A Phase I Study Of Panobinostat In Combination With ICE (Ifosfamide, Carboplatin and Etoposide) In Patients With Relapsed Or Refractory Classical Hodgkin Lymphoma (cHL)

Abstract The standard approach to patients with refractory or recurrent cHL is treatment with an effective salvage chemotherapy followed by stem cell transplantation. The best outcome from the transplant is expected in patients who achieve complete response (CR) after the salvage chemotherapy. The commonly used regimen, ICE produces CR rate ranging from 26% (response evaluation by CT, Moskowitz CH et al. Blood 2001) to 61% (by augmented ICE, response evaluation by PET, Moskowitz CH et al. Blood 2012). Panobinostat is a potent oral pan-deacetylase inhibitor that has shown activity against refractory or recurrent cHL after transplant with acceptable toxicity profile with a dose limiting toxicity of reversible thrombocytopenia (Younes A et al. JCO 2012). We conducted a phase I study of oral panobinostat in combination with standard ICE for patients who had recurrent or refractory disease after ABVD based chemotherapy. The treatment consisted of oral panobinostat on Monday/Wednesday/Friday starting from 1 week before first ICE, and to be continued during ICE through the second cycle. Third cycle was administered without panobinostat concerning the potential adverse impact on stem cell collection. The starting dose of panobinostat was 20mg, and the target dose was 30mg based on 3+3 design, with planned expansion at the highest dose. As the time of data cut off (July 2013), a total of 23 patients were registered and 21 were assessable for toxicity and response. The median age of patients were 31 (range 19-60), male/female 14/7 patients, primary refractory disease in 9 patients. At 20mg, dose limiting toxicity (DLT, febrile neutropenia) was observed in one of the 6 patients. At 30mg, 3 patients were enrolled without DLT. Thus, we expanded the cohort at 30mg in two different schedules (A: panobinostat to be started one week before first ICE, then 1st and 2nd week of ICE [n=10], B: panobinostat to be started one week before ICE, then only 1st week of ICE of each cycle [n=2, ongoing]). Overall, there was no grade 3/4 non-hematologic toxicity observed. The common non-hematologic toxicity of grade 1/2 (>10%) was fatigue (43%), nausea (43%), and vomit (29%). Hematologic toxicity included anemia (grade 1/2 in 24%, grade 3 in 5%), neutropenia (grade 1/2 in 5%, grade 3 in 10%, grade 4 in 57%), thrombocytopenia (grade 1/2 in 5%, grade 2 in 10%, grade 4 in 81%) and febrile neutropenia (grade 3 in 10%). All 21 patients were assessed for response and overall response rate was 86%, with complete response rate of 71%. All responding patients (86%) proceeded to autologous stem cell transplant after this regimen. Patients who did not have a stem cell collection after 3rd cycle of ICE received stem cell mobilizing chemotherapy. There were no issues with stem cell harvest and engraftment in any of patients. In conclusion, panobinostat plus ICE is an effective first salvage regimen for recurrent or refractory cHL. We are currently evaluating schedule B, which is with shorter treatment with panobinostat, in an expansion cohort in this phase I study. Disclosures: Oki: Novartis: Research Funding. Fowler:pharmacyclics: Research Funding, Scientific advisory board Other; Jannsen: Scientific advisory board, Scientific advisory board Other; Roche: Honoraria, Research Funding, Scientific advisory board, Scientific advisory board Other; Celgene: Research Funding, Scientific advisory board, Scientific advisory board Other; gillead: Research Funding, Scientific advisory board Other, Scietific advisory board. Younes:Novartis: Research Funding.

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A Phase I Study of Vorinostat, Lenalidomide, and Dexamethasone In Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Excellent Tolerability and Promising Activity In a Heavily Pretreated Population

Blood ◽

10.1182/blood.v116.21.1951.1951 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1951-1951 ◽

Cited By ~ 4

Author(s):

Paul Richardson ◽

Donna Weber ◽

Constantine S. Mitsiades ◽

Meletios A. Dimopoulos ◽

Jean-Luc Harousseau ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Phase I Study ◽

