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In: The Lancet, Elsevier BV, Vol. 403, No. 10442 ( 2024-06), p. 2416-2425

Type of Medium: Online Resource

ISSN: 0140-6736

URL: Article

DOI: 10.1016/S0140-6736(24)00549-X

Language: English

Publisher: Elsevier BV

Publication Date: 2024

detail.hit.zdb_id: 2067452-1

detail.hit.zdb_id: 3306-6

detail.hit.zdb_id: 1476593-7

SSG: 5,21

In: The Lancet, Elsevier BV, Vol. 403, No. 10442 ( 2024-06), p. 2405-2415

Type of Medium: Online Resource

ISSN: 0140-6736

URL: Article

DOI: 10.1016/S0140-6736(24)00548-8

Language: English

Publisher: Elsevier BV

Publication Date: 2024

detail.hit.zdb_id: 2067452-1

detail.hit.zdb_id: 3306-6

detail.hit.zdb_id: 1476593-7

SSG: 5,21

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 297-297

Abstract: Introduction: Preclinical data suggest that PD-1 and PD-L1/PD-L2 mediate immune evasion in CLL. However, clinical data (Ding, BLOOD 2017) demonstrate that pembrolizumab monotherapy (pembro) is ineffective in relapsed/refractory (r/r) CLL patients (pts) (ORR 0%, med PFS 2.4 months). Additional data with an anti-PD1 demonstrated a 90% failure rate in Richter's Transformation (RT) with a med 2-month OS (Rogers, BJH 2018). Combinations may represent the future of anti-PD-1 therapy in CLL/RT, especially in RT pts rel/ref to ibrutinib, where median OS is ~3.5 mos. We hypothesized synergistic activity with PD-1 + PI3K blockade. Umbralisib (UMB), is a highly-specific PI3K-δ inhibitor with additional effects on casein kinase-1 epsilon (CK-1ε), which may have an inhibitory effect on Treg function (Deng et al, 2016). We tested the safety and activity of UMB in combination with the anti-CD20 mAb ublituximab (UTX) and pembro in r/r CLL and RT - the first reported combination of a PD-1 inhibitor + PI3K-δ inhibitor in this population. Methods: Ph I (3+3 design), multicenter study to assess the safety/efficacy of UMB + UTX + pembro in pts with r/r CLL and RT. Treatment for CLL pts involved three stages: Induction: UMB (800mg daily) and UTX (900mg 3 out of 4 wks) for the first two 28-day cycles. Consolidation: Pembro (dose level 1=100mg, dose level 2=200mg) was then initiated every 3 wks in combination with UMB and UTX (900mg week 2 of cycle 4 and 6) for cycles 3-6. Maintenance: Cycle 〉 6, UMB 800 mg daily until progressive disease (PD) or unacceptable AE. For RT pts, all study drugs are started in cycle 1 with the following schedule: UMB 800 mg daily; UTX 900 mg cycle 1 (D1, 8, 15), D1 cycles 2-4, cycle 7 and q3 cycles thereafter; and pembro D3 of cycle 1 and D2 of cycles 2-4. The primary endpoint is safety of the triple combination with efficacy as a secondary endpoint. Response assessments for CLL, based on the iwCLL 2008 criteria, were performed after cycles 2, 6 and 12. RT response assessments (Cheson 2007) were completed at the end of cycles 2, 4 and every 3 cycles until month 12. Peripheral blood and/or bone marrow biopsy, enriched for mononuclear cells, were obtained for correlative analyses at screening, month 2 and 6. Results: Fourteen pts have been treated to date: 9 with CLL (3 at 100 mg pembro / 6 at 200 mg pembro) and 5 with RT (4 at 100 mg pembro / 1 at 200 mg). Baseline demographics were as follows: male/female (9/5), med age 71 yrs (range 60-81), med prior therapies 2 (1-8), 79% were refractory to immediate prior therapy. 10 pts had prior ibrutinib of which 9 were ibrutinib refractory. 64% of pts had at least 1 high risk genetic feature (del17p, del11q, TP53 mut, NOTCH1 mut or complex karyotype). AE's (all causality) were manageable. Grade 3/4 AE's occurring in ≥ 3 pts included neutropenia (n=6, 43%), ALT/AST increase (n=3, 21%) and hypophosphatemia (n=3, 21%). One DLT occurred in a CLL pt at 200 mg dose level (ALT/AST elevation) which trigged expansion to 6 pts. No additional DLTs were reported, and no MTD was achieved. No increase in expected grade ≥ 3 PI3Kδ-associated toxicities were noted (1 pneumonitis event, no colitis events). ORR was 89% for CLL pts with ORR of 75% in BTK refractory CLL pts (3/4). Notably 2/4 BTK refractory CLL pts achieved a response to UMB + UTX (U2) induction alone prior to the addition of pembro. 4/5 RT pts were eligible for efficacy evaluation with 50% ORR (2/4, CR). The 2 RT CRs were durable and are ongoing (15+ mos and 7+ mos); both pts were ibrutinib refractory and had 7 (including SCT) and 8 prior lines respectively, and one had failed CAR-T. With a med follow up of 15 mos, 10/14 (71%) remain progression free (range 3 - 44 mos, Fig 1), including one CLL pt who completed consolidation and has been off therapy for 27+ mos. Sequential sampling for correlative studies demonstrated modest changes in Tregs numbers (Fig 2). Conclusion: The triplet combination of umbralisib + ublituximab + pembro was well-tolerated. Responses were durable in BTK refractory, high risk pts, including two CR's in RT pts. In contrast to pembro monotherapy, data suggest that CLL/RT pts who achieve ≥ PR with this checkpoint inhibitor-containing regimen can achieve durable responses. Correlative studies suggest that maintenance of Tregs may limit autoimmune sequelae. Enrollment is ongoing in both the CLL (BTK refractory only) and RT cohorts. Disclosures Mato: AbbVie: Consultancy, Research Funding; Portola: Research Funding; Regeneron: Research Funding; AstraZeneca: Consultancy; Johnson & Johnson: Consultancy; Celgene: Consultancy; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Acerta: Research Funding; Prime Oncology: Honoraria. Svoboda:Regeneron: Research Funding; KITE: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding. Schuster:Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding; Dava Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Research Funding. Becker:GlycoMimetics: Research Funding. Brander:DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Dwivedy Nasta:Aileron: Research Funding; Pharmacyclics: Research Funding; Debiopharm: Research Funding; Incyte: Research Funding; Rafael/WF: Research Funding; Roche: Research Funding; Takeda/Millenium: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Other: DSMC. Landsburg:Takeda: Consultancy; Curis: Consultancy, Research Funding. Kennard:AbbVie, Gilead, Verastem: Consultancy. Zelenetz:Abbvie: Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy; Novartis/Sandoz: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding. Purdom:TG Therapeutics: Employment, Equity Ownership. Paskalis:TG Therapeutics: Employment, Equity Ownership. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics: Employment, Equity Ownership. Weiss:TG Therapeutics: Employment, Equity Ownership. Shadman:Gilead Sciences: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy; Beigene: Research Funding; AbbVie: Consultancy; Genentech: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; Genentech: Consultancy; Mustang Biopharma: Research Funding; Acerta Pharma: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding; Verastem: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-117526

