig1). Conclusions: The association of Len with R-CHOP21 appears to overcome the negative prognostic impact of ABC phenotype determined by GEP, with high PFS, TTP and OS rate, maintained at a long-term FU analysis. Figure 1. Figure 1. Disclosures Chiappella: Teva: Other: lecture fees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Nanostring: Other: lecture fees; Roche: Other: lecture fees; Amgen: Other: lecture fees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees. Gaidano:Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Morphosys: Honoraria. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Vitolo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sandoz: Speakers Bureau; Gilead: Speakers Bureau.

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Outcomes in Relapsed/Refractory Burkitt Lymphoma: A Multi-Centre Canadian Experience

Blood ◽

10.1182/blood-2021-146036 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2525-2525

Author(s):

Farheen Manji ◽

Eric Chow ◽

Alina S. Gerrie ◽

Neil Chua ◽

Robert Puckrin ◽

...

Keyword(s):

Overall Survival ◽

B Cell ◽

Board Of Directors ◽

Burkitt Lymphoma ◽

Research Funding ◽

Second Line ◽

Cns Involvement ◽

Advisory Committees ◽

Relapsed Disease

Abstract Introduction: Burkitt lymphoma (BL) is an aggressive B cell lymphoma with a distinct morphology, immunophenotype and characteristic C-MYC gene rearrangement. When treated with intensive chemotherapy, outcomes are excellent with a reported overall survival of greater than 80% at 3 years. A small subset of patients have primary refractory or relapsed disease, but there have been few reports of treatment and outcomes of these patients due to the rarity of this lymphoma and its otherwise good prognosis. Objective: The objective of this study was to review the characteristics, treatments and outcomes of patients with relapsed/refractory BL. Methods: We included patients 18 years or older with a pathologically confirmed BL diagnosed between 2003 and 2018 at eight Canadian centres who received curative intent frontline chemotherapy and who had primary refractory or relapsed disease. Data were retrospectively reviewed at each site independently. Staging and response assessment was based on computed tomography (CT). Descriptive statistics were used for baseline characteristics and treatment regimens. Kaplan Meier Survival Analysis was used to estimate overall survival (OS) which was calculated from time of relapse. Results: A total of 74 patients were included in the study. Median age was 48 years (IQR 32-61) and 81% were male. Nine patients (12%) were known to be HIV positive. Most patients had advanced disease with stage III/IV (n=47, 64%), bone marrow involvement (n=32, 43%) and at least one extranodal site (n=67, 91%). Nineteen patients (26%) had central nervous system (CNS) involvement at diagnosis. The most common induction regimen was CODOX-M-IVAC (n=43, 58%) followed by CHOP or EPOCH (n=14, 19%) and hyperCVAD (n=7, 9%). Forty five (61%) patients received rituximab with their first line treatment. The median time to relapse from diagnosis was 5 months with a majority of cases being primary refractory (n=57, 77%). Patients had systemic relapse (n=44, 59%), isolated CNS relapse (n=19, 26%) or both (n=11, 15%). Forty three (58%) patients received second-line salvage chemotherapy while 28 (39%) were treated with palliative oral chemotherapy and/or radiation. A variety of salvage regimens were used including systemic and CNS-directed second line regimens: most common GDP (n=7, 9%), hyperCVAD (n=5, 7%) and DHAP (n=5, 7%). Rituximab was given at relapse to 23 patients (31%). Progressive disease during or after salvage was noted in 23 (31%) patients. Twenty patients received a second-line transplant (15 autologous, 5 allogeneic). The median OS of the whole cohort was 3.2 months and 2 year OS was 17.2% (95% CI 9.4-26.9). Median OS for patients receiving salvage was 5.4 months compared to 1.3 months for those who received palliative therapy (p<0.05). Amongst the patients who died (n=62, 84%), the most common cause of death was disease progression (n=57, 77%), while 2 died from treatment-related toxicity (3%) and 3 from second malignancies (4%). Patients with both systemic and CNS involvement at the time of relapse had a worse prognosis than those with isolated systemic or isolated CNS relapse (median OS 1.9 months vs 3.4 months, p=0.03). Nine of 11 surviving patients received either an autologous (n=8) or allogeneic (n=1) stem cell transplant. One patient was lost to follow up shortly after progressing. Median follow up for survivors was 50 months (range 2-201 months). Conclusion: Relapsed/refractory BL has very poor prognosis, even in the rituximab era. There is no standard approach to salvage treatments in this population. Despite advances in novel agents and cellular therapies in aggressive lymphoma, patients with BL are often excluded from these clinical trials. This study highlights the need for inclusion of this population in trials evaluating novel therapies for aggressive B cell lymphomas. Figure 1 Figure 1. Disclosures Gerrie: Astrazeneca: Honoraria, Research Funding; Sandoz: Honoraria; Roche: Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Chua: Merck: Honoraria; Pfizer: Honoraria; Eisai: Honoraria; Gilead: Honoraria. Stewart: Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria; Amgen: Honoraria; Sandoz: Honoraria; Teva: Honoraria. Kuruvilla: Seattle Genetics: Honoraria; TG Therapeutics: Honoraria; Medison Ventures: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria, Other: Data and Safety Monitoring Board; Gilead: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria; Antengene: Honoraria; Merck: Honoraria; Novartis: Honoraria; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria. Crump: Novartis: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Epizyme: Research Funding; Roche: Research Funding.

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Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: 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, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

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