Response Rate ◽

Advisory Board ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 1951 Background: Although novel treatment combinations for multiple myeloma (MM) have improved outcomes, the disease remains incurable and new drug combinations are urgently needed. Vorinostat is an oral histone deacetylase inhibitor approved in the United States for treatment of patients (pts) with advanced cutaneous T-cell lymphoma who failed prior therapies. Vorinostat alters gene expression and protein activity, promoting MM cell death through multiple pathways, and has been shown in preclinical studies to synergistically enhance the anti-MM activity of bortezomib and immunomodulatory drugs, including lenalidomide, with or without dexamethasone. Aims: The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) of vorinostat plus lenalidomide and dexamethasone in pts with relapsed or relapsed and refractory MM. Secondary objectives included overall safety, tolerability, response rate, duration of response, and time to progression (TTP). Methods: Pts in this Phase I multicenter open-label study were sequentially enrolled into 1 of 5 escalating doses of the combination regimen using a standard 3 + 3 design for ≤8 cycles. Pts who tolerated treatment and experienced clinical benefit were eligible for enrollment in an extension phase. Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria (version 3.0). Response was assessed using the modified European Group for Blood and Marrow Transplantation criteria and International Myeloma Working Group Uniform Criteria. Safety and efficacy data were analyzed using summary statistics, except for TTP, which was estimated by the Kaplan-Meier method. Results: As of July 15, 2010, 31 pts were treated and evaluable for toxicity; 4 pts remain on study. Most pts had received prior thalidomide (n=22; 71%), bortezomib (n=20; 65%), or lenalidomide (n=14; 45%), with a median of 4 prior therapies (range, 1–10). The patient population contained both high-risk and low-risk pts, based on cytogenetic and/or fluorescence in situ hybridization analyses. Most adverse events (AEs) were mild or moderate in severity. The most common grade ≥3 treatment-related AEs, experienced by 19 (61%) pts, were neutropenia (26%), thrombocytopenia (16%), diarrhea (13%), anemia (10%), and fatigue (10%); 8 pts discontinued due to toxicity. One dose-limiting toxicity (grade 3 diarrhea lasting >48 h) was observed at the maximum assessed dose (level 5), but MTD was not reached (Table) and there were no treatment-related deaths. Among 30 pts evaluable for response, the median TTP was 32 weeks (5 mo), and 4 pts remain on study as of the data cutoff date; 26 of 30 pts (87%) have achieved at least stable disease (SD). Best single responses included 2 complete responses, 3 very good partial responses (VGPR), 11 partial responses (PR), and 5 minimal responses (MR), with 5 pts achieving SD and 4 developing progressive disease, resulting in an overall response rate (ORR; PR or better) of 53%. Of 13 evaluable pts who had previously received lenalidomide, a best single response of SD or better was observed in 9 (69%; 2 VGPR, 3 PR, 1 MR, 3 SD), resulting in a 38% ORR. Notably, SD or better (2 PR, 1 MR, 3 SD) was observed in 60% of 10 evaluable pts who were relapsed, refractory, or intolerant to previous lenalidomide-containing regimens. Conclusions: Preliminary data from this Phase I study suggest that vorinostat plus lenalidomide and dexamethasone is a convenient and generally well-tolerated regimen with promising activity for relapsed or relapsed and refractory MM. The MTD for this combination was not reached. Importantly, responses were observed in pts who had received prior lenalidomide, bortezomib, and thalidomide. Further evaluation of this regimen is planned in future trials. Disclosures: Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Vorinostat, Lenalidomide, and Dexamethasone for treatment in Multiple Myeloma. Weber:Novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; Celgene- none for at least 2 years: Honoraria; Millenium-none for 2 years: Honoraria; Celgene, Millenium, Merck: Research Funding. Mitsiades:Millennium: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Merck & Co.: Consultancy, Honoraria; Kosan Pharmaceuticals: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Centrocor: Consultancy, Honoraria; PharmaMar: Patents & Royalties; OSI Pharmaceuticals: Research Funding; Amgen Pharmaceuticals: Research Funding; AVEO Pharma: Research Funding; EMD Serono: Research Funding; Sunesis: Research Funding; Gloucester Pharmaceuticals: Research Funding; Genzyme: Research Funding. Dimopoulos:MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Harousseau:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Houp:Merck Research Laboratories: Employment. Graef:Merck Research Laboratories: Employment. Gause:Merck Research Laboratories: Employment. Byrne:Celgene Corporation: Employment, Equity Ownership. Anderson:Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; BMS: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board.

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Evaluation of the Regimen Brentuximab Vedotin Plus ESHAP (BRESHAP) in Refractory or Relapsed Hodgkin Lymphoma Patients: Preliminary Results of a Phase I-II Trial from the Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO)

Blood ◽

10.1182/blood.v126.23.582.582 ◽

2015 ◽

Vol 126 (23) ◽

pp. 582-582 ◽

Cited By ~ 9

Author(s):

Ramon Garcia-Sanz ◽

Anna Sureda ◽

Sara Alonso-Alvarez ◽

Ana Pilar Gonzalez ◽

Antonia Rodriguez ◽

...

