Combination of Ofatumumab and Lenalidomide in Patients with Relapsed Chronic Lymphocytic Leukemia (CLL): Results of a Phase II Trial

Abstract Abstract 720 Based on the demonstrated activity of ofatumumab and lenalidomide as monotherapy in patients (pts) with CLL and on the activity of rituximab in combination with lenalidomide in pts with relapsed CLL, we conducted a phase II study to investigate efficacy and tolerability of a combination regimen of ofatumumab and lenalidomide in patients with relapsed CLL who had received prior treatment with purine analogs. Thirty-six pts entered this study between January 2010 and January 2011. All pts had an indication for therapy. Other inclusion criteria required prior treatment with purine analogs, an ECOG PS score of 0–2 and adequate organ function (creatinine clearance > 30ml/min, total bilirubin < to 2 mg/dl, ALT < 2 X ULN). Pts with any neutrophil count were eligible. Pts were excluded for platelets < 30,000 mm3, positivity for HIV, active hepatitis B or C or recent history of tuberculosis. Treatment consisted of ofatumumab IV given weekly for 4 weeks (300 mg week 1; 1,000 mg weeks 2 and thereafter), monthly during months 2–6 and every other month during months 7–24, and lenalidomide 10 mg PO/day started on day 9 and continued for 24 months. Allopurinol 300 mg PO daily was given during the first two weeks of cycle 1. No pts received antibiotic or DVT prophylaxis. The use of growth factors was allowed according to ASCO guidelines. Responses were assessed (2008 IWG criteria) at months 3 and 6 and every 6 months thereafter. Thirty-four pts are evaluable (one pt withdrew consent prior to treatment with lenalidomide, and one was excluded because of concomitant MDS at study entry). Median age was 64 yrs (34–82). Twenty-two pts (65%) had Rai stage III-IV disease. Median β-2M level was 4.1 mg/dL (1.7–16). Twenty-two pts (65%) had unmutated IgHV and 23 pts (68%) expressed ZAP-70. Nine pts (26%) had del(17p), and 4 pts (12%) had del(11q). Median number of prior treatments was 2 (1–8). All pts had been previously treated with FCR and 13 pts (38%) were fludarabine-refractory. Three pts (9%) had relapse following SCT.Twenty-three pts achieved a response, for an overall response (OR) rate of 68%. Eight pts (24%) achieved a complete response (CR), including 3 MRD-negative CR, and 15 pts (44%) achieved a partial response (PR). Median duration of response is 22 months (4–30), with a median follow up of 24 months. Among the 9 pts with del17p, 5 (55%) achieved a PR. The average daily dose of lenalidomide was 10 mg in 9 pts (26%), 7.5 mg in 4 pts (12%), 5 mg in13 pts (38%) and 5 mg in 8 pts (23%). Seventy-six % of the pts are alive. No pt deaths occurred while on therapy. Eight deaths occurred after discontinuation of therapy: progression of CLL despite subsequent therapy (5 pts), complications of HSCT (1 pt), CLL/lung cancer (1 pt) and causes unrelated to CLL(1 pt). Seven pts are still on therapy and 10 pts have an ongoing response. Six pts discontinued therapy despite an ongoing response due to transition to HSCT (3 pts), toxicity (2 pts) and physician choice (1 pts), and 7 pts discontinued therapy because of loss of response [after 12 (1 pt), 16 (2 pts), 19 (2 pts), 22 (1 pt) and 29 (1 pt) months].The most common grade 3–4 treatment-related hematological adverse events consisted of neutropenia in 16 pts (47%), thrombocytopenia in 3 pts (9%) and anemia in 2 pts (6%). One pt (3%) experienced G4 pulmonary embolism while on ESAs. One pt (3%) had G3 infusion reaction to ofatumumab. Fourteen G3 infectious episodes occurred: pneumonia (4), fever/bacteremia (5), parotitis (1), cellulitis (2), HZV (1) and CNS toxoplasmosis (1). No G3-4 tumor lysis syndrome or tumor flare reaction (TFR) was observed. G1-2 TFR was observed in 8 pts (24%), In conclusion, the combination of ofatumumab and lenalidomide induced responses in 68% of pts with relapsed CLL, including pts with del17p, all of whom had received prior chemoimmunotherapy. This treatment was well tolerated and neutropenia was the most common toxicity. The severity of TFR with this combination was less than with single agent lenalidomide, possibly due to attenuation by the addition of treatment with ofatumumab. Several studies are currently investigating the combination of anti-CD20 mAb and lenalidomide used both as initial and salvage therapy of CLL. Disclosures: Ferrajoli: Celgene Corporation: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. O'Brien:GlaxoSmithKline: Consultancy; Celgene Corporation: Consultancy. Wierda:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding. Keating:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Five-Year Experience with Single-Agent Ibrutinib in Patients with Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

Blood ◽

10.1182/blood.v128.22.233.233 ◽

2016 ◽

Vol 128 (22) ◽

pp. 233-233 ◽

Cited By ~ 53

Author(s):