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1648-1648

Abstract: Introduction Transformation of chronic lymphocytic leukemia (CLL) into Hodgkin lymphoma (HL) is a rare, but recognized complication of CLL. The prognosis of CLL with HL Transformation (HT) appears significantly worse than de novo HL, but most series are small and there are limited published data. These reports have prompted several groups to recommend aggressive therapy with stem cell transplantation (SCT) in first complete remission (CR1). We describe the largest reported series of HT patients (pts) with analyses of the clinicobiologic characteristics, treatment patterns, and clinical outcomes based upon our multi-institutional clinical experience. Methods Pts diagnosed with HT from 01/2000 - 01/2018 were retrospectively identified in 13 tertiary cancer centers. Clinicobiologic characteristics, treatment type, and survival outcomes for each pt were analyzed. Overall survival (OS) was measured from the time of HT diagnosis until time of death. OS estimates were calculated using the Kaplan-Meier method. The log-rank test was used to calculate differences in survival. Results Ninety-four pts with HT were identified. Median age at HT was 67 years (yrs; range, 38-85) and 81% of the pts were male. Median time from CLL diagnosis to HT was 5.5 yrs (range, 0-20.2; 7 pts with simultaneous diagnosis of CLL and HL). At initial CLL diagnosis, 31%, 34%, 21%, 10%, and 4% were Rai Stage 0, 1, 2, 3, and 4, respectively. At CLL diagnosis, 67% (25/37) had an un-mutated IgVH gene, 36% (21/59) had del(13q), 32% (14/44) had trisomy 12, 24% (14/59) had del(11q), and 15% (9/61) had del(17p). Prior to HT diagnosis, pts had a median of 2 (range, 0-12) therapies for CLL. Seventeen (18%) had no prior CLL treatments. Forty-three (46%) and 25 (27%) patients had received purine analogue- and ibrutinib-based therapy prior to HT, respectively. Baseline characteristics at HT are described in Table 1. As initial therapy for HL, the majority of pts (61%, n = 62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine) at full (n = 48) or reduced (n = 14) doses. Of these, CD20 monoclonal antibody was added in 6 and Bruton-tyrosine kinase inhibitor was added in 2. Ten (11%) received a brentuximab-based regimen. Seven (7%) received an RCHOP-based regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Six patients (6%) received no therapy for HT due to frailty. Subsequent therapy included autologous SCT and allogeneic SCT in 7 (7%) and 11 (12%) of patients, respectively. Two (2%) and 5 (5%) pts received their autologous and allogeneic SCT while in CR1, respectively. The median number of treatments for HT per pt was 1 (range, 0-5) with 59 (61%) pts only receiving one line of therapy. After HT diagnosis, pts had a median follow-up of 1.6 yrs (range, 0.0 - 15.1). Two-yr OS after HT diagnosis was 72% (95%CI 62 - 83%). The pts who received any CLL directed therapy (n = 80) prior to HT had a significantly lower estimated 2-yr OS of 69% (95%CI 58 - 82%) compared with pts who did not receive any prior CLL-directed therapy (n = 17; 93%; 95%CI 82-100%; p 0.02; Figure 1). Pts who received purine-analogue-based therapy for their CLL prior to HT had a significantly lower estimated 2-yr OS of 60% (95%CI 46 - 79%) compared with pts who did not receive purine-analogue-based CLL-directed therapy prior to HT (n = 51; 83%; 95%CI 73 - 96%; p 0.009; Figure 2). Although limited by small sample size, the pts who underwent SCT for HT in CR1 had a similar 2-yr OS (n = 7; 67%; 95%CI 38-100%) to pts who did not undergo SCT for HT in CR1 (n = 87; 72%; 95%CI 63 - 84%; p 0.46; Figure 3). Conclusions In this retrospective analysis, we describe the largest reported series of pts with HT from CLL. Two-yr survival in pts with HT was shorter than what is historically expected in patients with de novo HL, but longer than what is expected in CLL pts who transform to diffuse large B-cell lymphoma. Pts with HT who have received prior CLL-directed therapies (specifically purine-analogue-based treatments) are estimated to have a shorter 2-yr OS, likely due to underlying immunosuppression. The majority of pts (61%) only received 1 line of HL therapy and only 20% went on to receive SCT (7% while in CR1), indicating that these patients can have prolonged OS after achieving response to first-line therapy for HT and may not require SCT in CR1. Further study of this rare population is required to determine optimum management. Disclosures Kander: AstraZeneca: Consultancy. Parikh:Gilead: Honoraria; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Research Funding; MorphoSys: Research Funding; Pharmacyclics: Honoraria, Research Funding. Shadman:Acerta Pharma: Research Funding; Verastem: Consultancy; Celgene: Research Funding; Gilead Sciences: Research Funding; Mustang Biopharma: Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Consultancy; Beigene: Research Funding; Genentech: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; AbbVie: Consultancy; TG Therapeutics: Research Funding; Genentech: Consultancy. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Mato:Portola: Research Funding; AstraZeneca: Consultancy; Acerta: Research Funding; Prime Oncology: Honoraria; Regeneron: Research Funding; Celgene: Consultancy; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding; Johnson & Johnson: Consultancy; AbbVie: Consultancy, Research Funding. Hill:Amgen: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: 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; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: 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; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Danilov:Verastem: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Astra Zeneca: Consultancy; Gilead Sciences: Consultancy, Research Funding. Phillips:Abbvie: Research Funding; Bayer: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy. Brander:Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Smith:BMS: Consultancy; Portola: Honoraria. Davids:Surface Oncology: Research Funding; Roche: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Surface Oncology: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; MEI Pharma: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Research Funding; Roche: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; BMS: Research Funding; MEI Pharma: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy; Merck: Consultancy; Celgene: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Celgene: Consultancy; BMS: Research Funding; Surface Oncology: Research Funding; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-113173