Keyword(s):

Stem Cell ◽

Phase I ◽

Hodgkin Lymphoma ◽

Complete Response ◽

Brentuximab Vedotin ◽

High Dose ◽

Hematologic Toxicity ◽

Pet Ct ◽

Grade 3 ◽

Dose Limiting Toxicity

Abstract Introduction: Around 30% of Hodgkin Lymphoma (HL) patients are refractory or relapse (RR) after first line therapy. Salvage chemotherapy followed by high-dose chemotherapy and with Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) can cure many patients, but those who are transplanted with active disease detectable by PET-CT have a very poor prognosis. Therefore, the current challenge in HL is to improve the results of the pre-transplant chemotherapy. Phase 2 single agent trials with Brentuximab Vedotin (BV) in highly RRHL patients have demonstrated overall and complete response rates of 75% and 34%, respectively (Younes, JCO 2012; 30:2183); as 2nd line, BV has provided very promising results in combination with chemotherapy (LaCasce, Blood 2014; 124(21):3099) Objectives: We conducted a phase I/II trial to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and response rate with combined Brentuximab vedotin with ESHAP chemotherapy [BRESHAP] as 2nd line therapy for RRHL prior to APBSCT (ClinicalTrials.gov #NCT02243436). Methods: The primary efficacy endpoint was the proportion of complete responses (CR) pre-APBSCT. It is a phase I-II trial with dose escalation followed by expansion. Treatment consisted of Etoposide (40 mg/m2/day IV, D1-4), Solumedrol (250 mg/day IV, D1-4), High dose AraC (2 g/m2 IV, D5) and cisPlatin (25 mg/m2/day IV, D1-4). BV was administered at three dose levels: 0.9, 1.2 or 1.8 mg/kg IV on day 1 to each cohort of patients, following the scheme of cohorts of 3 patients each, to assess the maximum tolerable dose (MTD). The dose limiting toxicity (DLT) was defined as Grade 4 hematologic toxicity extended over 3 weeks or non-hematologic toxicity grade ≥3 during the first treatment cycle. Patients were evaluated weekly. Results: Patients with relapsed or refractory classical HL (cHL) after one prior line of therapy were eligible. To date, 27 patients have been included in the trial. The first 9 have completed the three courses as scheduled, without TLD doses. Fifteen patients have received the first full cycle, presenting 4 episodes of severe adverse reactions: non-neutropenic fever due to IV AraC and to complicated catheter insertion; one pneumothorax after catheter insertion; and one febrile neutropenia recovered with antibiotic treatment. Grade 4 hematologic toxicity presented in three of these nine patients: 2 neutropenia and thrombocytopenia 1. All nine patients underwent stem cell mobilization after the 1st or the 2nd treatment cycle with subcutaneous G-CSF 5 mcg/Kg days +7 to +14, collecting >2·10e6/Kg peripheral blood CD34+ cells in all cases, with no grade 3-4 toxicity. The number of harvesting procedures was one & two in seven & two patients, respectively. The transplant has been done in 6 patients, with a median of 9 days and 10 days for neutrophil and platelet recovery, respectively. All nine patients had no evidence of disease before the transplant by PET-CT, although one patient had residual FGD uptaking areas without underlying anatomical lesions on CT (metabolic complete response: 89%). Six patients have been evaluated after the APBSCT and they are all in metabolic CR. The phase II of the trial was open on April the 12th 2015, with BV at the recommended dose of 1.8 mg/kg per course. At the submission of this report, there were 28 patients recruited, and 17 evaluated pre-transplant, achieving 16 CR. The complete results will be presented during the meeting; the projected recruitment by the meeting is 45 (65% of the total planned recruitment). Conclusions: BRESHAP is a tolerable treatment scheme as remission induction prior to transplant in patients with refractory or relapsed Hodgkin lymphoma, and it offers very promising results. Disclosures Off Label Use: Brentuximab Vedotin in Resistant or Relapsed Hodgkin Lymphoma patients who are candidates to Autologous Stem Cell Transplant. Sureda:Seattle Genetics Inc.: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau. Caballero:Takeda: Honoraria, Research Funding.

