Azacitidine (AZA) for Patients with Vexas and Myelodysplastic Syndrome (MDS): Data from the French Vexas Registry

Abstract Background MDS are associated in 10% to 25% of the cases with systemic inflammatory or auto-immune diseases (SIAD). The management of SIADs in this context includes glucocorticoids and biologics with variable response rates, but we and others found that hypomethylating agents, especially azacytidine (AZA), can have some efficacy in SIADs associated with lower risk MDS (Fraison, J.-B. et al. Leuk. Res. 43, 13-17 (2016).). The recently described VEXAS syndrome (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome) (Beck et al, NEJM 2020) an autoinflammatory disease characterized by somatic mutation of the UBA1 gene, is often associated with hematological disorders, especially MDS, and its treatment is often unsuccessful Based on a French nationwide registry of patients with VEXAS syndrome, we described the efficacy and safety of AZA in VEXAS syndrome patients with concomitant MDS. Patients A French nationwide registry of 116 patients with VEXAS syndrome was established in Jan 2021. We collected in this registry patient cases with concomitant MDS (according to WHO 2016) who received at least 1 full cycle of AZA (5 to 7 days). Major response of autoinflammatory disease to AZA was defined by at least 50% steroids dose reduction to less than 10 mg/day during at least one month, and minor response by at least 50% steroid dose reduction but to > 10 mg/day, during at least one month. Results Of the 58 patients with concomitant MDS included in the French VEXAS registry, 11 had received at least 1 cycle of AZA. All patients were males and median age was 64 (range 54-73), WHO : MDS MLD (n=6) , MDS SLD (n=1), MDS EB1 (n=4) ) ,R-IPSS low (n=7), intermediate (n=3) high (n=1). Median time from MDS diagnosis to AZA onset was 8 (range 0-88) months. VEXAS phenotype mostly included skin lesions (100%), fever (91%) and constitutional symptoms (91%). All patients, except one, were steroid dependent at AZA onset. In addition to steroids, patients had received a median of 1 immunosuppressive treatment (IST) (range 0-6). The median number of AZA cycles was 11 (range 2-35). Median follow up from AZA onset was 32 months (range 12-75). Five (46%) patients discontinued AZA before the end of follow-up, after 2 to 10 cycles due to failure (n=4) and persistent response after 6 cycles (n=1). Response of autoinflammatory disease to AZA was achieved in 5 patients (45%) including major response in 2 patients, and minor response in 3, while 6 patients had no response. Best response was observed after 4 cycles (n=4) and after 6 cycles (n=1). In responders, prednisone could be discontinued in 1 patient. Duration of response was 6, 8+, 12, 21, 27+ months (Median 16.5). Three of the 5 responders subsequently received another IST. Of 10 anemic and 5 thrombocytopenic patients,3 obtained erythroid and 2 obtained platelet response, respectively (IWG 2006 criteria). Two patients experienced serious adverse events during AZA treatment, including pneumocystis pneumonia (n=1), severe colitis and bacterial pneumonia (n=1). Conclusions Our results, in a limited patient number, suggest that AZA can improve auto inflammatory symptoms in 45% of patients with VEXAS syndrome and underlying MDS, allowing decrease or even discontinuation of steroids, during a median time > 1 year, with concomitant hematological response in about 50% of the cases and limited side effects. A prospective study with more patients will be needed to confirm those results. Disclosures Comont: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau. Riviere: Octapharma: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Terriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Terrier: LFB: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees. Georgin-Lavialle: Novartis: Membership on an entity's Board of Directors or advisory committees; Soby: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Fenaux: Syros Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding.

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Routine Use of Gemtuzumab Ozogamicin in 7+3-Based Inductions for All "Non-Adverse" Risk AML

Blood ◽

10.1182/blood-2020-142691 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Gavin Hui ◽

Abdullah Ladha ◽

Edna Cheung ◽

Caroline Berube ◽

Steven Coutre ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Gemtuzumab Ozogamicin ◽

Intermediate Risk ◽

Newly Diagnosed ◽

Myeloablative Conditioning ◽

Advisory Committees ◽

Monosomy 7

Introduction: The addition of gemtuzumab ozogamicin (GO) to 7+3 chemotherapy for newly diagnosed acute myeloid leukemia (AML) has been shown to significantly improve event-free survival (EFS) for cytogenetically favorable-risk AML, with marginal benefit for intermediate-risk AML, and no benefit for cytogenetically adverse-risk AML. Of note, with the exception of mutated FLT3-ITD, little is known about the impact of GO in ELN 2017-defined genotypically adverse-risk AML, and a recent randomized trial found no EFS benefit for 7+3+GO in patients (pts) with genotypically favorable-risk, NPM1-mutated AML. Since 2017, our institution incorporated GO into 7+3-based inductions for all "non-adverse" risk AML pts, as defined by wild-type FLT3 and no abnormalities on rapid FISH analysis for del(5q)/monosomy 5, del(7q)/monosomy 7, and del(20q). We report our experience treating all pts with "non-adverse" risk AML-as defined by this algorithm-with 7+3+GO. Methods: An institutional database was queried in order to identify all pts ≥18 years old who received 7+3-based chemotherapy for newly diagnosed AML between 2017 and 2020; pts who received the FDA-approved fractionated dose of GO were included in the analysis. Data collection included demographic variables, karyotype/FISH, targeted PCR analyses, and multigene NGS panels for AML-related mutations including, but not limited to, mutations in FLT3, NPM1, CEBPA, TP53, RUNX1, and ASXL1. Outcome data included response to induction, relapse, and death, as well as hematopoietic cell transplant (HCT) rates, conditioning regimens, and post-transplant complications. Results: Between January 2017 and July 2020, 96 pts received 7+3-based induction at our institution. Of these, 29 (30%) received 7+3 in combination with GO. Median age at diagnosis was 46 years (range 23-66), with 17 (59%) males. Sixteen (55%) pts had ELN favorable-risk AML (5 [31%] by cytogenetics and 11 [69%] by genotype), 6 (21%) pts had ELN intermediate-risk AML, and 7 (24%) pts had ELN adverse-risk AML (4 [57%] by cytogenetics and 3 [43%] by genotype). Median time from diagnosis to start of induction was 4 days (range 0-43). For cytogenetically adverse-risk pts, median time from diagnostic bone marrow biopsy to receipt of adverse karyotype results was 8 days (7-14). Median time from start of induction to receipt of multigene NGS results for all pts was 15 days (3-32). Overall, 22 (76%) pts achieved remission. All genotypically adverse-risk pts (1 with mutated TP53 and 2 with mutated RUNX1) were refractory to induction, while 3 of 4 (75%) cytogenetically adverse-risk pts (1 with t(6;9), 1 with monosomy 7, and 2 with 11q23 abnormalities) achieved remission. Eight of the 29 (28%) pts proceeded to HCT, including 4 adverse-risk pts. Of the adverse-risk pts, all received myeloablative conditioning prior to HCT and 3 (75%) developed veno-occlusive disease (VOD), with 2 (50%) requiring defibrotide therapy. In favorable/intermediate-risk pts, 4 (18%) proceeded to HCT (2 intermediate-risk pts in first remission and 2 favorable-risk pts in second remission). Of these, 2 (50%) received myeloablative conditioning and 1 (25%) developed VOD. At last follow-up, 23 of 29 pts (79%) remained alive, with a median overall survival not reached (range 1-29 months) and a median EFS of 20 months (9-31). The percentage of ELN favorable-, intermediate-, and adverse-risk pts who remained event-free at last follow-up was 75%, 33%, and 43%, respectively. Discussion: This single-center, retrospective cohort describes the outcomes of pts with "non-adverse" risk AML who received induction chemotherapy with 7+3+GO according to a pre-defined algorithm. Using this algorithm, 30% of all pts receiving 7+3-based inductions received GO. Of these, nearly 25% were ultimately found to have adverse-risk AML as defined by ELN 2017 criteria, largely driven by long turn-around times for karyotyping and NGS multigene panel results. No patient with genotypically adverse-risk AML by ELN criteria responded to induction chemotherapy, and 75% of cytogenetically adverse-risk pts who proceeded to HCT developed VOD. Routine use of 7+3+GO induction outside of the context of cytogenetically favorable-risk AML remains controversial, and further study is needed to define the role of GO, particularly for pts with ELN genotypically adverse-risk AML. Table Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.