Susan M. O'Brien ◽

Richard R. Furman ◽

Steven E. Coutre ◽

Ian W. Flinn ◽

Jan Burger ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3 ◽

Over Time

Abstract Background: Ibrutinib (ibr), a first-in-class, once-daily Bruton's tyrosine kinase inhibitor, is approved by the US FDA for treatment of patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) including pts with del17p. The phase 1b/2 PCYC-1102 trial showed single-agent efficacy and tolerability in treatment-naïve (TN; O'Brien, Lancet Oncol 2014) and relapsed/refractory (R/R) CLL/SLL (Byrd, N Engl J Med 2013). We report efficacy and safety results of the longest follow-up to date for ibr-treated pts. Methods: Pts received 420 or 840 mg ibr QD until disease progression (PD) or unacceptable toxicity. Overall response rate (ORR) including partial response (PR) with lymphocytosis (PR-L) was assessed using updated iwCLL criteria. Responses were assessed by risk groups: unmutated IGVH, complex karyotype (CK; ≥3 unrelated chromosomal abnormalities by stimulated cytogenetics assessed by a reference lab), and in hierarchical order for del17p, then del11q. In the long-term extension study PCYC-1103, grade ≥3 adverse events (AEs), serious AEs, and AEs requiring dose reduction or discontinuation were collected. Results: Median age of the 132 pts with CLL/SLL (31 TN, 101 R/R) was 68 y (range, 37-84) with 43% ≥70 y. Baseline CK was observed in 41/112 (37%) of pts. Among R/R pts, 34 (34%) had del17p, 35 (35%) del11q, and 79 (78%) unmutated IGVH. R/R pts had a median of 4 prior therapies (range, 1-12). Median time on study was 46 m (range, 0-67) for all-treated pts, 60 m (range, 0-67.4) for TN pts, and 39 m (range, 0-67) for R/R pts. The ORR (per investigator) was 86% (complete response [CR], 14%) for all-treated pts (TN: 84% [CR, 29%], R/R: 86% [CR, 10%]). Median progression-free survival (PFS) was not reached (NR) for TN and 52 m for R/R pts with 60 m estimated PFS rates of 92% and 43%, respectively (Figure 1). In R/R pts, median PFS was 55 m (95% confidence intervals [CI], 31-not estimable [NE]) for pts with del11q, 26 m (95% CI,18-37) for pts with del17p, and NR (95% CI, 40-NE) for pts without del17p, del11q, trisomy 12, or del13q. Median PFS was 33 m (95% CI, 22-NE) and NR for pts with and without CK, and 43 m (95% CI, 32-NE) and 63 m (95% CI, 7-NE) for pts with unmutated and mutated IGVH, respectively(Figure 2). Among R/R pts, median PFS was 63 m (95% CI, 37-NE) for pts with 1-2 prior regimens (n=27, 3 pts with 1 prior therapy) and 59 m (95% CI, 22-NE) and 39 m (95% CI, 26-NE) for pts with 3 and ≥4 prior regimens, respectively. Median duration of response was NR for TN pts and 45 m for R/R pts. Pts estimated to be alive at 60 m were: TN, 92%; all R/R, 57%; R/R del17p, 32%; R/R del 11q, 61%; R/R unmutated IGVH, 55%. Among all treated pts, onset of grade ≥3 treatment-emergent AEs was highest in the first year and decreased during subsequent years. With about 5 years of follow-up, the most frequent grade ≥3 AEs were hypertension (26%), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%). Study treatment was discontinued due to AEs in 27 pts (20%) and disease progression in 34 pts (26%). Of all treated pts, 38% remain on ibr treatment on study including 65% of TN pts and 30% of R/R pts. Conclusions: Single-agent ibrutinib continues to show durable responses in pts with TN or R/R CLL/SLL including those with del17p, del11q, or unmutated IGVH. With extended treatment, CRs were observed in 29% of TN and 10% of R/R pts, having evolved over time. Ibrutinib provided better PFS outcomes if administered earlier in therapy than in the third-line or beyond. Those without CK experienced more favorable PFS and OS than those with CK. Ibrutinib was well tolerated with the onset of AEs decreasing over time, allowing for extended dosing for 65% of TN and 30% of R/R pts who continue treatment. Disclosures O'Brien: Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Furman:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Coutre:Janssen: Consultancy, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Burger:Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses. Sharman:Gilead: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Wierda:Abbvie: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Gilead: Research Funding. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Luan:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses. James:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Chu:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership.

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Safety and Efficacy of Combined Ruxolitinib and Thalidomide in Patients with Myelofibrosis: Initial Results of a Phase II Study

Blood ◽

10.1182/blood-2018-99-114125 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 354-354 ◽

Cited By ~ 7

Author(s):

Raajit K. Rampal ◽

Srdan Verstovsek ◽

Sean M Devlin ◽

Eytan M. Stein ◽

Tapan M. Kadia ◽

...

Keyword(s):

Platelet Count ◽

Combination Therapy ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Single Agent ◽

Response Assessment ◽

Platelet Response ◽

Advisory Committees ◽

Grade 3

Abstract Background: Among the most frequent and challenging hematologic manifestations of myelofibrosis (MF) are anemia and thrombocytopenia, the presence of which portends an adverse outcome. Few effective modalities to address these cytopenias exist, particularly thrombocytopenia. Further, although the FDA-approved JAK1/2 inhibitor Ruxolitinib (RUX) has demonstrated significant clinical efficacy in MF patients, RUX frequently results in anemia and thrombocytopenia. Thrombocytopenia in particular often results in dose attenuation of RUX. Thalidomide (THAL) is a first-in-class immunomodulatory agent. Studies of THAL in MF patients, alone and with prednisone, have demonstrated improvements in anemia and thrombocytopenia. We therefore sought to examine whether combination of RUX and THAL could result in improvement in both disease-related and therapy-related cytopenias, as well as improve overall disease response in patients with MF. Here we report initial analysis of this study (NCT03069326). Methods: We conducted a multicenter two stage phase II trial designed to assess the effect of RUX and THAL combination in subjects with primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. Patients taking RUX at the time of enrollment must have had less than PR per IWG-MRT/ELN 2013 criteria, or be refractory, to RUX single-agent therapy. Patients must have been taking RUX for a minimum of 3 months, and must have been on a stable dose of RUX for a minimum of 4 weeks immediately prior to enrollment. Treatment-naïve patients received single-agent RUX for 3 months (run-in phase) per label, and went on to combination therapy if they achieved less then a PR per IWG-MRT/ELN criteria. Each cycle of therapy was 28 days. Response assessment was evaluated according to the IWG-MRT/ELN 2013 criteria. Platelet response criteria in patients with baseline thrombocytopenia (less than lower limit of normal) included: Major response (≥75% increase in platelet count), Intermediate Response (≥50% increase) and Minor Response (≥25% increase). Adverse events were assessed using the NCI CTCAE v. 4.0. The primary endpoint was the proportion of treated subjects that achieved a response by IWG-MRT criteria and by platelet response criteria. Results: A total of 25 patients are planned to be accrued. At the time of this writing, a total of 18 patients have been accrued. The median age was 70.5 years (47-85). 8 patients had received prior therapies other than RUX, including imetelstat, momelotinib, danazol, pomalidomide, darbepoetin alpha and sotatercept. 7 patients enrolled to the run-in phase. 14 patients received red blood cell transfusions prior to study enrollment. Evaluation of platelet count in patients with baseline thrombocytopenia demonstrated a significant increase in platelet count at cycle 3 of therapy compared to baseline (Figure 1A and B; P<0.05). An increase in Hgb was observed over successive cycles of combination therapy (Figure 1C and D). 5 of 18 accrued patients completed ≥6 cycles of combined therapy at the time of abstract submission and were thus evaluable for response assessment. The overall response rate in these patients was 80% (4/5 patients). Clinical Improvement (Anemia response and Symptom response) occurred in 3 patients (both responses observed in all 3 patients). Major platelet response was observed in 4 of 5 patients with baseline thrombocytopenia. 1 patient met criteria for spleen response (Table 1). Grade 3/4 non-hematologic adverse events regardless of attribution included; limb edema, diverticulitis, hypertension, syncope. 1 patient experienced a thromboembolic event. 1 patient experienced a grade 3 hematologic AE (neutropenia). Conclusions: The combination of THAL and RUX has demonstrated a promising efficacy signal in this initial analysis of an ongoing phase II study, and appears to be well tolerated. Platelet count increases were observed in all patients who entered study with baseline thrombocytopenia, a response which appears to be maintained in the majority of patients observed 6 months after starting combination therapy. As well, anemia responses were observed in 3 of 5 evaluable patients. Collectively, these data indicate a potential role for this regimen in patients with anemia and/or thrombocytopenia, who otherwise have limited treatment options. Updated data on duration of response and overall response of all accrued patients will be presented. Disclosures Rampal: Constellation: Research Funding; Celgene: Honoraria; Incyte: Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Stemline: Research Funding. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Stein:Celgene: Consultancy; Bayer: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Kadia:Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding. Mauro:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Takeda: Consultancy. Pemmaraju:SagerStrong Foundation: Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; abbvie: Research Funding; cellectis: Research Funding; samus: Research Funding; Affymetrix: Research Funding; stemline: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; plexxikon: Research Funding. Bose:Blueprint Medicines Corporation: Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding.