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Preliminary Results of a Phase I Study of Obinutuzumab, Venetoclax, and Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2018-99-117172 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4185-4185 ◽

Cited By ~ 1

Author(s):

Kami J. Maddocks ◽

Farrukh T. Awan ◽

Ying Huang ◽

Sabarish Ayyappan ◽

Robert A Baiocchi ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Phase I Study ◽

Hematologic Toxicity ◽

Tumor Lysis ◽

Genetics Research ◽

Non Hodgkin Lymphoma ◽

Grade 3

Abstract Introduction: Combined obinutuzumab (O) and lenalidomide (L) has demonstrated safety and preliminary efficacy in follicular lymphoma1. Venetoclax (V), a BCL2 inhibitor, as a single agent2 and in combination with rituximab3 is under development in several subtypes of B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of O, V, and L to determine the maximum tolerated dose, dose-limiting toxicities (DLT), and preliminary efficacy. Methods: Pts with relapsed/refractory diffuse large B-cell (DLBCL), transformed, high grade B-cell, Burkitt, marginal zone, and follicular (FL) lymphoma who have received ≥ 1 prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant were permitted. Prior L or BCL2 family inhibitors, CNS involvement, and active hepatitis or HIV infection were not permitted. ANC > 1000/mm3, platelets > 75,000/mm3, creatinine clearance ≥50 ml/min, ALT/AST ≤ 3 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of L days 1-21 and V days 1-28 of a 28 day cycle (Table 1). O 1000 mg was administered on days 1, 8 and 15 of cycle 1 and then on day 1 of cycles 2-6. A 3+3 dose escalation schema was followed. DLTs included: treatment delays > 28 days; ANC < 500 / mm3 or platelets <25, 000 / mm3 persisting > 28 days; grade 4 febrile neutropenia or infection or grade 3 that fails to resolve within 7 days; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, tumor flare reaction controllable with steroids, tumor lysis syndrome that does not require dialysis, diarrhea, nausea, or vomiting responsive to medical treatment, transient electrolyte abnormalities or elevations of ALT / AST that resolve ≤ grade 1 within 48 hours, grade 3 infusion reactions responsive to medical therapy. Pts without significant toxicity or progression could continue treatment up to 12 cycles. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: 14 pts have been treated. Median age is 61 years (range 35-78 years) with 10 males. Median prior therapies is 2 (range 1-10). 5 pts had bulky disease (≥ 7.5 cm) and median baseline lactate dehydrogenase was 274 U/L (range 151-894, 12/14 above ULN 190 U/L). 10 pts were refractory to their last therapy. Histologies include DLBCL/transformed lymphoma (n=11) and FL (n=3). 3 pts were treated at dose level (DL) 1 (V 400 mg / L 15 mg). One pt experienced DLT, grade 3 neutropenic fever lasting > 7 days. DL 1 was expanded and no additional DLTs occurred. One pt with DLBCL was replaced for disease progression. 4 pts were then treated at DL 2 (V 600 mg / L 15 mg), and no DLTs were encountered. One pt was replaced due to missed doses of the oral agents. A total of 3 pts have been treated at DL 3 (V 800 mg / L 15 mg) and no DLTs have occurred at the time of data cutoff. Related grade 3-4 toxicities were primarily hematologic including neutropenia (n= 11, 78.6%), anemia (n=1, 7%), and thrombocytopenia (n=2, 14.3%). Grade 3-4 infections included sepsis, febrile neutropenia, pneumonia and a urinary tract infection. No clinically significant tumor lysis has occurred. Pts have received a median of 3 cycles (range 1-12) and 4 remain on therapy. Five pts have achieved a response. At DL 1, a pt with DLBCL, GC type, achieved a complete response (CR) and 2 pts with transformed FL achieved a partial response (PR). At DL 2, 1 pt with FL achieved a CR. At DL 3, 1 pt with transformed FL/double hit achieved a PR. Ten pts have discontinued, 6 with progression and 1 for DLT, alternative treatment, physician preference, and diagnosis of MDS in a patient with 3 prior lines of chemotherapy, respectively. Conclusions: Combined treatment with O, V, and L administered up to 12 cycles has been feasible with hematologic toxicity being the most common adverse event. Enrollment is ongoing and will include expansion cohorts in FL and DLBCL.Fowler et al. Activity of the immunologic doublet of lenalidomide plus obinutuzumab in relapsed follicular lymphoma: Results of a phase I/II study. JCO 2015; 35: 7531.Gerecitano et al. A Phase 1 Study of Venetoclax (ABT-199 / GDC-0199) Monotherapy in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma. Blood 2015; 126: 254.Zinzani et al. Phase 2 Study of Venetoclax Plus Rituximab or Randomized Ven Plus Bendamustine+Rituximab (BR) Versus BR in Patients with Relapsed/Refractory Follicular Lymphoma: Interim Data. Blood 2016; 128:617. Disclosures Maddocks: Merck: Research Funding; Pharmacyclics/Janssen: Honoraria; BMS: Research Funding; Pharmacyclics: Research Funding; Teva: Honoraria; Novartis: Research Funding; AstraZeneca: Honoraria. Jaglowski:Juno: Consultancy; Kite Pharma: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Blum:Celgene: Research Funding; Novartis: Research Funding; Morphosys: Research Funding; Seattle Genetics: Research Funding. Christian:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Immunomedics: Research Funding.