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Observational Prospective Registry for the Assessment of the Clinical Impact of Starting Anti-Myeloma Treatment at Biological Relapse

Blood ◽

10.1182/blood.v124.21.4765.4765 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4765-4765

Author(s):

Adrian Alegre ◽

Merche Gironella ◽

Juan Miguel Bergua ◽

Esther Gonzalez ◽

Fernando Escalante ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Marrow Transplant ◽

Clinical Relapse ◽

First Line ◽

Advisory Committees ◽

Free Survival

Abstract Introduction: Despite the great medical advances associated with the introduction of thalidomide, bortezomib (BORT), and lenalidomide (LEN) for the treatment of multiple myeloma (MM), it remains an incurable disease. Most patients (pts) show disease progression, consistent with the clinical evolution of MM, and only a low percentage achieve long-term responses and extended progression-free survival (PFS). The heterogeneous nature of MM in both the clinical and biological setting is reflected in the heterogeneity of MM relapses. The International Myeloma Workshop Consensus Panel (Rajkumar, Blood 2011) states that treatment (Tx) shall begin either at clinical relapse with symptoms (clinR), or in the event of asymptomatic relapse with significant paraprotein relapse, biological relapse (BR). The purpose of this Spanish registry is to describe MM relapse patterns comparing the impact of Tx decisions in pts who meet the criteria for biological relapse (BR) according to IMWG criteria with those in whom Tx was delayed until clinical relapse (clinR). Here, the preliminary results of this study are presented. Methods: MM pts in (or previous to) first or second BR who have achieved ≥ PR since their last Tx are eligible for inclusion in this observational prospective registry at the time BR is detected. Evaluations performed at least bi-monthly are mandatory. A total of 41 Spanish sites participated in the registry following approval from their independent ethics committees, with 410 pts expected to be included, without physician’s decision of prescribing Tx affecting the inclusion. The main objective of the registry is to assess the time to progression (TTP) from the start of anti-MM Tx at the onset of asymptomatic BR vs. the start of Tx at the time of clinR. Secondary objectives are to describe demographics of BR; to assess the median time elapsing from BR to clinR; to assess overall response rate (ORR), event-free survival (EFS), PFS, overall survival (OS) at BR and at clinR (if appropriate); to asses safety and quality of life (QoL) using 2 validated questionnaires (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and QLQ-MY24); to document the tolerability profile of the Tx; and to describe the use of associated resources. Here, we summarize baseline characteristics and preliminary results from 83 pts (out of 126 registered pts) who had basal data in the registry at the time of this report. Results: Overall, 79% of pts presented with a BR and 21% were in a bi-monthly watchful waiting follow up. The mean age of pts was 67 years, 53% were female, 57% were in first relapse, 43% and 27% had an ECOG performance status (PS) of 0 and 1, respectively, while the ECOG PS was unknown in 30% of pts at the time of this report. In total, 30% of pts had ISS stage I, 26% had ISS stage II, and 22% had ISS stage III, while ISS stage data were not available or unknown for 12% and 10% of pts, respectively. MM types were IgG Κ (37% of pts), IgG λ (23%), IgA Κ (13%), IgA λ (9%), and type was unknown in 17% of pts. 28% of IgG/IgA MM types were Bence-Jones. Cytogenetic risk assessments were available in 66% of pts. Among those pts with a BR, 51% received active Tx without waiting for a ClinR. First-line Tx was BORT-based in 70% of pts. Overall, 55% of pts had undergone autologous stem cell transplantation, 15% had received consolidation Tx and 34% had received maintenance Tx. After first-line Tx, 17% of pts achieved a stringent complete response (sCR), 31% achieved a CR, 24% achieved a very good partial response (VGPR), and 10% achieved a PR. The median time to BR was 24.53 months. Most (63%) pts who registered after second relapse received LEN-based Tx. Conclusions: To our knowledge, this is the first prospective study in MM to evaluate BR as well as the effects of Tx based on the decision to start Tx at BR vs. clinR. In this preliminary cohort, the physicians’ decision to start active Tx at BR, before the onset of clinR in 50% of cases, was noteworthy. Further follow-up is needed to identify the differences between these two strategies. Updated clinical results will be presented at the meeting. MM-BR Study, Spanish Myeloma Group-GEM/PETHEMA Bibliography Alegre A, et al. Haematologica. 2002;87:609-14. Brioli A, et al. Blood. 2014;123:3414-9. Fernández de Larrea C, et al. Bone Marrow Transplant. 2014;49:223-7. Lenhoff S, et al. Haematologica. 2006;91:1228-33. Rajkumar SV, et al. Blood. 2011;117:4691-5. Zamarin D, et al. Bone Marrow Transplant. 2013;48:419-24. Disclosures Alegre: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lahuerta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ruiz:Celgene: Celgene Stock options as part of the employee's compensation plan Other, Employment. Vilanova:Celgene: Contracted by Celgene Other.