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 183-183

Abstract: Introduction: Venetoclax is a potent BCL-2 inhibitor that is approved as monotherapy and in combination with rituximab for patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) in the United States, and as a monotherapy for patients with 17p deletion or TP53 mutation in the European Union and other countries. Here we report the long-term efficacy and safety of the combination of venetoclax and rituximab from this phase 1b study with a median follow up of 〉 4 years, two years beyond when initially published. Methods: Patients received daily venetoclax (200 - 600mg) and 6 - 9 doses of rituximab over 6 months, then venetoclax monotherapy.(NCT01682616; Seymour, et al. Lancet Oncol. 2017; 18(2):230-240.) Minimal residual disease (MRD) was assessed in bone marrow (BM) using ≥4-color flow cytometry (min sensitivity: 0.01%). As amended in specific protocol versions, patients who achieved complete remission (CR) or BM MRD-negativity regardless of CR status (collectively considered as deep responses) could stop venetoclax and remain on study, retreating with venetoclax +/- rituximab at clinical disease progression (iwCLL criteria). Results: Forty-nine patients, with a median 2 (range: 1 - 5) prior therapies, were enrolled. As of June 4, 2018 (N=49), the median time on study was 4.1 years (range: 0 - 5.8) and the median time on venetoclax was 2.5 years (range: 0 - 5.8). The overall response rate (N=49) was 86%, CR rate was 51%, and BM MRD-negativity rate was 61%. The 48-month estimates (N=49) for overall survival was 89% (95% CI: 75%, 95%), progression free survival was 61% (95% CI: 45%, 74%), and duration of response was 64% (95% CI: 46%, 77%) (for patients with BM MRD-negativity, 88% [95% CI: 66%, 96%]). The adverse events of any grade occurring in 〉 15% of patients beyond 2 years of treatment were upper respiratory infection, neutropenia, and diarrhea (Table). Disease progression occurred in 17 patients, 14 while on continuous therapy: 5 with Richter transformation at a median of 5 months (range 1 - 8), 9 with CLL progression at a median of 29 months (range: 12 - 55). Three patients (2 MRD-positive CR and 1 MRD-negative CR with CLL cells detectable below the threshold of 10-4) progressed after stopping venetoclax (asymptomatic progression at 23, 24 and 38 months off venetoclax). All three have been re-treated with venetoclax plus rituximab, resulting in CR in one patient (duration of ongoing subsequent CR, 17 months), one partial response (PR) followed by progressive disease 18 months later, and results are pending for the third patient. Fifteen additional patients stopped venetoclax per protocol following the achievement of a deep response (median duration [range] of treatment 19 months (range: 8 - 40);13 MRD-negative CR, 2 MRD-negative PR) (Figure). Four have discontinued the study (withdrew consent [n=4] ) and 11 remain on study in long term follow up with a median duration of ongoing response of 49 months (range: 32 - 59), and a median of 33 months (range: 12 - 58) off venetoclax to date. Twelve patients who have received continuous venetoclax and remain on study, remain free of disease progression: 8 in CR (7 MRD-negative, 1 MRD-positive) and 4 in MRD-negative PR. Median duration of response on therapy is 51 months (range: 44 - 66). The 4 patients with PR do not meet CR criteria because of lack of BM biopsy results (n=2) and residual adenopathy (n=2; max node dimension; 17 and 23 mm). The other 5 patients have discontinued because of withdrawal of consent (n=2; 1 without response, 1 MRD-positive PR) and adverse events (n=3; tumor lysis syndrome, worsening peripheral neuropathy, both without response, and fatal ischemic heart disease considered unrelated to therapy in MRD-negative CR [n=1]). Conclusions: Venetoclax with rituximab induces deep and durable responses in patients with previously treated CLL, with 51% achieving CR and 61% achieving BM MRD-negativity. Those with a deep response can discontinue venetoclax and maintain prolonged treatment-free remission of more than three years, especially if MRD-negative. Disclosures Brander: Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Seymour:Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding. Ma:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Acerta: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: 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; Genentech: Membership on an entity's Board of Directors or advisory committees. Anderson:Genentech: Research Funding; AbbVie, Inc: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties. Choi:Genentech: Speakers Bureau; AbbVie, Inc: Consultancy, Speakers Bureau; Rigel: Consultancy; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Speakers Bureau. Kipps:Genentech Inc: Consultancy, Research Funding; Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Masud:AbbVie, Inc: Employment, Equity Ownership. Nandam:AbbVie, Inc: Employment, Equity Ownership. Kim:Abbvie: Employment, Equity Ownership. Verdugo:AbbVie, Inc: Employment, Equity Ownership. Roberts:AbbVie: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-183