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Updated Results of a Phase I Study of Ibrutinib and Lenalidomide in Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽

10.1182/blood.v126.23.3983.3983 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3983-3983 ◽

Cited By ~ 2

Author(s):

Beth A Christian ◽

John G. Kuruvilla ◽

Sonali M. Smith ◽

Pierluigi Porcu ◽

Kami J. Maddocks ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Disease Progression ◽

Dose Level ◽

Dose Escalation ◽

Research Funding ◽

Phase I Study ◽

Hematologic Toxicity ◽

Off Label ◽

Grade 3

Abstract Introduction: Lenalidomide, an immunomodulatory agent, and ibrutinib, a selective and covalent inhibitor of Bruton's tyrosine kinase, are orally bioavailable agents with single-agent activity in several histologic subtypes of relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of ibrutinib and lenalidomide to determine the maximum tolerated dose, dose limiting toxicities (DLT), and preliminary efficacy in pts with relapsed/refractory NHL and updated results are presented. Methods: Patients (pts) with relapsed/refractory B-cell NHL including diffuse large B-cell (DLBCL), transformed, mantle cell (MCL), marginal zone (MZL), lymphoplasmacytic (LPL), and follicular (FL) lymphoma who have received at least one prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant and prior lenalidomide were permitted. Prior ibrutinib, CNS involvement, and pts requiring anticoagulation were not permitted. ANC > 1000/mm3, platelets > 50,000/mm3, and creatinine < 2.0 mg/dL, ALT/AST ≤ 2.5 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of lenalidomide days 1-21 and ibrutinib days 1-28 of a 28 day cycle. A standard 3+3 dose escalation schema was followed. DLTs included: treatment delays > 14 days for toxicity; grade 5 toxicity; tumor lysis syndrome requiring dialysis; tumor flare reaction nonresponsive to corticosteroids; ANC < 500/mm3 or platelets <25, 000/mm3 persisting > 7 days; grade 3 or 4 febrile neutropenia or infection; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, diarrhea, nausea or vomiting amenable to medical therapy, correctable electrolyte abnormalities; grade 3 fatigue, or grade 3 maculopapular rash that resolved within 7 days. Pts without significant toxicity could continue treatment until disease progression. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: Twenty-five pts have been treated. Median age is 67 years (range 45-85) with 16 males. Histologies include DLBCL/transformed lymphoma (n=9), MCL (n=7), FL (n=4), MZL (n=2), and LPL (n=3). Four pts were treated at dose level (DL) 1 (lenalidomide 15 mg/ibrutinib 420 mg). One pt was replaced for rapid disease progression and 1 pt experienced DLT consisting of a grade 2 ischemic stroke. As a result of this DLT, DL 1 was expanded to 6 evaluable pts. A second DLT was observed, a grade 3 rash that resolved within 7 days but recurred on day 22. A total of 6 pts were then treated at DL-1 (lenalidomide 10 mg/ibrutinib 280 mg), and no DLTs were encountered. The protocol was amended to include additional dose levels. Pts enrolled on dose level -1A with lenalidomide 10 mg and ibrutinib 420 mg. One DLT occurred at this dose level, a grade 3 rash that failed to resolve within 7 days. The dose level was expanded to 6 pts without further DLT. DL-1B includes an intra-pt dose escalation of the lenalidomide from 10 mg in cycle 1 to 15 mg in cycle 2 with ibrutinib 420 mg. Six pts have been enrolled on this dose level. Three pts have been replaced including 2 with cytopenias not meeting DLT criteria but precluding dose escalation and one with progressive disease. Three pts at DL-1B remain on treatment. Related grade 3-4 toxicities occurred in 16/24 currently evaluated pts (67%), including primarily hematologic toxicity, rash, increased LFTs, pneumonia, hypokalemia, and syncope. Pts have received a median of 3 cycles of therapy to date (range 1-19) and 9 remain on therapy. At DL 1, a pt with DLBCL achieved a complete response (CR) and a pt with transformed follicular achieved a partial response (PR). At DL-1, a pt with DLBCL achieved a CR and 1 pt each with MCL and FL achieved PR. At DL -1A, 1 pt each with MCL and MZL achieved a PR. Overall response rate for 18 assessable pts is 39%. Five pts had best response of stable disease. Sixteen pts have discontinued the study including 3 pts with DLTs, 2 for alternative treatment, 2 for toxicity, and 9 pts with progression. Conclusions: Combined therapy with lenalidomide and ibrutinib in pts with relapsed NHL is well-tolerated, although DLTs of recurrent rash and stroke were encountered. Lenalidomide 10 mg and ibrutinib 420 mg was tolerated and pts are currently enrolling in an intra-pt dose escalation cohort. Preliminary efficacy has been observed in pts with relapsed/refractory DLBCL, MCL, FL, MZL, and transformed NHL. Disclosures Christian: Pharmacyclics: Research Funding; Acerta: Research Funding; Immunomedics: Research Funding; Celgene: Consultancy; Novartis: Other: IDSM; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding. Off Label Use: The use of ibrutnib and lenalidomide in combination in relapsed/refractory non-Hodgkin's lymphoma is off-label. Kuruvilla:Karyopharm: Honoraria, Research Funding; Roche Canada: Honoraria; Seattle Genetics: Honoraria, Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Porcu:Cell Medica: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Shape: Research Funding. Maddocks:Acerta: Research Funding; Pharamcyclics: Research Funding; Novartis: Research Funding. Byrd:Pharmacyclics: Research Funding. Blum:Celgene: Research Funding; cephalon: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding.