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Ibrutinib Dose Reduction Does Not Affect Progression-Free Survival in Patients with Waldenstrom Macroglobulinemia

Blood ◽

10.1182/blood-2018-99-111626 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1598-1598

Author(s):

Jorge J. Castillo ◽

Joshua Gustine ◽

Andrew Keezer ◽

Kirsten Meid ◽

Toni Dubeau ◽

...

Keyword(s):

Dose Reduction ◽

Median Time ◽

Research Funding ◽

Regression Models ◽

Progression Free Survival ◽

Free Survival ◽

Waldenstrom Macroglobulinemia ◽

Major Response ◽

Dose Reductions

Abstract Introduction: Ibrutinib is an oral Bruton Tyrosine Kinase inhibitor, approved for the treatment of symptomatic Waldenstrom Macroglobulinemia (WM). MYD88 and CXCR4 mutations affect progression-free survival (PFS) in patients with WM. In some cases, ibrutinib dose reductions are needed for the management of toxicity. However, it remains unclear if ibrutinib dose reductions adversely affect PFS in WM patients. Methods: We evaluated 217 consecutive patients with the clinicopathological diagnosis of WM who were symptomatic and received treatment with ibrutinib. We analyzed relevant clinical features and their association with the risk of dose reduction, using logistic regression models, as well as PFS using Cox proportional-hazard regression models. Time to events was estimated using the Kaplan-Meier method. p<0.05 were considered statistically significant. Results: All 217 patients were initiated on ibrutinib monotherapy at the approved dose of 420 mg by mouth (PO) once daily (QD). At a median follow-up of 26 months (95% CI 22-31 months), 159 patients (73%) continued ibrutinib without dose-reduction, while 58 (27%) patients had a decrease in their ibrutinib dose. There was no difference in follow-up between those with and without dose reduction. Of the 58 patients that dose reduced, 45 (78%) were reduced to 280 mg daily; 12 patients (21%) were reduced to 140 mg daily, and 1 (2%) to 140 mg every other day. The median time to ibrutinib dose reduction from 420 mg PO QD to 280 mg PO QD was 155 days (95% CI 89-282 days), and median time to dose reduction from 280 mg PO QD to 140 mg PO QD was 55 days (95% CI 24-260 days). Reasons for ibrutinib dose reduction included cytopenia(s) (n=13; 24%), arrhythmia (n=9; 17%), musculoskeletal discomfort (n=8; 15%), constitutional symptoms (n=6; 11%), skin changes/rash (n=5; 9%), mouth sores (n=4; 7%), gastrointestinal symptoms (n=3; 6%), infections (n=3; 6%), bleeding (n=2; 4%) and transaminase elevation (n=1; 2%). Patients in whom ibrutinib dose reduction was needed were more likely to be older than 65 years (76% vs. 47%; p<0.001), had higher International Prognostic Scoring System for WM (IPSSWM) at ibrutinib initiation (IPSSWM 1, 2 and 3 were 19%, 23% and 58% vs. 24%, 39% and 37%, respectively; p=0.03), and were more likely to have attained a major response (93% v. 69%; p<0.001) than patients in whom ibrutinib dose was not reduced. There were no differences in baseline characteristics including sex, hemoglobin levels, platelet counts, beta-2-microglobulin levels, serum IgM levels, bone marrow involvement, previous treatment, MYD88 and CXCR4 mutational status and time from WM diagnosis to ibrutinib initiation between those with and without dose reduction. Regression analyses showed higher odds of dose reduction occurring in patients >65 years (OR 3.6, 95% CI 1.8-7.1; p<0.001) and those who had attained a major response (OR 6.0, 95% CI 2.1-17.5; p=0.001). The median PFS for the entire group was not reached, and the 3-year PFS rate was 76% (95% CI 68-83%). Factors associated with a worse PFS were platelet count <100 K/uL (HR 3.9, 95% CI 1.8-8.7; p=0.001) and CXCR4 mutations (HR 3.0, 95% CI 1.5-6.0; p=0.001). Expression of mutated MYD88 (HR 0.01, 95% CI 0.00-0.09; p<0.001) and attainment of major response (HR 0.23, 95% CI 0.12-0.43; p<0.001) were associated with a better PFS. Importantly, those who experienced a reduction in their ibrutinib dose showed no significant difference in PFS (HR 1.19, 95% CI 0.61-2.35; p=0.61; Figure 1A). There were no differences between patients who reduced to 280 mg PO QD (HR 1.0, 95% CI 0.5-2.2; p=0.99) or 140 mg PO QD (HR 1.9, 95% CI 0.7-5.5; p=0.22) versus those without dose reduction (Figure 1B). Conclusion: Ibrutinib dose reduction occurred in 27% of patients with WM, at a median time to dose reduction of 155 days. Patients older than 65 years and those with major responses were more likely to have a dose reduction. With a median follow-up time of 26 months, ibrutinib dose reduction did not significantly impact PFS. Figure 1. Figure 1. Disclosures Castillo: Millennium: Research Funding; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Genentech: Consultancy. Hunter:Pharmacyclics: Consultancy. Treon:Johnson & Johnson: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding.

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Updated Results of a Phase II Randomized Study (ROMULUS) of Polatuzumab Vedotin or Pinatuzumab Vedotin Plus Rituximab in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood.v124.21.4457.4457 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4457-4457 ◽

Cited By ~ 22

Author(s):

Franck Morschhauser ◽

Ian Flinn ◽

Ranjana H Advani ◽

Catherine S. Diefenbach ◽

Kathryn Kolibaba ◽

...