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A Phase I/II Study of NMS-03592088, a FLT3, KIT and CSF1R Inhibitor, in Patients with Relapsed or Refractory AML or CMML

Blood ◽

10.1182/blood-2019-121954 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3855-3855

Author(s):

Marina Ciomei ◽

Lucia Zanetta ◽

Federico Lussana ◽

Erika Ravelli ◽

Francesco Fiorentini ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Single Agent ◽

Dose Titration ◽

Advisory Committees ◽

Secondary Resistance ◽

Support Research ◽

Refractory Aml

Background: NMS-03592088 is a novel, potent inhibitor of the FLT3, CSF1R and KIT receptor tyrosine kinases (KD < 1 nM for all three targets). The compound demonstrated high preclinical efficacy following oral administration in all tested target-dependent tumor models, including those harboring kinase domain secondary resistance mutations, such us the FLT3 residue 691 gatekeeper mutation and the KIT residue 670 and exon 17 mutations. In a FLT3-ITD model of disseminated AML, efficacy observed following single agent treatment with NMS-03592088 was further significantly increased when administered in combination with cytarabine, with excellent tolerability. In preclinical studies conducted in non-human primates, a dose-related increase of circulating CSF1 levels was observed in association with the administration of NMS-03592088, consistent with in vivo inhibition of CSF1R by the compound, thus providing the opportunity for the use of CSF1 levels as a potential pharmacodynamic biomarker of CSF1R modulation in the clinical setting. All three targets of NMS-03592088 are relevant in different settings of hematologic malignancies and solid tumors. In particular, FLT3 mutations occur in approximately 30% of acute myeloid leukemia patients (AML), and are associated with a poor prognosis; KIT mutations are reported in patients with the core-binding factor (CBF) subtype of AML and the CSF1 and/or CSF1R genes are frequently expressed in AML blasts. Recent experimental evidence suggests a potential therapeutic rationale for CSF1R blockade in AML, possibly due to interference with microenvironmental support [Edwards DK et al, Blood, 2019, 133: 588]. Furthermore, chronic myelomonocytic leukemia (CMML) blasts express high levels of CSF1R and NMS-03592088 was able to effectively inhibit their proliferation, concomitant with the suppression of intracellular CSF1R dependent signalling. A clinical trial exploring safety, tolerability and efficacy of NMS-03592088 in patients with AML and CMML is therefore warranted. Trial design: This first-in-human study (EudraCT Number: 2018-002793-47) is designed as an open-label multicenter Phase I/II trial including patients with relapsed or refractory AML or CMML who have exhausted standard treatment options, or for whom standard therapy is considered unsuitable. The study is designed to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics and to explore the preliminary anticancer activity of NMS-03592088 administered orally as single agent once daily for 21 consecutive days, followed by a 7-day break within a 28 day cycle. The study includes an initial conventional phase I part with an accelerated dose titration design in subsequent cohorts of 3+3 patients aimed at defining the maximal tolerated dose (MTD) and the recommended phase 2 dose (RP2D), followed by a limited dose expansion to confirm the RP2D. Once the RP2D is confirmed, a single-stage exploratory Phase II part will start comprising two parallel cohorts, one cohort will consist of AML FLT3 mutated patients and one of patients with CMML. Patients previously treated with FLT3 inhibitors are allowed to participate. The primary endpoint of the Phase II portion of the study is Overall Response Rate. Efficacy will be assessed according to standard criteria [Döhner H et al, Blood 2017, 129: 424; Savona MR et al., Blood, 2015, 125: 1857]. Exploratory endpoints are included to evaluate the potential effects of treatment with NMS-03592088 on circulating levels of CSF1 in plasma, the potential correlation of cellular CSF1R expression levels with clinical outcome in both AML and CMML, and the mutational status of a panel of leukemia-related genes, not limited to FLT3. The Phase I part started in Italy in March, 2019 and is currently ongoing. Disclosures Ciomei: NMS: Employment. Zanetta:Clioss: Employment. Fiorentini:Accelera: Employment. Bosotti:NMS: Employment. Ardini:NMS: Employment. Lombardi Borgia:NMS: Employment. Pulci:Accelera: Employment. Gatto:Clioss: Employment. Di Sanzo:Clioss: Employment. Colajori:Clioss: Consultancy. Davite:Clioss: Employment. Galvani:NMS: Employment. Gan:NMS: Employment. Rossi:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria; Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees. Rambaldi:Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Isacchi:NMS: Employment.

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Combination Therapy with Ofatumumab and Lenalidomide in Patients with Relapsed Chronic Lymphocytic Leukemia (CLL): Results of a Phase II Trial

Blood ◽

10.1182/blood.v118.21.1788.1788 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1788-1788 ◽

Cited By ~ 5

Author(s):

Alessandra Ferrajoli ◽

Susan O'Brien ◽

William G. Wierda ◽

Stefan Faderl ◽

Xavier Badoux ◽

...