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Overall Survival Benefit for Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance with Bortezomib-Thalidomide (VMPT-VT) Versus Bortezomib-Melphalan-Prednisone (VMP) in Newly Diagnosed Multiple Myeloma Patients

Blood ◽

10.1182/blood.v120.21.200.200 ◽

2012 ◽

Vol 120 (21) ◽

pp. 200-200 ◽

Cited By ~ 7

Author(s):

Antonio Palumbo ◽

Sara Bringhen ◽

Davide Rossi ◽

Maide Cavalli ◽

Roberto Ria ◽

...

Keyword(s):

Research Funding ◽

Incidence Rates ◽

Advisory Board ◽

Hematological Toxicity ◽

Second Primary ◽

Risk Of Death ◽

Scientific Advisory Board ◽

Scientific Advisory ◽

Grade 3

Abstract Abstract 200 Background: In a multicenter phase 3 randomized trial, VMPT-VT was superior to VMP for response rates, progression-free survival and time to next treatment (Palumbo A, et al. J Clin Oncol 2010). Here we report an updated analysis on survival after 4 years of follow-up. Methods: Patients (N=511) were randomly assigned to receive nine 6-week cycles of VMPT-VT (induction: bortezomib 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2 d 1–4, prednisone 60 mg/m2, d 1–4, thalidomide 50 mg d 1–42; maintenance: bortezomib 1.3 mg/m2 every 14 days and thalidomide 50 mg/day up to 2 years) or VMP alone. After the inclusion of 139 patients, the protocol was amended: both VMPT-VT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m2 d 1,8,15,22, all cycles). Results: After a median follow-up of 47.2 months, median OS was not reached in the VMPT-VT arm and was 58.2 months in the VMP arm; 5-year OS rates were 59.3% and 45.9%, respectively (HR 0.74, p=0.04), with 26% reduced risk of death for patients receiving VMPT-VT (Figure-panel A). This benefit was more evident in patients younger than 75 years (5-year rates 67.8% for VMPT-VT vs 49.9% for VMP, HR 0.63, p=0.01, Figure-panel B) and in patients in complete response (CR) after induction (5-year rates 81.4% for VMPT-VT vs 48.2% for VMP, HR 0.38, p=0.006, Figure-panel C) while no significant differences were evident in patients with standard- or high-risk features detected by FISH (HR 0.99, p=0.99). A 1-year landmark analysis for patients completing induction was performed: the 4-year OS was 64.6% in the VMPT-VT group and 49.7% in the VMP group, with 33% reduced the risk of death for patients receiving VT maintenance (HR 0.67, p=0.02). Forty-nine percent of VMPT-VT and 70% of VMP patients relapsed and received subsequent salvage therapies; there was no difference in survival from relapse in the two groups (2-year OS rates 40.7% vs 50.2%,HR 1.11, p=0.54). The median duration of VT maintenance was 23.8 months. During VT maintenance 7% of patients experienced grade 3–4 peripheral neuropathy, 5% grade 3–4 hematological toxicity, 3% grade 3–4 infection and 12% discontinued due to adverse events. Second primary malignancies were reported in 7/254 patients in the VMPT-VT group and 7/257 patients in the VMP group. These corresponded to incidence rates of 0.9 and 1.05 per 100 patient-years, respectively, and were consistent with background incidence rates in the general population (aged 65–74 years 1.9, aged ≥ 75 years 2.3, SEER database). Conclusions: VMPT-VT significantly prolonged OS compared with VMP, especially in patients younger than 75 years and in patients achieving CR after induction. In patients 67–75 years of age, VMPT-VT reduced the risk of death by 37% and it should be considered a new standard of care. Disclosures: Palumbo: Celgene: Advisory Board, Advisory Board Other, Consultancy, Honoraria; Janssen: Advisory Board Other, Consultancy, Honoraria. Bringhen:Janssen: Honoraria; Celgene: Honoraria. Gentilini:Janssen: Honoraria; Celgene: Honoraria. Patriarca:Janssen: Honoraria. Guglielmelli:Janssen: Honoraria; Celgene: Honoraria. Musto:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Petrucci:Janssen: Honoraria; Celgene: Honoraria. Boccadoro:Janssen: Consultancy, Research Funding, Scientific Advisory Board Other; Celgene: Consultancy, Research Funding, Scientific Advisory Board, Scientific Advisory Board Other.