Keyword(s):

Follicular Lymphoma ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Clinical Activity ◽

Advisory Committees ◽

Advisory Boards ◽

Grade 5 ◽

Grade 3

Abstract Background: Previously reported results from an ongoing study of polatuzumab vedotin (PoV) and pinatuzumab vedotin (PiV), antibody drug conjugates (ADC) containing the anti-mitotic MMAE targeting CD79b (PoV) and CD22 (PiV), showed clinical activity in combination with rituximab (R) in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Here we report updated results of ADC + R at the RP2D of 2.4 mg/kg and initial results of PoV + R in r/r FL at the PoV dose of 1.8 mg/kg. Methods: Pts were randomized to receive PoV or PiV + R (ADC 2.4 mg/kg + R 375 mg/m2). In a separate non-randomized cohort (Cohort C), r/r FL pts were treated with PoV (1.8 mg/kg) + R. ADC + R was given every 21 days. Tumor assessments were performed every 3 months. Results: As of 21 February 2014, 59 pts received PoV + R (39 DLBCL; 20 FL), 63 PiV + R (42 DLBCL; 21 FL); 20 r/r FL pts were treated in Cohort C. Median time of follow-up was 10 mo. for PoV + R, 9 mo. for PiV + R, and 5 mo. for Cohort C. Median prior therapies [DLBCL, 3 (1-10); FL, 2 (1-8)] were balanced among the randomized treatment (tx) arms, median prior therapies in Cohort C was 2 (1-13); overall 44% were R refractory. Median tx cycles in DLBCL: 6 PoV (range 1-16) and 7 PiV (1-15); FL: 10 PoV (3-17), 7 PiV (1-14), and 6 Cohort C (2-10). Overall safety profiles of both regimens in the randomized arms receiving 2.4 mg/kg ADC were similar. The most common tx-emergent adverse events (AE) ≥25%: fatigue (55%), diarrhea (43%), nausea (37%), peripheral neuropathy (PN) (39%), neutropenia (27%), constipation (26%), sensory PN (25%), and decreased appetite (25%). Grade ≥ 3 AE >3%: neutropenia (24%), diarrhea (6%), dyspnea (5%), febrile neutropenia (4%), hyperglycemia (4%), fatigue (3%), and thrombocytopenia (3%). Serious AEs were reported in 43% and 36% of PiV and PoV treated pts, respectively. Discontinuation of study treatment for AE was reported in 49% and 41% of PiV and PoV treated pts, respectively. Thirty-five pts discontinued treatment due to PN with a median time to discontinuation of 5.6 mo. PN reversibility was observed following treatment interruptions and ADC dose modifications. Two of 9 Grade 5 AEs (sepsis, urosepsis) were attributed to CD22 ADC; no Grade 5 AEs were attributed to CD79b ADC. In Cohort C the most common tx-emergent AE ≥ 25%: fatigue (55%), nausea (45%), neutropenia (40%), sensory PN (30%), diarrhea (25%), constipation (25%) and pyrexia (25%). Grade ≥ 3 neutropenia was reported in 7 pts; no other Grade ≥ 3 AE was reported in >1 pt. Serious AE were reported in 5 pts. Two pts discontinued study treatment for AE. No Grade 5 AEs were reported. Overall response rate (ORR), complete (CR) and partial (PR) response rates, n (%) [95% CI], and median PFS in DLBCL (95% CI) are shown in the table. Median PFS in the FL cohorts are not reported due to insufficient follow-up duration. Table PoV (CD79b) + R PiV (CD22) + R PoV [1.8 mg/kg] + R (Cohort C) R/R DLBCL ORR CR PR mPFS (mo.) N=39 22 (56%) [41, 71] 6 (15%) [7, 30] 16 (41%) [26, 58] 5.4 (2.8-8.4) N=42 24 (57%) [41, 72] 10 (24%) [12, 39] 14 (33%) [20, 48] 5.2 (4.1-NR) N/A R/R FL ORR CR PR N=20 14 (70%) [47, 86] 8 (40%) [21, 64] 6 (30%) [14, 53] N=21 13 (62%) [40, 80] 2 (10%) [2, 30] 11 (52%) [30, 72] N=16 7 (44%) [20, 70] 0 7 (44%) [20, 70] Pharmacokinetic profiles were similar for both ADCs across DLBCL and FL with no free MMAE accumulation. Pts receiving PoV at 1.8 mg/kg had proportionately lower exposure of antibody conjugated MMAE compared to pts treated at the 2.4 mg/kg dose level. Conclusions: PoV and PiV + R were generally well-tolerated with similar toxicity profiles. Neutropenia, PN, and diarrhea were the principal toxicities. Similar efficacy was observed with both ADCs in heavily pretreated pts with DLBCL. The higher CR rate with PoV + R compared to PiV + R suggests greater clinical activity in r/r FL. Lower overall response rates were observed in r/r FL pts treated with a lower dose of PoV. Results based on longer follow-up to further assess differences in safety and tolerability between the two PoV doses in r/r FL will be presented. Additional data of pts who received crossover ADC + R treatment following documented disease progression on initial ADC + R treatment will also be presented. Combination studies of PoV + R with chemotherapy and with ADC schedules to reduce PN are ongoing or in planning. Disclosures Morschhauser: Genentech/roche: Honoraria, travel grants Other; Celgene: advisory boards, advisory boards Other, Honoraria. Off Label Use: obinutuzumab and lenlidomide in relapsed follicular lymphoma. Flinn:Genentech, inc.: Research Funding. Advani:Genentech, inc.: Research Funding. Diefenbach:Genentech, inc.: Research Funding. Press:Genentech, inc.: Research Funding. Chen:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Salles:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tilly:Genentech, inc.: Research Funding. Cheson:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Assouline:Roche: Honoraria, Research Funding. Dreyling:Roche: Honoraria, Research Funding. Hagenbeek:millenium: Membership on an entity's Board of Directors or advisory committees. Zinzani:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Yalamanchili:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment. Sharman:Gen: Research Funding.

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Safety and Efficacy Data for Combined Checkpoint Inhibition with Ipilimumab (Ipi) and Nivolumab (Nivo) As Consolidation Following Autologous Stem Cell Transplantation (ASCT) for High-Risk Hematological Malignancies — CPIT-001 Trial

Blood ◽

10.1182/blood-2018-99-113586 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 256-256 ◽

Cited By ~ 5

Author(s):

Alan P Skarbnik ◽

Michele L. Donato ◽

Robert Korngold ◽

Rena Feinman ◽

Scott D. Rowley ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Median Time ◽