Keyword(s):

Pulmonary Embolism ◽

Phase Ii ◽

Research Funding ◽

Thrombotic Event ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Combination Regimen ◽

Treatment Indications ◽

Superficial Vein Thrombosis ◽

Grade 3

Abstract Abstract 1788 Patients with relapsed CLL have limited effective treatment options, and new therapies are needed. We report the results of a phase II study which investigated the efficacy and tolerability of a combination regimen with ofatumumab and lenalidomide in patients (pts) with relapsed CLL. These agents were evaluated as a combination regimen for pts with relapsed CLL based on their documented single-agent efficacy, distinct and potentially complimentary mechanisms of action and non-overlapping toxicities. Furthermore, the combination of rituximab and lenalidomide was active in relapsed CLL (Badoux et al. 2010). Pts with symptomatic disease who met treatment indications were eligible. Other inclusion criteria required prior treatment with purine analogs, an ECOG PS score of 0–2, and adequate organ function (creatinine clearance > 30ml/min, total bilirubin < to 2 mg/dl, ALT < 2 × ULN). Pts with any neutrophil count were eligible. Pts were excluded for platelets < 30,000 mm3, positivity for HIV, active hepatitis B or C or recent history of tuberculosis. Pts received ofatumumab IV weekly for four weeks (300mg week 1; 1,000 mg weeks 2 to 4), monthly during months 2–6, and every other month during months 7–24. Lenalidomide 10 mg PO daily was started on day 9 and continued daily for a maximum of 24 months. Allopurinol 300mg PO daily was given during the first two weeks of cycle 1. No pts received antibiotic or DVT prophylaxis. The use of growth factors was according to standard guidelines. Responses were assessed after 3, 6, 12, 18 and 24 months. Between January 2010 and January 2011, 36 pts were enrolled and 34 pts are evaluable (one pt withdrew consent prior to treatment and one was excluded because of concomitant MDS). The median age of the pts was 62 yrs (34–82). Twenty pts (59%) had Rai III-IV disease. The median beta-2M level at start of therapy was 4.4 mg/dL (1.7-16.5). The median number of prior treatments was 2 (1–8). All pts had received prior chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR). Twelve pts (35%) were fludarabine-refractory. Twenty-two pts (65%) had unmutated IgHV genes, 9 (26%) del(17p) and 4 (12%) del(11q). Responses were evaluated according to the 2008 NCI-WG criteria: 5 pts (15%) achieved CR (including 1 CRi) and 17 pts (50%) PR, for an ORR of 65%. Of the 5 CR pts, 1 was MRD-negative by flow cytometry. Two of the PR pts achieved marrow CR and only had persistent lymphadenopathy. Of the 22 responders, 13 are continuing on therapy with ongoing response (median time on therapy 14 months, range 8–20 months). Despite ongoing response, 7 pts discontinued therapy due to: transition to HSCT (3 pts; after 3, 6 and 6 months, respectively), pulmonary embolism (1 pt; after 4 months), recurrent zoster infection (1 pt; after 17 months of therapy) and physician choice (2 pts; after 9 and 16 months of therapy). Two pts discontinued therapy because of loss of response after 12 and 18 months of treatment, respectively. Thirty-one pts (91%) are alive. There have been no deaths on therapy. Three deaths occurred after discontinuation of therapy due to refractory disease (1), following HSCT (1) and due to progressive disease and adenocarcinoma of the lung (1). The most common grade 3–4 treatment-related hematological adverse events included neutropenia (15 pts, 44%), thrombocytopenia (3 pts, 9%) and anemia (1 pt, 3%). Thrombotic events occurred in 2 pts (6%). One pt experienced grade 3 pulmonary embolism and another patient grade 2 superficial vein thrombosis. In both cases with thrombotic event, ESAs were concomitantly administered. One pt (3%) experience a grade 3 infusion reaction during the first ofatumumab administration. Eight grade 3 infectious episodes occurred: pneumonia (3), neutropenic fever (2), parotitis (1), LE cellulitis (1) and CNS toxoplasmosis based on radiological findings (1). Intermittent grade 1–2 diarrhea was reported by 8 pts (24%). Grade 1–2 lenalidomide-associated tumor flare reaction was seen in 8 pts (24%). The median tolerated daily dose of lenalidomide was 5 mg/day (2.5-10 mg). In conclusion, the combination of ofatumumab and lenalidomide is well tolerated. Neutropenia was the most common toxicity. This combination induced responses in 65% of pts with relapsed CLL, all of whom had received prior chemoimmunotherapy. Responses are durable and ongoing in some pts. Disclosures: Ferrajoli: GlaxoSmithKline: Research Funding; Celgene: Research Funding. O'Brien:GlaxoSmithKline: Consultancy; Celgene: Consultancy. Wierda:GlaxoSmithKline: Research Funding.

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Phase II Study of Midostaurin + Chemotherapy in Pediatric Patients with Untreated, Newly Diagnosed, FLT3-Mutated Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood-2019-128043 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3835-3835

Author(s):

Dirk Reinhardt ◽

Christian Michel Zwaan ◽

Albert Hoenekopp ◽

Julie Niolat ◽

Sophie Ifrah ◽

...

Keyword(s):