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Romidepsin in Combination with Gemcitabine, Oxaliplatin, and Dexamethasone Shows Durable Responses in Aggressive Lymphomas

Blood ◽

10.1182/blood-2019-124185 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1550-1550

Author(s):

Neha Mehta-Shah ◽

Peter A. Riedell ◽

Nancy L. Bartlett ◽

Amanda F Cashen ◽

Brad S. Kahl ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Phase I Study ◽

Histone Deacetylase Inhibitors ◽

Complete Response ◽

Hematologic Toxicity ◽

Treatment Schedule ◽

Advisory Committees ◽

Platinum Based Chemotherapy

Background: Histone deacetylase inhibitors (HDACi) and combination chemotherapy are independently used to treat relapsed/refractory (R/R) lymphoma. In vitro studies suggest that the addition of HDACi to platinum-based chemotherapy is synergistic. We conducted a phase I study of the combination of romidepsin, gemcitabine, oxaliplatin and dexamethasone in R/R lymphomas with an expansion cohort in T-cell lymphomas. Here we present the initial efficacy results. The maximum tolerated dose (MTD) determination was presented at ASH 2018. Methods: The safety and tolerability of the combination of romidepsin, gemcitabine, oxaliplatin, and dexamethasone was assessed in this phase I study to determine the MTD with a 9 pt cohort expansion at the MTD. The treatment schedule included: gemcitabine 1000 mg/m2 (day 1), oxaliplatin 100 mg/m2 (day 1); romidepsin (day 2), dexamethasone 20 mg (days 1-4) and pegfilgrastim 6 mg (day 3) of a 21-day cycle. A 3+3 dose escalation was followed with 3 dose levels (DL) of romidepsin: 1) 8 mg/m2, 2) 10 mg/m2, 3) 12 mg/m2. The study originally included romidepsin administration on days 2 and 8 but due to prolonged cytopenias, the day 8 dose was eliminated after the first 6 pts. Dose-limiting toxicity (DLT) was defined in cycle 1 as ≥ gr3 non-hematologic toxicity, any gr4 hematologic toxicity, gr≥ 3 related laboratory changes not responsive to supportive measures, and gr≥2 toxicity resulting in a >14 day treatment delay. Patients could be treated until progression, intolerance, or response adequate to allow autologous or allogeneic transplantation, to a maximum of 8 cycles. Those in complete remission at restaging could limit treatment to 2 cycles beyond complete response. Results: 24 patients with R/R lymphoma (10 PTCL-NOS, 7 AITL, 6 DLBCL, 1 ALCL) were enrolled with all patients evaluable for toxicity and 23 for response (1 AITL pursued supportive care without progression in cycle 1). The median age was 70 years (range 53-81) with 50% men. The median number of prior therapies was 2 (range: 1-4). DL 2 was the MTD. There was 1 DLT in 6 pts treated in DL 1 (pneumonia); 1 DLT in 6 pts treated in DL 2 (bleeding); and 2 DLTs in 3 pts treated in DL 3 (neutropenic fever, grade 4 thrombocytopenia). SAEs included hospitalizations for pneumonia (1), nausea/vomiting (1), fever (1), tumor lysis (1), eosinophilic pneumonia (1), febrile neutropenia (1), post-procedural bleeding (1) and for complications of disease progression (7). Other grade 3-4 treatment related toxicities included thrombocytopenia (79%), neutropenia (21%), anemia (13%), hypophosphatemia (21%), hyperglycemia (8%), hypoglycemia (8%), hypokalemia (8%), diarrhea (4%), peripheral neuropathy (4%), and hypernatremia (4%). The overall response rate (ORR) was 52% (12/23) with complete response (CR) rate 43% (10/23) and the partial response (PR) rate 9% (2/23). At the MTD, ORR was 53% (8/15) and CR 40% (6/15). In patients with TCL, ORR was 58% (10/17) and CR 47% (8/17). CRs were seen in AITL (6/6), PTCL-NOS (2/10) and DLBCL (2/6). PR was seen in PTCL-NOS (2/10). CRs were since in 3 pts refractory to their most recent therapy. The median progression free survival (mPFS) for all pts was 2.8 months (95% CI: 1.3-10.3) and median overall survival (mOS) was 10.4 months (95% CI: 2.8-33.4) and 10.4 months (95% CI: 1.7-N/A) and 3.3 months (95% CI: 1.2-30.4) respectively in TCL. The median duration of response for all patients was 5.8 months (range: 0.7 - 45.1). At the MTD, mPFS and mOS were 7.6 months (95% CI: 1.2-10.3) and 10.4 (95% CI: 1.7-20.8). 4 patients proceeded to transplant after study treatment (2 allogeneic and 2 autologous) and were censored at transplant. The median time to response was 6.0 weeks. Of others, who achieved a complete response: 2 remain in CR at 18.6 (PTCL) and 37.6 (AITL) months. Three others progressed after >6 months: 45.1 mo (DLBCL), 29.5 mo (AITL), 9.0 mo (AITL). Conclusions: MTD was identified as romidepsin 10 mg/m2 in combination with gemcitabine 1000 mg/m2, oxaliplatin 100 mg/m2, and dexamethasone 20 mg. There were no unexpected toxicities. The ORR and CR rates of this regimen are promising, particularly in AITL where 6/6 patients had a CR. Durable responses were seen in AITL, PTCL-NOS and DLBCL. Four patients have had responses for >12 months, 4 proceeded to transplant, and 2 remissions are ongoing. Given the durable complete remissions seen in this difficult to treat patient population, this regimen warrants further study. Figure Disclosures Mehta-Shah: Verastem Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding; Kiowa Hakka Kirin: Consultancy; Celgene: Research Funding; Roche/Genentech: Research Funding; Bristol Myers Squibb: Research Funding. Riedell:Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Bayer: Honoraria, Speakers Bureau; Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bartlett:Pharmacyclics: Research Funding; Bristol-Myers Squibb: Research Funding; Forty Seven: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Janssen: Research Funding; Genenetech: Research Funding; Affimed: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Seattle Genetics: Research Funding; Millenium: Research Funding; Merck: Research Funding. Cashen:Celgene: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau. Kahl:ADC Therapeutics: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy; Seattle Genetics: Consultancy. Fehniger:Cyto-Sen Therapeutics: Consultancy; Horizon Pharma PLC: Other: Consultancy (Spouse). Carson:Flatiron Health, Inc., which is an independent subsidiary of the Roche Group: Employment, Research Funding; Roche: Equity Ownership.