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 1-3

Abstract: Introduction: Medical comorbidities influence survival in CLL. We previously reported on a simplified CLL-specific comorbidity scale, the CLL-CI (Gordon et al. 2019), which required assessment of only three organ systems and was predictive of outcomes in a heterogeneous retrospective patient cohort. Herein we analyzed CLL-CI among patients treated with ibrutinib. Methods: This retrospective study included 339 CLL patients treated with ibrutinib at 9 academic centers between 2014-2019. Vascular, endocrine and upper-gastrointestinal organ systems were assessed at the time of ibrutinib initiation. Each was scored from 0 to 3, in order of increasing severity of dysfunction to generate the CLL-CI score (range, 0-9; Figure A). As established previously, CLL-CI≥2 was deemed high-risk. Event free survival (EFS) was measured from start of ibrutinib to development of new CLL-related symptoms, disease progression, start of a new therapy or death. Overall survival (OS) was measured from treatment initiation to death. Patients with no EFS or OS events were censored at last follow up. The Kaplan-Meier method and log-rank test were used to estimate and compare survival. Multivariable Cox regression was utilized to model EFS and OS. Differences between CLL-CI groups were evaluated with Wilcoxon rank sum and Fisher's exact tests. Results: Median age was 68 years (range, 30-91), 240 (71%) were treated in the relapsed/refractory setting (range of prior therapies, 0-10). Advanced Rai stage (3-4) was present in 206 (61%) and TP53 aberrancy was present in 93 (27%) patients at the start of ibrutinib therapy. Median follow up was 23 months (range, 1-71). CLL-CI score was high (≥2) in 202/339 patients (60%). Patient characteristics were well balanced between subgroups (CLL-CI & lt;2 vs ≥2). The median number of prior therapies was 1 in both groups. The distribution of Rai stage, TP53 aberrancy and IGHV mutational status (available in 48% of patients), were similar. In multivariate models adjusted for age, del(17p) and relapsed disease, high CLL-CI was associated with shortened EFS (HR=1.65; p=0.014, Figure) and OS (HR=1.73; p=0.1). CIRS score≥7 also correlated with EFS (HR=1.91; p=0.002) and OS (HR=2.78; p=0.006). Ibrutinib discontinuation rates due to adverse events were more frequent in patients with CLL-CI ≥2 (25% vs 14%; p=0.014). However, dose reduction rates were similar (24% vs 20%; p=0.51). Fifty-two deaths occurred: 40 in the high CLL-CI subgroup and 12 in the low CLL-CI subgroup. Cause of death was known in 31 patients. Death due to disease progression was more frequent in the high CLL-CI subgroup (28% vs 8%; p & lt;0.001). Infection was the second most common cause of death and occurred at a similar rate in both groups (13% vs 16%; p=0.66). Two deaths occurred due to cardiac causes, both in the high CLL-CI group. Since some of the key ibrutinib toxicities (atrial fibrillation, hypertension) may not have been accounted for in the CLL-CI we further elucidated their possible impact. Cardiac disease was significantly more prevalent among patients with high CLL-CI (37% vs 16%, p & lt;0.001; severe - 13% vs 5%; p=0.013) as was hypertension (63% vs 35%; p & lt;0.001; severe - 27% vs 13%; p=0.004). When computing pairwise correlation coefficients, we found that vascular and endocrine comorbidities significantly correlated with both cardiac disease and hypertension (Spearman ρ = 0.15 to 0.27). However, re-computing CLL-CI score upon inclusion of those categories did not influence the EFS concordance probability (CLL-CI, 0.669 vs CLL-CI plus cardiac and hypertension, 0.664). Conclusions: Here we present the largest cohort of CLL patients treated with ibrutinib in whom comorbidities have been systematically assessed. We find that the CLL-CI (which assesses endocrine, vascular and upper gastrointestinal conditions) correlates with survival and tolerance of therapy in this population. Unexpectedly, we found that hypertension and cardiac comorbidities did not improve CLL-CI's discriminatory power. This result combined with the simplicity of scoring the CLL-CI makes it an attractive tool for clinical practice. CLL-CI needs to be explored prospectively in patients treated with ibrutinib and other targeted therapies. Disclosures Patel: Genentech: Consultancy, Speakers Bureau; BeiGene: Consultancy; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Kite: Consultancy. Cohen:Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy; Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding. Choi:Pharmacyclics/Abbvie: Research Funding; Genentech: Consultancy. Hill:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Shadman:Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding; Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy. Stephens:Innate: Consultancy; Gilead: Research Funding; Verastem: Research Funding; Janssen: Consultancy; Acerta: Research Funding; Pharmacyclics: Consultancy; MingSight: Research Funding; Beigene: Consultancy; Arqule: Research Funding; Juno: Research Funding; Karyopharm: Consultancy, Research Funding. Brander:Novartis: Consultancy, Other; NCCN: Other; Tolero: Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; Ascentage: Other, Research Funding; ArQule: Consultancy, Other, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; Novartis: Consultancy, Other; NCCN: Other; Verastem: Consultancy, Honoraria, Other, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Pfizer: Consultancy, Other; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; MEI Pharma: Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; Genentech: Consultancy, Honoraria, Other, Research Funding; DTRM: Other, Research Funding; BeiGene: Other, Research Funding; Teva: Consultancy, Honoraria. Danilov:BeiGene: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy; Bristol-Myers Squibb: Research Funding; Rigel Pharmaceuticals: Consultancy; Astra Zeneca: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Verastem Oncology: Consultancy, Research Funding; Takeda Oncology: Research Funding; Gilead Sciences: Research Funding; Bayer Oncology: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Nurix: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-136808