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Pediatric Patients ◽

Single Agent ◽

High Dose ◽

Consolidation Therapy ◽

Advisory Committees ◽

Advisory Boards ◽

High Dose Cytarabine

Background: In pediatric patients with AML, the presence of FLT3-internal tandem duplication (ITD) mutation is indicative of high-risk disease and confers a worse prognosis and a greater chance of relapse. Midostaurin is a multikinase inhibitor with potent activity against both mutated and non-mutated FLT3. In adult patients with FLT3-mutated AML, midostaurin in combination with chemotherapy has demonstrated good safety/tolerability and significantly improved overall survival (OS) and event-free survival (EFS) compared with placebo + chemotherapy. We present here the design of an ongoing phase II study (NCT03591510) evaluating midostaurin combined with standard chemotherapy and as a single-agent post-consolidation therapy in newly diagnosed pediatric patients with FLT3-mutated AML, other than acute promyelocytic leukemia. Study Design and Methods: This open-label, single-arm study is composed of 2 parts. For Part 1, the primary objective is to determine the recommended phase II dose (RP2D) of midostaurin in combination with chemotherapy, as determined by the occurrence of dose-limiting toxicities. For Part 2, in which patients will receive the RP2D of midostaurin, the primary objective is to evaluate the efficacy of midostaurin + chemotherapy as measured by the EFS rate at 24 mo (for regulatory purposes outside the US) or to assess the safety/tolerability of midostaurin + chemotherapy (for regulatory purposes within the US). Secondary objectives include safety/tolerability (outside US) and EFS at 24 mo (within US), other efficacy parameters (including OS, complete remission [CR], CR with incomplete blood count recovery [CRi], cumulative incidence of relapse, and minimal residual disease-negative status), and characterization of the pharmacokinetics of midostaurin. Eligible patients are aged 3 mo to < 18 yr with expected survival of > 12 wk, have a Lansky or Karnofsky performance status of ≥ 60, and have previously untreated de novo AML with FLT3 mutation: ITD and/or mutation in the tyrosine kinase domain, with mutant/wild-type signal ratio cutoff of ≥ 0.05. Exclusion criteria include any concurrent malignancy, Philadelphia chromosome or BCR-ABL1-positive AML, AML associated with Down syndrome, secondary AML, symptomatic leukemic central nervous system involvement, bone marrow failure syndrome, or prior treatment with a FLT3 inhibitor. Patients are to receive 5 treatment blocks: 2 of standard induction (Blocks 1-2) and 3 of consolidation (Blocks 3-5) chemotherapy, each with sequential twice-daily (BID) oral midostaurin. In Part 1 of the study, midostaurin will be given at a starting dose of 30 mg/m2 BID; dose escalation and determination of RP2D will be facilitated by a Bayesian hierarchical logistic regression model guided by escalation with overdose control principle. In Part 2, midostaurin will be administered at the RP2D. Induction therapy will be the local standard chemotherapy regimen with midostaurin starting after 24 hr from identification of FLT3 abnormalities and continuing for 14 d for Block 1, and FLADx (fludarabine + high-dose cytarabine on D1-5, daunorubicin on D2, 4, 6) with sequential midostaurin on D8-21 for Block 2. Patients demonstrating CR or modified CRi will proceed to consolidation with the following chemotherapy regimens, each with sequential midostaurin on D8-21: HAM (high-dose cytarabine on D1-3, mitoxantrone on D3, 4) for Block 3, HA3E (high-dose cytarabine on D1-3, etoposide on D1-5) for Block 4, and HiDAC (high-dose cytarabine on D1-3) for Block 5. Patients must be in continued remission (CR or modified CRi) to receive each block of consolidation therapy. Patients who complete Block 5 and remain in remission will proceed to 12 × 28-d cycles of post-consolidation therapy with single-agent midostaurin. Patients may undergo allogeneic hematopoietic stem cell transplantation at any time at the investigator's discretion. Overall, the aim is to recruit a minimum of 52 patients, including at least 49 at the RP2D dose. This study is currently enrolling patients at 13 centers in 7 countries (as of July 26, 2019), and a total of 37 centers in 14 countries are planned. Disclosures Reinhardt: Novartis: Other: Participation in Advisory Boards; Jazz: Other: Participation in Advisory Boards, Research Funding; CSL Behring: Research Funding; Roche: Research Funding. Zwaan:BMS: Research Funding; Servier: Consultancy; Sanofi: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Other: Travel support; Roche: Consultancy; Incyte: Consultancy. Hoenekopp:Novartis Pharma AG Basel: Employment, Equity Ownership. Niolat:Novartis Pharma: Employment. Ifrah:Novartis: Employment. Noel-Baron:Novartis: Employment, Equity Ownership. Locatelli:Miltenyi: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BluebirdBio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Midostaurin is a kinase inhibitor approved in combination with chemotherapy for the treatment of FLT3-mutated AML in adults; the study reported here is in pediatric patients with FLT3-mutated AML.

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Brentuximab Vedotin (BV) and Lenalidomide (Len) in Relapsed and Refractory (r/r) Cutaneous (CTCL) and Peripheral (PTCL) T-Cell Lymphomas; A Planned Interim Analysis of Phase II Trial

Blood ◽

10.1182/blood-2019-123801 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2853-2853

Author(s):

Basem M. William ◽

Ying Huang ◽

Amy Johnson ◽

Jonathan E Brammer ◽

John C. Reneau ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Large Cell ◽

Median Number ◽

Brentuximab Vedotin ◽

Advisory Committees

Background: Patients with r/r tumor stage CTCL and/or PTCL have a poor prognosis. BV is currently FDA approved for CD30 positive CTCL and anaplastic large cell lymphoma (ALCL) with single agent activity in additional PTCL subtypes. Len also has single agent activity in patients with r/r CTCL/PTCL. The safety of the combination was established in a phase I trial in patients with r/r diffuse large B-cell lymphoma. Methods: We conducted a single-institution phase II trial to determine the safety and efficacy of BV+Len combination in patients with r/r CTCL/PTCL. Simon's 2-stage optimal design was followed to test the null hypothesis of overall response rate (ORR) ≤0.3 versus the alternative hypothesis of ORR≥0.5. Patients with ≥ 1 line of systemic therapy or 2 lines of skin directed therapy, at least stage IB (for CTCL), and no prior progression on BV were eligible regardless of CD30 staining. All patients were treated with BV 1.2 mg/kg IV and Len 20 mg PO daily q3 weeks for a maximum 16 cycles. After 7 patients were treated, we reduced Len to 10 mg given safety/tolerability concerns. Responses are assessed by the International Society for Cutaneous Lymphomas and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (ISCL/EORTC) Global response criteria (for CTCL) and Cheson year criteria (for PTCL). The effect of treatment on quality of life is assessed by Skindex-16. Results: As of July 1, 2019, 17 subjects were treated; 10 (59%) with mycosis fungoides (MF), 2 (12%) with Sezary syndrome (SS), 2 (12%) with CD30+ lymphoproliferative disorder, and 3 (18%) with PTCL. Median age was 60 (49-90) years and 76% were males. CD30 was completely negative (<1%) in 3 (18%) of patients and median CD30 staining (by immunohistochemistry) was 7.5% (range 1-75%). Of 12 patients with MF/SS, 5 (42%) had evidence of large cell transformation at accrual. Of 14 patients with CTCL, median baseline mSWAT was 54.5 (range 4.4-190). Median number of prior therapies was 5 (range 1-9). Grade 3 adverse events (AEs) were reported in 11/17 patients; including neutropenia (4), thrombocytopenia (1), bronchitis (1), dyspnea (1), abdominal pain (2), vertigo (1), , DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome (1), urinary tract infection (1), and tumor flare (2). Median number of cycles received was 4 (range 1-17). Best response in 14 evaluable patients were 2 (14%) complete response, 3 (21%) partial response, and 8 (57%) stable disease with ORR of 33% (95% confidence interval:12-62%). Of 17 patients, 5 (29%) remain on treatment, and 12 (71%) discontinued treatment because of disease progression (7; 58%), AEs (4; 33%), or patient preference (1; 2%). Median duration of response was 3.2 (range 2.5-13) months. Of note, 7/14 patients (50%) patients with CTCL had >50% reduction in their Skindex-16 scores after a median of 2 cycles (range 1-3). Conclusions: BV + Len is combination is safe and efficacious in a heavily pre-treated patients with T-cell lymphomas. Len doses higher than 10 mg daily are poorly tolerated and associated with excess tumor flare. Recruitment of both CTCL and PTCL patients for this trial is ongoing. Disclosures William: Guidepoint Global: Consultancy; Kyowa Kirin, Inc.: Consultancy; Defined Health: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy. Brammer:Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Grantier:Pharmacyclics LLC and Janssen Oncology: Other: Advisory Board. Hoffman:Pharmacyclics LLC and Janssen Oncology: Other: Advisory Board. Baiocchi:Prelude: Consultancy. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Christian:Triphase: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Acerta: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Cephalon: Research Funding; Merck: Research Funding; Janssen: Research Funding; Millennium Pharmaceuticals Inc: Research Funding. Maddocks:BMS: Research Funding; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Brentuximab vedotin is being used off-label for CD30 negative peripheral and cutaneous T-cell lymphoma. Lenalidomide is being used off-label for both conditions (within a phase II clinical trial)