Patient Population ◽

Research Funding ◽

Hematological Malignancies ◽

Checkpoint Inhibition ◽

Advisory Committees ◽

Safety And Efficacy

Abstract Rationale: ASCT remains a standard-of-care as consolidation or salvage for multiple myeloma (MM), post-salvage consolidation for Diffuse Large B-Cell Lymphoma (DLBCL) and upfront consolidation or salvage for Peripheral T-Cell Lymphomas (PTCL) Pts with high-risk disease still show poor outcome and frequent progression within the first 18 months. Maintenance strategies post ASCT, particularly in lymphomas, have failed to show benefit, underlining the need for novel approaches to help disease control following ASCT. We have previously reported on the preliminary safety and efficacy of checkpoint inhibitor consolidation with Ipi and Nivo following ASCT trying to take advantage of the immunological milieu during post-ASCT recovery (Skarbnik et al., ASH 2017). Here we present updated data from our Phase I CPIT-001 trial. Methods: Pts with high-risk DLBCL, PTCL or MM (as defined in Table 1, divided in cohorts) were eligible if they experienced at least stable disease after most recent salvage therapy (NHL, PTCL or relapsed MM) or after induction therapy for high-risk MM. Pts were enrolled prior to ASCT, starting in July 2016. All pts with DLBCL/PTCL received BEAM (carmustine 300 mg/m2 day -6, etoposide 200 mg/m2 and cytarabine 200 mg/m2 days -5 to -2, melphalan 140 mg/m2 day -1) as conditioning regimen for ASCT, all pts with MM received melphalan 200 mg/m2 on day -1 For pts who achieved appropriate hematologic recovery (ANC >800/mm3 and platelets > 20,000/mm3), Ipi/Nivo were started between days 14 and 28 post ASCT. The infusion schedule was: Ipi: 1 mg/kg; 6 doses Weeks 1, 4, 7, 10, 16, 22Nivo: 3 mg/kg; 12 doses Weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26 Primary objectives were: Safety profile evaluation; PFS and OS at 18 months (PFS18 and OS18). Cox proportional hazards regression was utilized to determine predictors of outcome. Results: 31 pts received at least one dose of Ipi/Nivo following ASCT and were included in the intent-to-treat population. Median follow up for the whole cohort is 16 months. As of February 2018, the FDA has halted all studies including checkpoint inhibitors for pts with MM. At that time, only one pt with MM was actively receiving Ipi/Nivo, which was then discontinued. At 18 months post ASCT, estimated PFS for the entire cohort was 67% and OS was 84% (Figures 1 and 2). Disease-specific PFS18 and OS18 are described in Table 2. At study entry, 48% of pts were in CR (NHLs) or stringent CR (sCR, MMs). At most recent follow-up (range 2-25 months) 71% of pts were in CR (NHL) or sCR (MM). Disease status at study entry (i.e. CR vs <CR) didn't correlate with PFS nor OS. 65% of pts developed immune-related adverse events (irAEs) grade 2 or higher, requiring treatment with systemic steroids. Most common irAEs of any grade were: colitis (58%), rash (48%), thrombocytopenia (45%), anemia (45%) and transaminitis (32%). One pt (3%) died from complications of pneumonitis related to study drugs. All other irAEs resolved. Median time from 1st Ipi/Nivo to development of irAEs was 4 weeks. Median time to improvement to Grade 1 or baseline was 1 week after high-dose steroids were initiated. Treatment-related AEs of any grade that led to discontinuation of Ipi/Nivo occurred in 6 pts (19%). Development of irAEs, use of steroids or length of steroid-exposure did not correlate with PFS or OS. Conclusion: At 18 months post-ASCT, PFS for pts with high-risk hematological malignancies is 67%. This number underscores the potential for longer remissions by associating checkpoint inhibition with ASCT. For patients in the transplant-naïve MM with high-risk cytogenetics cohort, the 71% PFS18 (fig 3) is particularly striking, when compared to median PFS of 13-15 months in previous reports of ASCT alone in this patient population (Sonneveld et al, Blood 2016). In addition, the primary-refractory DLBCL population (43% of which were not in CR at time of ASCT) presented with a PFS18 of 83% (fig 4), while the reported PFS18 for this patient population with ASCT alone is 50% (Crump et al, Blood 2017). The cohort of pts with DLBCL relapsed within 1 year of induction had the poorest outcomes, possibly related to these pts being the most heavily pretreated in the whole cohort (median of 3 prior lines of therapy), with 57% of pts in this cohort refractory to most recent line of therapy. The manageable toxicity profile, coupled with the encouraging efficacy outcomes warrant further evaluation of this approach in a Phase II trial, which is currently planned. Disclosures Skarbnik: Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau. Munshi:Kite: Speakers Bureau. Siegel:BMS: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Feldman:Pharmacyclics: Speakers Bureau; KITE: Speakers Bureau; Portola: Research Funding; Celgene: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Johnson and Johnson: Speakers Bureau; Janssen: Speakers Bureau. Biran:BMS: Research Funding; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Merck: Research Funding. Atkins:BMS: Consultancy; Merck: Consultancy.

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Quality of Life Scores Improve with Increasing Hemoglobin but Optimal Thresholds Vary According to Transfusion Dependence and Clinical Risk Scores: A Canadian Cross Sectional Study of 689 Patients with 2969 Measurements

Blood ◽

10.1182/blood.v128.22.3192.3192 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3192-3192

Author(s):

Rena Buckstein ◽

Richard A. Wells ◽

Nancy Y Zhu ◽

Michelle Geddes ◽

Mitchell Sabloff ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Advisory Board ◽