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 19-22

Abstract: Introduction: Venetoclax has demonstrated deep responses and sustained progression-free survival and is well tolerated in patients (pts) with previously untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) in clinical trials. Some early studies provided initial insight of venetoclax utilization in the real-world (RW), but RW evidence focusing on venetoclax effectiveness and safety is still limited. This study assessed venetoclax effectiveness, safety, and treatment patterns in CLL pts treated in clinical practice. Methods: The CLL Collaborative Study of Real-World Evidence (CORE), a large multicenter chart review across 21 institutions in 4 countries, enrolled adult pts who initiated a first line (1L) therapy on/after 01/01/2012 or a new line of therapy (LOT) for R/R CLL/SLL on/after 02/12/2014 (current data cut through 06/08/2020). Clinical responses were abstracted from the medical records as assessed by treating physicians or investigators (iwCLL criteria were provided as reference). Overall response rate (ORR) was calculated as the proportion of pts with complete response (CR) or partial response (PR) out of pts with documented response assessments. Treatment patterns included choice of regimens and sequences, dose interruption, dose reduction, and discontinuation. Treatment discontinuation was defined as ending therapy for any reason(s) other than the completion of planned duration of therapy. Interruption was defined as a gap in the same LOT. All analyses were descriptive. Results: Of the 1231 CLL pts in the CORE data, 155 received venetoclax (21 in 1L and 134 in R/R) and were included in this study. Most of the sample were male (65%) and the median age at venetoclax initiation was 67.5 (range 37-91). For high-risk features among pts with available data, 33% (43/132 pts) had del(17p) or TP53 mutation, 24% (31/131 pts) had complex karyotype (≥ 3 abnormalities), and 77% (61/79 pts) had unmutated IGHV. At venetoclax initiation, 46%, 40%, and 14% of 151 pts with available data had low, medium, and high tumor burden, respectively. Median follow-up time from venetoclax initiation across all lines was 7.0 (0.1-43.1) months. Median number of prior LOT for R/R pts was 2 (1-5); the largest proportion of pts (36%) received venetoclax in 2L followed by 3L (26%). In 1L, venetoclax was most frequently used (62%) in combination (Figure 1), while in R/R setting venetoclax monotherapy was more commonly used (61%) followed by venetoclax + rituximab (25%; Figure 2). Majority of R/R pts (63%) received Bruton's tyrosine kinase inhibitors (BTKi) prior to venetoclax (Figure 2). Response was assessed and documented for 114 pts (74%). Among these, ORR was 75% (CR=40%, PR=35%) overall. Pts ≥65 years old had an ORR of 79% (CR=41%, PR=38%, n=74), and pts & lt;65 years old had an ORR of 70% (CR=40%, PR=30%, n=40). ORR was 77% (CR=40%, PR=37%; n=30) for pts with del(17p) or TP53 mutation and 78% (CR=34%, PR=44%; n=64) for pts without del(17p) or TP53 mutation. ORR was 87% (CR=48%, PR=39%; n=23) for pts with complex karyotype and 74% (CR=32%, PR=42%; n=71) for pts without complex karyotype. ORR was 72% (CR=36%, PR=36%; n=53) for pts with unmutated IGHV and 91% (CR=36%, PR=55%; n=11) for pts with mutated IGHV. Overall, 48% of pts had adverse events (AEs) recorded. Five R/R pts (3.2%) had TLS events (defined by Howard or Cairo-Bishop criteria), of which 3 (1.9%) were clinical. Of the 5 pts, 2 had high tumor burden, and 3 had medium burden. Other AEs of interest include neutropenia (17%), thrombocytopenia (9%), and diarrhea/colitis (5%). Overall, 32% of pts discontinued venetoclax; 13% of all pts discontinued venetoclax due to AEs (primarily neutropenia [n=2] and thrombocytopenia [n=2] ), followed by disease progression (8%). Venetoclax interruption rate was 14%, and dose reduction rate was 22% overall. Conclusions: Consistent with trial experiences, venetoclax demonstrates high response rates, including high-risk groups, and a manageable safety profile with low rates of TLS in clinical practice. Despite limitations of RW research, this study provides useful insights into treatment practices with venetoclax. Future research with longer follow-up is warranted to better understand the long-term clinical outcomes associated with venetoclax regimens. Disclosures Zheng: AbbVie: Current