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A Phase Ib/II Study of Ibrutinib in Combination with Obinutuzumab-Gazyva As First-Line Treatment for Patients with Chronic Lymphocytic Leukemia > 65 Years Old or with Coexisting Conditions

Blood ◽

10.1182/blood-2018-99-118990 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1863-1863

Author(s):

Juliana Velez Lujan ◽

Michael Y. Choi ◽

Chaja Jacobs ◽

Colin McCarthy ◽

Alaina Heinen ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Single Agent ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Grade 3

Abstract Standard treatment for patients with chronic lymphocytic leukemia (CLL) is rapidly evolving and gradually has incorporated the combined use of monoclonal antibodies (mAbs) and targeted therapy with small molecules. Single agent Ibrutinib (Ibr), a first-in-class BTK inhibitor, is effective in previously untreated patients including those that are older than 65 or considered unfit to receive chemotherapy-based combinations. The complete response rate in patients receiving single agent Ibr is relatively low (overall response rate of 86% and complete response of 4% based on 2008 iwCLL criteria), though most patients have durable remissions. The combination of Ibr with mAbs like Obinutuzumab-Gazyva (G), a third-generation anti-CD20 mAb, can ameliorate the Ibr-induced lymphocytosis and increase the overall and complete response rates. Accordingly, we initiated an open-label phase Ib/II clinical study of Ibr in combination with G for first-line therapy of previous untreated pts with CLL. The study completed enrollment of 32 previously untreated patients with CLL. Patients received G administered based on FDA dosing recommendations for 6 cycles (28 days/cycle) and Ibr 420mg po (1-3 hours before starting G infusion), and daily for up to 3 years. All patients received prophylactic medications. Patients were assessed for response by 2008 iwCLL criteria two months after completion of G, as the primary efficacy endpoint. The median age of the patients was 65 (range: 46-78) years. 84% of the patients had a CIRS >6, 45% had a Rai stage III-IV and 19% had an ECOG performance ≤2. The median baseline absolute lymphocyte count (ALC) was 79x103/mm3(range: 1.4-412.4). Patients showed the following FISH/cytogenetic abnormalities: del(13q) in 55%, trisomy 12 in 23% and del(11q) in 19%. Only 2 (6%) of these patients showed del(17p). From the patients with IGVH mutational status available (n=17), 11 (65%) were unmutated (>98% homology). Most adverse events (AEs) were grade 1-2 (74%). Six patients (19%) had grade 1-2 G-infusion-related reaction (IRR) and only one patient (3%) showed grade 3 IRR (without the need for G discontinuation). We observed neutropenia (all grades: 52%, grade 3-4: 23%), thrombocytopenia (all grades: 71%, grade 3-4: 19%) and anemia (all grades: 26%). There were no cases of febrile neutropenia. Two patients (6%) had grade 1 bleeding (one patient with asymptomatic lower gastrointestinal bleeding and the second patient with epistaxis) that resolved spontaneously without requirement of blood transfusion or study treatment discontinuation. Two patients (6%) developed pneumonia, one was community-acquired pneumonia requiring inpatient treatment with IV antibiotics; the study treatment was held until resolution of symptoms and re-initiated at full dose. The most frequent non-hematological AEs were diarrhea, transaminitis, hyperbilirubinemia, hyperglycemia, and electrolyte alterations (grade 1-2). Three patients (9%) discontinued Ibr due to atrial fibrillation grade 1 (n=1), rash and headaches grade 2 (n=1), and persistent grade 4 thrombocytopenia (n=1). Twenty-three patients were evaluable for response assessment by 2008 iwCLL criteria (median follow-up of 11 months). 84% of the patients showed a rapid decrease in ALC from baseline during the first cycle of treatment and only four patients (13%) required more than 3 cycles of treatment to achieve an ALC response. The overall response rate was 100%. The majority of pts had a partial response and six of 23 evaluable patients (26%) achieved a complete remission with detectable Minimal Residual Disease in the bone marrow by multiparametric flow cytometry. In summary, Ibr-G combination has been generally well tolerated. AEs have been consistent with the known safety profiles of Ibr and G individually. The patients that discontinued Ibr remain in follow-up without disease progression. 100% of evaluable patients achieved response after 6 months of combination therapy, and 26% of patients met CR criteria. One important finding thus far has been a very low rate of IRR, (19% grade 1-2 and 3% grade 3-4), suggesting that Ibr can strongly mitigate the incidence and severity of G associated IRR. Disclosures Choi: AbbVie, Inc: Consultancy, Speakers Bureau; Rigel: Consultancy; Gilead: Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Speakers Bureau. Amaya-Chanaga:AbbVie: Equity Ownership, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.; Pharmacyclics, an AbbVie Company: Employment, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.. Kipps:Janssen: Honoraria, 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; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy; Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Genentech Inc: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Castro:F. Hoffmann-La Roche: Consultancy; Genentech, Inc: Consultancy; Pharmacyclics, LLC, an AbbVie Company:: Consultancy.