Risk Scores ◽

Advisory Committees ◽

Cross Sectional ◽

And Function

Abstract Background : We previously presented that selected quality of life (QOL) domains in MDS patients are impaired compared with age-matched controls and most impacted by hemoglobin (Hgb) level, transfusion dependence, frailty and comorbidity in an initial cohort of 236 patients from a Canadian MDS registry (Buckstein R. et al, Abstract 699, ASH 2012 and Abstract 2500, ASH 2009). The optimal Hgb threshold associated with improved QOL may vary according to health states that may fluctuate for any given patient. With longer follow up and greater sample size, we now examine the impact of Hgb levels on QOL in transfusion dependent (TD) versus independent (TI) patients and according to IPSS-R risk scores. Methods:Since 2008, we have prospectively assessed QOL in all patients registered in the Canadian national MDS registry using the instruments EORTC QLQ-C30, FACT-F, global fatigue scale (GFS) and EQ-5D, at enrollment and every 4-6 months. These QOL data are paired with disease specific and laboratory information at the same time intervals. Each patient could provide multiple QOL measurements at different time points. Clinically significant score differences were considered 10 points for the EORTC, 0.08 for the EQ-5D and 4 for the FACT F. General linear regression analysis was applied to search for a significant relationship between physical and social functioning, dyspnea, fatigue and QOL with Hgb, according to transfusion dependence, IPSS and IPSS-R measured categorically. To account for multiple comparisons among 5 Hgb categories, Bonferroni adjusted p-value < .01 was considered statistically significant. Results: 689 patients from 15 Canadian sites completed their first QOL assessment at a median time of 7.8 (IQR 2.7-23) months from MDS diagnosis. The median time from MDS diagnosis to death or last follow-up was 2.5 years (IQR 1.2-4.9). The median Hgb at enrollment was 100 g/L (IQR 86-113) and the distribution of risk scores included: very low (13%); low (35%); intermediate (28%); high (15%); and very high (10%). 27% of patients were TD at enrollment and 54% were TD at any time. The median number of QOL assessments per patient completed was 3 (IQR 2-6) with 547 patients completing at least 2, 424 at least 3 and 335 at least 4 serial QOL measurements at a median time interval of 17 weeks (IQR 13-25). When examined by Hgb thresholds, mean physical functioning, dyspnea, fatigue (QLQ-C30 and GFS) and global QOL improved with increasing Hgb. QOL symptom and function scores were clinically and statistically significantly superior in TI versus TD patients (table 1). The optimal discriminating Hgb threshold for improved symptom and function scores was 100 g/L for patients that were TI or with IPSS-R very low, low and intermediate risk MDS; and 90 g/L for high and very high risk disease (table 2). No discriminating threshold was found in TD patients. Conclusions: In the largest reported serial cross sectional population based assessment of QOL in MDS patients, we confirm that higher Hgb and transfusion independence have significant impact on QOL, symptoms and self-reported function and should be considered important surrogate endpoints for clinical improvement. Disclosures Buckstein: Novartis: Honoraria; Celgene: Honoraria, Research Funding. Wells:Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: advisory board; Novartis: Honoraria, Other: advisory board; Alexion: Honoraria, Other: Advisory board. Zhu:Celgene: Honoraria, 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; Novartis: Membership on an entity's Board of Directors or advisory committees. Geddes:Celgene: Other: Advisory Board, Research Funding. Sabloff:Gilead: Research Funding; Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Lundbeck: Research Funding. Leber:BMS Canada: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Keating:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Storring:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Leitch:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. St-Hilaire:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Membership on an entity's Board of Directors or advisory committees. Nevill:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: 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, Research Funding. Shamy:Celgene: Honoraria, Other: Advisory board; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: 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. Delage:Novartis: 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; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Upfront Autologous Stem Cell Transplantation for Newly Diagnosed Elderly Multiple Myeloma (MM) Patients: A Prospective Multicenter Study

Blood ◽

10.1182/blood.v126.23.1989.1989 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1989-1989

Author(s):

Laurent Garderet ◽

Cyrille Touzeau ◽

Anne-Marie Stoppa ◽

Denis Caillot ◽

Lionel Karlin ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Median Time ◽

Autologous Stem Cell Transplantation ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Introduction: Previous trials have shown that autologous stem cell transplantation (ASCT) is superior to conventional chemotherapy in terms of remission rate and PFS in younger MM patients. Concerns about toxicity and potential efficacy of ASCT in older MM patients lead most centers to limit ASCT indications to patients aged <65 years. However, at the era of novel induction regimens, and because of better patient selection and supportive care, ASCT may prove to be a valid treatment option even in older MM patients. Therefore, some investigators are questioning the widely used 65 years age limit. Patients and Methods: We prospectively analyzed the outcomes of 56 consecutive MM patients who had received ASCT between September 2012 and September 2014 in 6 institutions in France (protocol ClinicalTrials.gov Identifier: NCT01671826). Patients were newly diagnosed MM. For induction therapy, all patients received a bortezomib-based induction regimen (VD, VTD, VCD, or VRD, 4 to 6 cycles) according to center's local guidelines. Mobilization was performed with G-CSF or G-CSF+cyclophosphamide and plerixafor whenever needed. High-dose chemotherapy consisted of either 140 mg/m2 or 200 mg/m2 Melphalan. A short two months consolidation phase post ASCT was allowed (lenalidomide-dexamethasone, VD, VTD, VCD or VRD). No maintenance treatment was given. Response, disease progression and relapse were defined according to the IMWG uniform response criteria. All patients signed an informed consent form according to the EBMT guidelines. Results: At time of diagnosis, median age was 67 (range, 64-74) years with 23% of patients being >70 years. There were 30 males and 26 females. The immunoglobulin subtype was IgG (n=29), IgA (n=15), light chain (n=10), other (n=2). The Salmon and Durie stage was III in 89% of cases (n=47), and the ISS score was I (n=18; 35%), II (n=19; 37%), III (n=14; 27%). Patients had high risk cytogenetics features (t(4;14) and/or del17p) in 9 cases (16%). 10% of patients had a serum creatinine level >176 micromol/L. None of the patients underwent hemodialysis. The Sorror comorbidity score was 0 (34), 1 (6), 2 (2), 3 (6), 6 (1), unknown (7). The median age at time of ASCT was 68 years, and the median time from diagnosis to ASCT was 5 months. In an intention to treat analysis, out of 56 patients, 6 patients could not proceed to ASCT because of an early infectious death (n=1), serious comorbidity (n=2), disease refractoriness to induction (n=1), and failure to collect an adequate PBSC graft (n=2). A median of 5.31x106/Kg CD34+ cells could be collected. Disease status at time of ASCT was: CR (n=12; 24%), VGPR (n=19; 38%), PR (n=17; 34%), and SD/non-responding (n=2; 4%). The conditioning regimen consisted of 140mg/m² melphalan in 18 cases (36%) and 200mg/m2 in 32 patients (64%). Moreover, 4 patients (8%) received a tandem ASCT. The median time for neutrophils and platelets engraftment was 12 days. The day-100 post ASCT non-relapse mortality was 0% and the 2-year NRM was 4.2% (95% CI:[0.3-18.3]). The overall response rate at day 100 was 96% (CR: 34%, VGPR: 47%, PR: 15%, SD/non-responsive: 4%). At 3 months post ASCT, 82% patients were able to receive the planned post ASCT consolidation treatment. After a median follow-up of 12 months, the estimated progression-free (PFS) and overall survival (OS) rates at 2 years were 76% (95%CI: [61.6-94.1]) and 88% (95%CI: [76.7-100]), respectively. The incidences of infectious complications post ASCT, and response rates were comparable between the two melphalan dose levels (p=0.28). However, in the univariate analysis, the 200 mg/m2 melphalan conditioning group showed a better OS rate compared to the 140 mg/m2 group (1-year OS: 100% vs. 67%; p=0.012). Conclusion: These prospective multicenter results indicate that ASCT is a safe and effective treatment modality for elderly, but fit MM patients at the era of novel induction agents. Of note, patients above age 70 did not experience a worse prognosis. Thus, age per se should not be used as an exclusion criterion for ASCT. Longer follow-up data will be presented, but these results already set the frame for a randomized comparison to the non-transplant approaches in this patients' subgroup. Disclosures Garderet: Bristol-Myers Squibb: Consultancy. Touzeau:AbbVie: Research Funding. Stoppa:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. Karlin:Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees.