Employment. Sail:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Roeker:Abbott Laboratories: Other: spouse with minority ownership interest ; American Society of Hematology: Research Funding; AbbVie: Other: spouse with minority ownership interest . Manzoor:AbbVie: Current equity holder in publicly-traded company. Tuncer:AbbVie: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Allan:Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy. Ujjani:Gilead/Kite: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy; Atara: Consultancy, Honoraria; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding. Barr:Genentech: Consultancy; Merck: Consultancy; Abbvie/Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Verastem: Consultancy; TG therapeutics: Consultancy, Research Funding; Morphosys: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy, Research Funding. Brown:Novartis: Consultancy; Nextcea: Consultancy; Octapharma: Consultancy; MEI Pharma: Consultancy; Eli Lilly and Company: Consultancy; Astra-Zeneca: Consultancy; TG Therapeutics: Consultancy; Sunesis: Consultancy; Loxo: Consultancy, Research Funding; Sun: Research Funding; Rigel Pharmaceuticals: Consultancy; Pfizer: Consultancy; Catapult: Consultancy; Dynamo Therapeutics: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Gilead: Consultancy, Research Funding; Genentech: Consultancy; BeiGene: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Janssen: Honoraria; AbbVie: Consultancy; Kite: Consultancy; Juno/Celgene: Consultancy; Verastem: Consultancy, Research Funding; Acerta: Consultancy. Eyre:AbbVie: Consultancy, Honoraria, Other: travel support; KITE, AZ, Loxo Oncology at Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: travel support; Gilead: Consultancy, Honoraria, Other: travel support. Skarbnik:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CLL Society: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy; Beigene: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Verastem: Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bannerji:Regeneron Pharmaceuticals: Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc and Pharmacyclics LLC, an AbbVie Company: Research Funding; Sanofi-Pasteur: Other: Spouse is employee; AbbVie: Research Funding. Eichhorst:BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding. Brander:Verastem: Consultancy, Honoraria, Other, Research Funding; NCCN: Other; Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; MEI Pharma: Other, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; Pfizer: Consultancy, Other; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; NCCN: Other; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; Ascentage: Other, Research Funding; ArQule: Consultancy, Other, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; Novartis: Consultancy, Other; DTRM: Other, Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; BeiGene: Other, Research Funding. Sharmokh:AbbVie: Current Employment, Current equity holder in publicly-traded company. Jiang:AbbVie: Current Employment, Other: may hold stock or options. Pena:AbbVie: Current Employment, Current equity holder in publicly-traded company. Kamalakar:AbbVie: Current Employment, Other: may hold stock or other options. Emechebe:AbbVie: Current Employment, Current equity holder in publicly-traded company. Pivneva:Novartis: Consultancy, Other: Irina Pivneva is an employee of Analysis Group, Inc which received consultancy fees from Novartis.. Burne:Analysis Group, Inc., which has received consultancy fees from AbbVie: Current Employment. Guerin:Abbvie: Consultancy, Other; Novartis Pharmaceuticals Corporation: Consultancy, Other: Annie Guerin is an employee of Analysis Group, Inc. which received consultancy fees from Novartis.; Sanofi Genzyme: Consultancy, Other: Annie Guerin is an employee of Analysis Group, Inc. which received consultancy fees from Sanofi Genzyme.. Davids:Celgene: Consultancy; Research to Practice: Honoraria; AbbVie: Consultancy; Sunesis: Consultancy; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; BeiGene: Consultancy; Novartis: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; Adaptive Biotechnologies: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Gilead Sciences: Consultancy; Eli Lilly: Consultancy; Syros Pharmaceuticals: Consultancy; Zentalis: Consultancy; Merck: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Mato:AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-134676