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Patterns of Venetoclax Sensitivity in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2020-137674 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 12-14

Author(s):

James T Dibb ◽

Nicola Long ◽

Christopher A. Eide ◽

Stephen E Kurtz ◽

Cristina E. Tognon ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Ex Vivo ◽

Single Agent ◽

Drug Combinations ◽

Lymphocytic Leukemia ◽

Publicly Traded ◽

Private Company ◽

Advisory Committees

Patterns of Venetoclax Sensitivity in Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL) is predominantly a disease of older adults. The 5-year overall survival is 70-91%, depending on Rai/Binet stage at diagnosis (80% overall), and although a subset of CLL takes a very indolent course, it can be aggressive as well. Disease course and responsiveness to therapeutic agents may be predictable, to some degree, based on specific genetic lesions or other patient population characteristics. Monotherapies targeting specific cell pathways are rapidly increasing in prevalence. Ibrutinib (Bruton tyrosine kinase inhibitor) has shown promise as a single agent as well as in combination with other agents. In particular, ibrutinib has shown efficacy in combination with venetoclax (inhibitor of cell death suppressor BCL2). This combination appears to be particularly potent in patients with a del(11q) karyotype. Cytogenetic information is used already in several other leukemias to inform prognosis and treatment. Although CLL is a disease of monoclonal proliferation, precise definition of the diseased clone will allow for more individualized treatment. Stratification of drug sensitivity based on genetic and cytogenetic features will directly affect patient outcomes in CLL. Primary patient mononuclear cells (from either peripheral blood or bone marrow) were plated ex vivo with a panel of 49 drug combinations and the 16 respective single agents (SA) in 384-well plates using 10,000 cells/well. Drugs were tested in 7-point concentration series; wells with drug combinations were added at fixed molar ratios. Cell viability was assessed after a 72 hour culture period. In this assay, primary cells maintain viability but do not proliferate. In CLL, the most frequent mutations were: del(17p); del(11q); del(13q14); trisomy 12; complex karyotype (at least three chromosomal aberrations). Selected analysis of these data from 157 unique patients were performed by isolating the most potent inhibitors (defined by lowest median AUC) either as a single agent or in combination with known treatments. These were evaluated with nonparametric tests (Kruskal-Wallace, Mann-Whitney, Spearman rank coefficient) on the statistical software Prism. By subdividing the data by available genetic and cytogenetic information, patterns that have not been previously described in the literature emerged. In the cohort of patients with any karyotypic abnormality (not complex karyotype), SA venetoclax and the combination of venetoclax-ibrutinib (VEN/IBRUT) were equivalently effective with no significant difference in efficacy observed between SA venetoclax and the combination. As previously described, del(11q) independently predicts increased efficacy of SA venetoclax and VEN/IBRUT, and this efficacy was validated by ex vivo potency here as well. However, we show that male gender is an independent predictor of potency in both SA venetoclax and VEN/IBRUT as well. Interestingly, doramapimod (an inhibitor of p38 MAP kinase) was not particularly potent as a SA, however, the combination of venetoclax-doramapimod (VEN/DORA) proved to be the most potent of all combinations tested, more potent than even VEN/IBRUT. This effect could not be replicated in any subgroup, as VEN/DORA samples for the entire cohort were relatively limited (n=31). Although this analysis has inherent limitations, including underpowered data to analyze in less frequent cytogenetic events (e.g. del(6q)), we did find significant patterns of potency. These may or may not translate to clinical efficacy in CLL and do not address any potential toxicity. However, these data suggest future directions for more targeted research on these drugs and drug combinations. Disclosures Tyner: Petra:Research Funding;Janssen:Research Funding;Seattle Genetics:Research Funding;Incyte:Research Funding;Genentech:Research Funding;Constellation:Research Funding;AstraZeneca:Research Funding;Aptose:Research Funding;Gilead:Research Funding;Takeda:Research Funding;Syros:Research Funding;Agios:Research Funding;Array:Research Funding.Druker:EnLiven:Consultancy, Research Funding;Gilead Sciences:Consultancy, Membership on an entity's Board of Directors or advisory committees;Cepheid:Consultancy, Membership on an entity's Board of Directors or advisory committees;Dana-Farber Cancer Institute:Patents & Royalties;Bristol-Myers Squibb:Research Funding;Blueprint Medicines:Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees;Aptose Therapeutics Inc. (formerly Lorus):Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees;ARIAD:Research Funding;Third Coast Therapeutics:Membership on an entity's Board of Directors or advisory committees;The RUNX1 Research Program:Membership on an entity's Board of Directors or advisory committees;Pfizer:Research Funding;Patient True Talks:Consultancy;Oregon Health & Science University:Patents & Royalties;Novartis Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding;MolecularMD (acquired by ICON):Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees;Millipore (formerly Upstate Biotechnology):Patents & Royalties;VB Therapeutics:Membership on an entity's Board of Directors or advisory committees;Vivid Biosciences:Membership on an entity's Board of Directors or advisory committees;ALLCRON:Consultancy, Membership on an entity's Board of Directors or advisory committees;Amgen:Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees;Aileron Therapeutics:Membership on an entity's Board of Directors or advisory committees;Merck & Co:Patents & Royalties;McGraw Hill:Patents & Royalties;GRAIL:Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees;Henry Stewart Talks:Patents & Royalties;Iterion Therapeutics (formerly Beta Cat Pharmaceuticals):Membership on an entity's Board of Directors or advisory committees;Leukemia & Lymphoma Society:Research Funding.

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Favorable Patient Survival after Failure of Venetoclax (ABT-199/ GDC-0199) Therapy for Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v126.23.2939.2939 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2939-2939 ◽

Cited By ~ 7

Author(s):

Constantine Tam ◽

Mary Ann Anderson ◽

David S. Ritchie ◽

E. Henry Januszewicz ◽

Dennis Carney ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Disease Characteristics ◽