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Association between Quality of Response and Outcome in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib

Blood ◽

10.1182/blood-2018-99-111044 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1873-1873

Author(s):

Paolo Strati ◽

Mariela Sivina ◽

Ekaterina Kim ◽

Michael J. Keating ◽

William G. Wierda ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Treatment Initiation ◽

Treatment Discontinuation ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Genetics Research ◽

Baseline Characteristics

Abstract Introduction. In the context of chemoimmunotherapy, complete remission (CR) is more common and is associated with improved survival in patients with chronic lymphocytic leukemia (CLL). CR is less frequent in CLL patients treated with ibrutinib, and the prognostic significance of achieving CR with ibrutinib is indeterminate. Methods. We prospectively analyzed 208 CLL patients treated on a phase 2 study (NCT02007044) of first-line (deletion 17p only; n=27) or salvage ibrutinib (n=181), with or without rituximab, between 12/2013 and 01/2018. Response was assessed by international workshop on CLL 2018 guidelines. Categorical variables were compared using the χ2 or Fisher exact tests. Progression-free survival (PFS) was defined as time from treatment initiation to disease progression and/or death, and Kaplan-Meier curves compared using the log-rank test. A landmark analysis at median time of CR achievement (best response) was performed for PFS. Results. After a median follow-up of 34 months (range, 3-48 months), response was evaluable in 194 patients, overall response rate (ORR) was 99%, and CR rate was 24%, with negative minimal residual disease (MRD) in 3% of patients; median time to response was 10 months (range, 3-45 months) and median time to CR was 21 months (5-45 months). None of the patients' baseline characteristics associated with achievement of CR (Table). Among the 47 patients in CR, 7 (15%) discontinued treatment, after a median time from treatment initiation of 19 months (range, 10-39); the main cause of discontinuation was toxicity (5 patients), with second cancer (metastatic melanoma) and disease progression prompting treatment discontinuation only in 2 patients. Among the 145 patients in PR, 50 (34%) discontinued treatment, after a median time from treatment initiation of 14 months (range, 4-45 months); while the main cause of discontinuation was again toxicity (26 patients), 2nd cancers and progressive disease prompted treatment discontinuation in 5 and 14 patients, respectively. Remaining causes of treatment discontinuation among patients in PR were loss to follow-up (3 patients) and consolidation therapy (2 patients). Median PFS was not reached and 28 patients (13%) progressed and/or died. Achievement of CR significantly associated with prolonged PFS (4-year PFS 98% vs 78%, p=0.03)(Figure). The association between CR and prolonged PFS was also confirmed on a landmark analysis (21 months)(p=0.05). Among baseline characteristics shown in the Table, the only factor associated with prolonged PFS was absence of complex karyotype (4-year PFS 80% vs 40%, p=0.05). Median OS has not been reached and 16 (8%) patients have died; of these, only 1 patient was in CR (and cause of death was metastatic melanoma), whereas the remaining 15 were in PR. Among patients in PR, causes of death were: infections in 7 patients, 2nd cancers in 2 patients, Richter transformation in 2 patients and other in 4 patients (small bowel obstruction, colon perforation, intracranial hemorrhage, bradyarrhythmia). Conclusions. This is the first study showing that achievement of CR is a desirable endpoint for patients with CLL treated with ibrutinib, associating with prolonged PFS. Our results support the development of future combination studies, aimed at achieving higher rates of CR in patients treated with ibrutinib. Figure. Figure. Disclosures Wierda: AbbVie, Inc: Research Funding; Genentech: Research Funding. Jain:Infinity: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Infinity: Research Funding; ADC Therapeutics: Research Funding; Astra Zeneca: Research Funding; Cellectis: Research Funding; Verastem: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; ADC Therapeutics: Research Funding; BMS: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Adaptive Biotechnologioes: Research Funding; Celgene: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: 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; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:Adaptive Biotechnologies: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Dexamethasone, Rituximab and Cyclophosphamide (DRC) As Salvage Therapy for Waldenstrom Macroglobulinemia

Blood ◽

10.1182/blood.v128.22.2972.2972 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2972-2972 ◽

Cited By ~ 2

Author(s):