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 5301-5301

Abstract: The microenvironment emerged as an attractive therapeutic target for chronic lymphocytic leukemia (CLL) given increasing evidence of its essential role in CLL cell survival. Plerixafor, a small molecule inhibitor of the CXCR4 receptor, is responsible for homing CLL to the microenvironment via a concentration gradient of its cognate ligand CXCL12 and has been safely tested in CLL patients. Lenalidomide is an immunomodulatory small molecule with efficacy in CLL, though monotherapy responses are typically partial and delayed. The combination of plerixafor with lenalidomide offers a novel non-cytotoxic alternative to improve clinical activity. Laboratory correlatives were designed to improve understanding of the effects of individual and combination therapy on the biology of CLL, assess for CLL mobilization from the microenvironment, and discover targetable drug resistance mechanisms to improve therapeutic efficacy. In this single institution phase I clinical trial, subjects were dose escalated on lenalidomide before initiation of plerixafor (Fig. 1). Primary safety response assessment was after one month of combination therapy. After four cycles of combination therapy, the primary response assessment was performed. Peripheral blood was collected for correlates and included an extended CLL phenotype panel (CLL cell-surface markers, CD184/CXCR4, sIgM, CD38, CD40, CD52, CD80, CD86, CD95) by flow cytometry with analysis of CLL subpopulations by CXCR4 expression levels. Phosphoprotein analysis was performed by phosphor-flow cytometry (phosflow). Fifteen subjects were enrolled with 10 subjects initiating plerixafor. Subjects included 4 females with a median 62 years of age and 4 prior lines of therapy. Two dose limiting toxicities (neutropenia, thrombocytopenia) occurred in plerixafor dose level two. Four patients reached primary response assessment. One patient had a PR and three patients had SD, however, all assessed patients derived improvement in nodal mass and disease symptoms. Phenotyping demonstrated a statistically significant decrease in CD20 and an increase in CD40 and CD95 for subjects initiating plerixafor. For the four subjects completing to end of study (EOS), the statistically significant decline in CD20 continued and CD95 and CD52 declined significantly. In all subjects, the proportion of CLL expressing high CD184/CXCR4 decreased significantly by four hours after plerixafor administration (Fig. 2). Phosflow for subjects initiating plerixafor revealed significant increases in phosphorylation of p-Akt, p-Mek, and p-Erk with decreases after plerixafor addition. For subjects reaching EOS, there was a significant decline in p-Syk from time of plerixafor addition but an increase in p-Akt. Lenalidomide plus plerixafor is a novel non-cytotoxic therapeutic alternative with an acceptable safety profile in heavily pretreated CLL patients. Grade 3/4 toxicities (and DLTs) were predominantly related to myelosuppression. Though the study is ongoing, the first two patients of cohort 3 have reached safety response assessment without a DLT; therefore a minimum total of 5 subjects were safely treated at dose level one (plerixafor 0.24mg/kg) and it was identified as the MTD. Plans are to proceed to a phase II trial to evaluate efficacy. Early responses among patients able to escalate lenalidomide to 10mg target dose are encouraging given the duration subjects remained on trial without progression. Correlates support mobilization of CLL from the microenvironment with decreases in CXCR4 expression and downstream signaling. Increases of CD40, CD80 and CD86 on lenalidomide monotherapy suggest immunomodulatory actions. Ongoing study will confirm observed trends, and improve understanding of response and resistance mechanisms for translation into optimized treatment strategies. Disclosures: Brander: Celgene: Research Funding, Research Fund provided to lab but not author Other. Off Label Use: Lenalidomide and Plerixafor are being studied in this Phase I clinical trial but have not been FDA approved for the indication of CLL. Allgood:Celgene: Research Funding. Lanasa:Celgene: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.5301.5301

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1626-1626

Abstract: Abstract 1626 Background: Diffuse Large B-cell Lymphoma (DLBCL) patients with primary refractory or multiply relapsed disease have limited treatment options. Therefore it is imperative that novel drugs be tested to find new, effective approaches for these patients. With evidence demonstrating that increased vascularity and pro-angiogenic factors correlate with adverse prognosis in the hematologic malignancies, angiogenesis has emerged as a novel therapeutic target. PTK787/ZK222584 is an orally active amino-phthalazin that inhibits all known tyrosine kinase receptors of vascular endothelial growth factor (VEGF). The efficacy, safety and tolerability of PTK787/ZK222584 in patients with rel/ref DLBCL was evaluated in this non-randomized phase II study. Patients and Methods: Patients with relapsed or refractory DLBCL were eligible. Additional key inclusion criteria were negative proteinuria, and normal renal and liver function. Central nervous system disease, prior allogeneic transplant, recent chemotherapy, or previous anti-VEGF therapy excluded subjects from enrollment. All patients inititated PTK787/ZK222584 at a dose of 750mg by mouth (PO) daily on day 1 of a 28 day cycle. Drug dose was increased weekly, initially to a dose of 1000mg PO daily and then to a target dose of 1250mg daily unless a grade ≥2 toxicity (using NCI CTC V3.0) developed. Primary endpoint was response (complete response (CR) + partial response (PR)); secondary endpoints included safety and tolerability. Results: Twenty patients (11 female) with a median age of 60 years were enrolled. Sixty three percent of patients had received 〉 3 prior therapies and 26% had prior autologous stem cell transplantation. Patients received a median of 3 cycles of PTK787/ZK222584 (range 0–6). Ten patients were on study drug for at least 3 cycles and are evaluable for response: one patient had a CR, four patients had stable disease (SD), and the remaining 5 patients had progressive disease. The patient with a CR subsequently underwent autologous stem cell transplantation and was alive without evidence of disease 64 months after study completion. One patient with SD withdrew to pursue other treatment options and the other 3 continued study drug, but all developed progressive disease within the next 3 months. Of the 10 patients who withdrew prior to completing 3 cycles, six withdrew after a median of 1 cycle because of rapidly progressive disease. Three withdrew because of adverse events of sepsis resulting in death in one patient, altered mental status despite dose reductions in one, and recurrent grade 3 transaminitis in the third. One patient withdrew to pursue other treatment options. Eighteen of the 20 patients enrolled escalated to the full target dose of 1250mg, but 6 required at least 1 dose reduction due to adverse events (sepsis, vertigo, transaminitis, rash or fatigue). There were no episodes of grade 3 / 4 proteinuria but grade 3 / 4 hypertension occurred in 10% and grade 3 / 4 thrombocytopenia in 20%, with the remainder of grade 3 / 4 toxicities occurring in 〈 10%. The most common toxicities occurring in greater than 15% of patients across all grades included nausea (75%), fatigue (65%), anorexia (45%), anemia (35%), vomiting (35%), thrombocytopenia (25%), HTN (25%), diarrhea (25%), proteinuria (25%), fever (20%), constipation (20%), and dizziness (20%). Conclusion: PTK787/ZK222584 is an orally active VEGF inhibitor which was generally well tolerated in a heavily pretreated population of patients with DLBCL. Although 1 patient achieved a CR and remains disease free after autologous stem cell transplant, the remaining patients developed progressive disease or had adverse events suggesting that this agent is unlikely to be useful as a single agent in aggressive lymphoma. The excellent response in one patient, however, raises the possibility that drug response may occur in a subset of patients so the identification of tumor specific biomarkers to predict responding patients is needed. Disclosures: Rizzieri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.1626.1626