Btk Inhibitor ◽

Btk Inhibitors ◽

Support Research

Abstract Introduction Targeted inhibitors of BTK, PI3K or BCL-2 all induce durable responses in patients with chemotherapy-refractory CLL. In the case of the BTK inhibitor ibrutinib, two patterns of resistance have emerged: early (<12 - 24 months) progression with RichterÕs Syndrome (RS), and late progression with CLL often carrying BTK and/or PLCγ mutations. The survival of patients with disease progression after ibrutinib is reported to be poor, particularly for those with RS (median overall survival (OS) 2.6 - 3.5 months)(Blood 2015:2062, JAMA Oncol 2015:80). There are no available data in the context of venetoclax failure. Methods We analyzed our institutional experiences with 70 patients with relapsed / refractory CLL enrolled across 3 venetoclax studies between 2011 and 2015 (2 single agent, 1 rituximab combination). Twenty-eight patients (40%) ceased venetoclax for reasons other than voluntary drug hold after achieving complete remission; these patients had received a median 7.5 (range, 1 - 38) months of venetoclax therapy prior to cessation. Results Of 28 patients, 7 (25%) had CLL progression, 16 (57%) developed RS (3 Hodgkin, 13 DLBCL), and 5 (18%) ceased for other reasons. Patients who ceased therapy typically had high-risk disease characteristics including del(17p)/TP53 mutation or complex cytogenetics in 70%, unmutated IgHV in 88%, and a median of 4 (range 1 - 12) prior therapies before venetoclax. After a median survivor follow-up of 12.5 months (range 0 - 34), the median post-progression survival of patients who progressed with CLL and RS were: not reached (1 year OS 69%) and 12 months, respectively (p=0.88, Figure). Post-progression survival did not statistically differ by any of the following factors: response to venetoclax, progression on venetoclax before or after 12 months, cytogenetic risk, or the number of prior therapies (all p-values >0.18). Of the 7 patients with CLL progression, 5 remain alive on next-line ibrutinib (n=4) or corticosteroids (1). Of the 16 patients with RS, 15 received salvage therapy; R-CHOP (n=6) and R-ICE (3) being the most commonly used regimens. 4 received consolidation with stem cell transplantation. One allogeneic stem cell recipient died at 12 months from transplant-related complications, and the other remains alive and free of disease at 34 months. Both autologous transplant recipients have relapsed with CLL and were successful salvaged with BTK inhibitors. Conclusion Failure of venetoclax does not automatically portend a poor prognosis. The survival of patients who progress with CLL or RS on venetoclax therapy may be superior to that reported for BTK inhibitors. Figure 1. Figure 1. Disclosures Tam: Janssen: Consultancy, Honoraria, Research Funding. Off Label Use: Venetoclax is not licensed for treatment of CLL. Roberts:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Seymour: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; Phebra: Consultancy, 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, Other: Travel support, Research Funding, Speakers Bureau; Infinity: 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; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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BI 836826, a Novel Fc-Engineered Antibody in Combination with Phosphoinositide-3-Kinase Inhibitor for Treatment of High Risk Chronic Lymphocytic Leukemia and Lymphoma

Blood ◽

10.1182/blood.v128.22.2767.2767 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2767-2767

Author(s):

Deborah M Stephens ◽

Kyle A. Beckwith ◽

Priscilla Do ◽

Carolyn Cheney ◽

Xiaokui Mo ◽

...

Keyword(s):

B Cells ◽

Cell Viability ◽

B Cell ◽

Board Of Directors ◽

Cell Lines ◽

Research Funding ◽

Single Agent ◽

Annexin V ◽

Lymphocytic Leukemia ◽

Advisory Committees

Abstract Background Targeting new antigens in chronic lymphocytic leukemia (CLL) and lymphoma may increase flexibility in the clinic and help circumvent resistance. The tetraspanin CD37 domain mediates transduction of survival and apoptotic signals (Lapalombella et al.,Cancer Cell, 2014), and has been clinically validated by recent trials of otlertuzumab (TRU-016) in CLL and Non-Hodgkin Lymphoma . Ligation of CD37 by this reagent simultaneously induced pro-apoptotic signaling and inhibited pro-survival signaling of phosphoinositide 3-kinase δ (PI3Kδ), which introduces a unique opportunity to use combination strategies employing activation of CD37 and inhibition of PI3Kδ. A new agent BI 836826 is an Fc-engineered anti-CD37 IgG1 that displays improved effector activities as well as crosslinker-independent direct cytotoxicity. We have evaluated the efficacy of BI 836826 combined with the PI3Kδ-selective inhibitor idelalisib in diffuse large B-cell lymphoma (DLBCL) cell lines and primary human CLL B-cells in the University and then by industry to validate the synergistic finding initially reported. Methods Cell viability assays usedCellTiterGlo to measure inhibition of antibody, isotype control, idelalisib or a combination of antibody and compound over 72h in culture. The cell viability of vehicle is measured at the time of dosing (T0) and after seventy-two hours (T72). A GI reading of 0% represents no growth inhibition, GI 100% represents complete growth inhibition, and a GI 200% represents complete death of all cells in the culture well. Annexin V-FITC and propidium iodide measure by flow cytometry was used to assess enhanced killing of primary CLL cells, with incubation of BI 836826 (0.1 µg/mL) and/or idelalisib (1 µM) at 37°C for 24 hours. Trastuzumab included as a non-specific IgG1 control. Data was reported as percentage of viable cells (Annexin V negative, PI negative) normalized to untreated control. Results DLBCL cell lines were variably sensitive to single agent BI 836826. In most of the cell lines tested, the cell viability was inhibited by 40%-50% with BI 836826 in the concentration range of 1-1000 ng/mL (Figure 1A). A synergistic effect was noted in several DLBCL cell lines when BI 836826 was combined with idelalisib. When the maximal effect of BI 836826 was greater than isotype control (GI% > 12, dotted line) and the effect of idelalisib showed a GI50 < 1uM, 3/5 cell lines showed synergy in combination (red dot, Figure 1B). A shift in the EC50of idelalisib can be seen with the addition of increasing amounts of BI 836826 (Figure 1C). In primary CLL B-cell cultures, 1 µM idelalisib displayed weak single agent activity following 24-hour incubation. The cytotoxicity of BI 836826 at 0.1 µg/mL was more variable, although treatment of samples from most CLL patients resulted in 20-50% B-cell death. The combination of these 2 agents resulted in enhanced cytotoxic activity (Figure 2A), and this effect was not attenuated by the presence of del(17)(p13.1), as there was no significant difference in cytotoxicity against these cells compared to those with lower risk cytogenetics (Figure 2B,C). Additionally, the combination was beneficial in CLL B-cells isolated from patients who were refractory to ibrutinib (Figure 2D). Conclusions This collaborative industry and academic endeavor with cross validation of initial mechanistic studies of synergy between CD37 and idelalisib demonstrates that addition of idelalisib to BI 836826 augments cytotoxicity against DLBCL cell lines and primary human CLL B-cells in an additive-to-synergistic manner. In addition, it maintains efficacy against CLL B-cells with del(17)(p13.1) and those from ibrutinib-refractory patients. Further exploration of this therapeutic strategy in clinical trials is strongly warranted. Disclosures Jones: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Innate Pharma: Research Funding; Pharmacyclics: Consultancy; Novartis Oncology: Consultancy. Grosmaire:Gilead: Employment. Jones:Gilead: Employment. DiPaolo:Gilead: Employment. Tannheimer:Gilead Sciences: Employment. Heider:4Boehringer Ingelheim RCV: Employment.

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