Jonas Paludo ◽

Jithma P Abeykoon ◽

Amanda Shreders ◽

Sikander Ailawadhi ◽

Morie A. Gertz ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

International Workshop ◽

Time To Event ◽

Advisory Committees ◽

Incurable Cancer ◽

Mutation Status ◽

Best Response

Abstract Background WM remains an incurable cancer despite recent advances. While a phase II trial has demonstrated efficacy of dexamethasone, rituximab and cyclophosphamide (DRC) in the treatment-naïve (TN) patients, this regimen has not been studied systematically in the relapsed/refractory (R/R) setting. Recent data has suggested the MYD88mutation status in WM patients can serve as a predictive marker with therapies such as ibrutinib. We examined the efficacy and tolerability of up to 6 cycles of DRC, with focus on R/R population and activity of this regimen with respect to the patients' MYD88L265Pstatus. Methods Records of WM patients seen consecutively at Mayo Clinic campuses in Rochester, Arizona and Florida from 01/2007 to 12/2014 were reviewed. MYD88L265P status, as assessed by AS-PCR, was recorded when available. Data obtained from symptomatic patients treated with DRC (dexamethasone 20 mg intravenously followed by rituximab 375 mg/m2 intravenously on day 1 and cyclophosphamide 100 mg/m2 orally bid on days 1 to 5) were analyzed. Time-to-event analyses were performed from DRC therapy using the Kaplan-Meier method. We used the Consensus response criteria (6th International Workshop). Results Of 100 symptomatic patients who received DRC, 50 had R/R WM (40% refractory) and 50 were TN. Table 1 shows the patients' baseline characteristics. In the R/R population, DRC was 2nd line (range 2-8) therapy in 58% of patients. The median IgM levels declined from 3,870 mg/dL to 1,846 mg/dL (p=0.0001) at best response. Median follow-up from DRC was 51 months (95% CI: 38-55). The median time-to-best response was 6.8 (0.5-28) months. Overall response rate (ORR) was 87% [VGPR 4%, PR 64%, MR 19%]. Four patients (9%) achieved SD and 2 patients (4%) had PD. Of the sixteen deaths (32%) noted at time of analysis, 11 were related to progressive disease. The median disease-specific survival (DSS) from DRC was not reached (NR) (95% CI: NR-NR). The median progression-free survival (PFS) and time-to-next-therapy (TTNT) were 32 months (95% CI: 15-51) and 50 months (95% CI: 35-60), respectively. In contrast, in the TN patients the median IgM levels declined from 4,130 mg/dL to 1,250 mg/dL (p=0.0001) at best response; median time to best response was 11 (0.6-47) months; median follow-up from DRC was 30 months (95% CI: 21-36). ORR was 96% [VGPR 17% (n=8), PR 70% (n=32), MR 9% (n=4)]. Of the 7 deaths (14%) at time of analysis, 4 were related to WM progression. Median DSS from DRC was NR (95% CI: NR-NR); median PFS and TTNT were 34 months (95% CI: 23-NR) and NR (95% CI: 37-NR), respectively. Among 29 genotyped patients in whom MYD88 mutation status was available, MYD88L265P was present in 25 patients (8 of 10 TN and 17 of 19 R/R patients). The response rates and the time-to-event outcomes were similar in the MYD88L265P and wild-type patients. Grade ≥3 adverse effects included neutropenia (20%), thrombocytopenia (7%) and infections (3%). Conclusions Similar to the frontline setting, DRC is an active and well-tolerated salvage regimen. In contrast to ibrutinib, DRC offers a less expensive, limited-duration treatment option, with preliminary data suggesting activity independent of patients' MYD88 mutation status. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Kumar:Glycomimetics: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Kesios: Consultancy; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy. Dispenzieri:Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; pfizer: Research Funding; Celgene: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Kapoor:Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding.

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Overview of Primary and Secondary Myelofibrosis in Young Adults: Genomic Characteristics, Treatment Strategies and Outcomes

Blood ◽

10.1182/blood-2019-123536 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4177-4177

Author(s):

Andrew T Kuykendall ◽

Chetasi Talati ◽

Kendra L. Sweet ◽

Eric Padron ◽

David A Sallman ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Treatment Strategies ◽

Cell Transplant ◽

Advisory Committees ◽

Treatment History ◽

Secondary Myelofibrosis

Introduction: Primary and secondary myelofibrosis (MF) [i.e. occurring after a prior diagnosis of polycythemia vera [PV] or essential thrombocythemia (ET)] are myeloid malignancies often diagnosed in the 6th and 7th decade of life. In the rare occurrence that younger patients receive this diagnosis, prognostic recommendations are poorly extrapolated and optimal treatment strategies are unclear. Prior studies assessing young MF patients have suggested a more indolent course for this cohort. Here we aim to analyze our experience with young MF patients in terms of genetic makeup, treatment history, and outcomes. Methods: We assessed a database of primary and secondary MF patients who presented to our center between 1/2000 and 6/2019. We identified patients who were 50 years or younger at the time of MF diagnosis. Clinical and genetic features along with treatment history and outcomes were analyzed. Kaplan-Meier method was used for survival analysis. Patients surviving at 240 months after diagnosis were censored at that time. Results: Among 599 MF patients, 63 (11%) were ≤50 at the time of diagnosis. Median age at diagnosis was 43.6 years (yr). Median time from diagnosis to first presentation to our institution was 4.2 months (mo) (range 0-35 yr). Thirty-eight (60%) and 44 (70%) were seen within 1 and 5 years of diagnosis, respectively. Females accounted for 62% (n = 39) of patients. Forty-five (71%) patients had primary MF, 4 (6%) had post-PV MF and 13 (21%) post-ET MF. Median follow-up for the cohort was 94.9 mo. Among 62 patients in whom IPSS at diagnosis could be calculated, 20 (32%) were low, 27 (44%) intermediate-1, 12 (19%) intermediate-2, and 3 (5%) high-risk. JAK2 mutation was detected in 22/60 (37%), CALR in 21/44 (48%), MPL in 0/49 (0%). One patient was triple-negative. Extended targeted gene sequencing was performed in 42/63 patients during their clinical course. Sequencing occurred at a median time of 2.6 yr after diagnosis (range 0-35 yr). Genes most commonly mutated were ASXL1 (12%), TET2 (12%), EZH2 (10%), and DNMT3A (10%). No mutations involving SRSF2, U2AF1, ZRSR2, or SF3B1 were seen. Thirteen patients did not receive active treatment during follow-up. Among those receiving treatment, median time to first treatment was 9.4 mo (range 0-331 mo). The most common initial treatments were erythropoiesis-stimulating agents (ESAs) (14%), hydroxyurea (28%), and ruxolitinib (22%). In total, 29 (46%) received ruxolitinib with median time to ruxolitinib treatment of 27.2 mo. Median duration of ruxolitinib treatment was 44.5 mo. Fourteen patients underwent allogeneic hematopoietic stem cell transplant (AHCT) at a median of 57.4 mo after diagnosis (range 6-123 mo). Transformation to acute myeloid leukemia (AML) occurred in 5 patients at a median time of 99 mo (range 51-178 mo) after diagnosis. Median overall survival (OS) was not reached. Five and 10-year OS estimated at 93% and 77%, respectively. No difference was seen in OS for patients with primary and secondary MF (p = 0.40). Conclusions: Primary and secondary MF are rarely diagnosed in patients ≤ 50 years old. In this cohort, patients are often CALR mutant, have lower-risk disease, and lack splicing mutations. Initial treatment strategies are varied, but favor cytoreductive approaches. The prognosis in these patients is favorable, but high-risk mutations can occur and progression to AML occurs in a minority of patients. AHCT remains a curative option; however, optimal timing for transplant is not clear. Figure Disclosures Kuykendall: Celgene: Honoraria; Janssen: Consultancy; Abbvie: Honoraria; Incyte: Honoraria, Speakers Bureau. Talati:Astellas: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Agios: Honoraria; Pfizer: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Honoraria. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding. Komrokji:JAZZ: Consultancy; Agios: Consultancy; celgene: Consultancy; pfizer: Consultancy; Incyte: Consultancy; Novartis: Speakers Bureau; DSI: Consultancy; JAZZ: Speakers Bureau.

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