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 830-830

Abstract: Introduction: Venetoclax (VEN) is a selective, orally bioavailable BCL-2 inhibitor. This is a phase 1b, study of VEN plus rituximab (R) to determine safety, PK and preliminary efficacy in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). The recommended phase 2 dose for VEN plus R was previously reported to be 400mg/day. The aims of this analysis were to evaluate progression-free survival (PFS), overall survival (OS), and the durability of responses off all therapy in pts achieving CR. We also assessed minimal residual disease (MRD) status, which has previously been shown to be strongly predictive of PFS and OS after chemoimmunotherapy. Methods: Pts began once daily VEN (20 or 50 mg) to final cohort doses (200-600 mg/day) followed by R, given every 4 weeks for a total of 6 doses. VEN dosing was continuous. Responses were assessed by iwCLL criteria with CT scan and bone marrow (BM) biopsy after combination therapy (Month 7). MRD was assessed on BM aspirates in local laboratories using ≥4 color flow cytometry (minimum sensitivity of 0.01%). Results: 49 pts (48 CLL/1 SLL) were enrolled in 5 dose escalation cohorts (n=41; 200-600mg/day) and a safety expansion cohort (n=8; 400mg/day); results herein combine data from all cohorts. Median (range) age was 68 (50-88) years. The median (range) number of prior regimens was 2 (1-5). 45 (92%) received prior R and 14 (29%) had R-refractory disease; 29 (59%) received prior fludarabine and 9 (18%) had fludarabine-refractory disease. Of pts with available data, 9/46 (20%) had del(17p); 19/27 (70%) expressed unmutated IGHV. As of June 4, 2015, 12 pts have discontinued the study: 6 due to PD (5 were Richter's transformation), 3 due to AEs (neuropathy, TLS, and myelodysplasia [heavily pretreated and hypocellular marrow at study entry; pt achieved MRD-negative CR with incomplete marrow recovery, CRi, and proceeded to transplant]), and 3 withdrew consent (1 after achieving MRD-negative CR). The investigator-assessed ORR was 86% (42/49) with 20 (41%) CR/CRi, 1 (2%) nPR and 21 (43%) PR. 4 had SD, 2 had PD, and 1 died before assessment (fatal TLS). 9 with PR or SD at the 7 month assessment achieved CR after a median (range) additional time of VEN monotherapy of 6 (2-9) months. BM MRD was evaluated in 40 pts. MRD-negativity was achieved in 15/20 (75%) pts who achieved a CR/CRi and 26/49 (53%) overall. Disease has progressed in 5/42 (12%) responders; 89% are free from progression at 12-months. The median PFS has not been reached. At 12 and 24 months, actuarial PFS is 87% and 84%, respectively, with a median (range) follow-up for pts without events of 17.5 (0.03-32) months. 94% were alive at 12 months; the median OS has not been reached. Although the numbers are small, the ORR, CR rates, PFS, and OS were not significantly impacted by high-risk subgroups. 8 pts stopped VEN after achieving CR/CRi, 6 of whom were MRD-negative at the time. 2 withdrew from the study after achieving CR/CRi without evidence of progression; 6 remain in follow-up with a median (range) of 15 (4-24) months off VEN. The 2 MRD-positive pts had asymptomatic progression with rising lymphocytosis after 19 and 24 months off VEN; both are eligible for retreatment with VEN when clinically appropriate. Treatment-emergent AEs in 〉 25% of pts were neutropenia (55%), diarrhea (53%), nausea (49%), upper respiratory tract infection (45%), fatigue and pyrexia (each 37%), cough (35%), and headache (33%). Grade 3/4 AEs in 〉 10% were neutropenia (53%), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (10%). 1 treatment-emergent AE (TLS) led to death; no other fatal TLS events occurred after a protocol modification aimed at TLS risk management and prophylaxis. 2 deaths occurred after PD. Key efficacy data are summarized in the table. Conclusions: VEN plus R induces a high rate of deep and durable responses, independent of adverse prognostic factors, with a tolerable safety profile. 41% of pts achieved CR/CRi and 53% achieved BM MRD-negativity. Remission off all therapy has been maintained in pts achieving MRD-negative CR. The median PFS and OS have not yet been reached; 24-month PFS is estimated to be 84%. The high rate of MRD-negativity is an encouraging step towards prolonged PFS and durable elimination of CLL/SLL. VEN plus R versus bendamustine plus R is being evaluated in a phase 3 trial in pts with previously treated CLL (MURANO; NCT02005471). Table 1. Table 1. Disclosures Ma: Genentech, Pharmacyclics/Janssen and Gilead: Speakers Bureau; Genentech, Pharmacyclics/Janssen and Gilead: Consultancy; NCCN, AbbVie, Pharmacyclics, Novartis, Gilead, Celgene, and Xeme: Research Funding. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Seymour:Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kipps:Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria. Barrientos:Gilead, Pharmacyclics, and AbbVie: Research Funding; Pharmacyclics, Celgene, and Genentech: Membership on an entity's Board of Directors or advisory committees. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy. Anderson:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Choi:AbbVie: Consultancy, Other: Advisory Board, Research Funding; Gilead: Consultancy, Other: Advisory Board, Speakers Bureau. Tam:Roche: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Mason-Bright:AbbVie: Employment, Equity Ownership. Prine:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Kim:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Roberts:Walter and Eliza Hall Institute of Medical Research: Employment; Genentech: Research Funding; AbbVie: Research Funding; Servier: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.830.830

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7