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Carfilzomib, Elotuzumab and Dexamethasone for Relapsed or Refractory Myeloma Patients

Blood ◽

10.1182/blood-2020-138447 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 20-20 ◽

Cited By ~ 1

Author(s):

Raija Helena Silvennoinen ◽

Hareth Nahi ◽

Pekka Anttila ◽

Perttu Koskenvesa ◽

Juha Lievonen ◽

...

Keyword(s):

Multiple Myeloma ◽

Primary Endpoint ◽

Research Funding ◽

Advisory Board ◽

Board Meeting ◽

Scientific Advisory Board ◽

Scientific Advisory ◽

Grade 3

Introduction: Due to its heterogenous nature including evolving mutations, multiple myeloma (MM) is still an incurable disease. Several novel agents have been introduced during the last decade resulting in prolonged median overall survival (OS) up to 7-8 years. Nevertheless, disease relapse is expected and eventually all patients will end up with relapsed and refractory multiple myeloma (RRMM). To benefit from all available drugs, novel combinations should be evaluated for feasibility and efficacy. Bortezomib (B), elotuzumab and dexamethasone (d) showed superiority to Bd with progression-free survival (PFS) of 9.7 vs. 6.9 months, respectively, without excessive toxicity. In this study we investigated the safety and efficacy of carfilzomib (K), elotuzumab (E) and dexamethasone (D) combination (KED) in RRMM patients. Patients and methods: Altogether 15 RRMM patients after 1-3 prior lines including B or/and lenalidomide (Len) were included. Refractoriness for B or/and Len was allowed. The main exclusion criteria were age > 74 years, absolute neutrophil count < 1.0 x 109/L and platelet count < 75 x 109/L, hemoglobin < 80 g/L, active heart disease or left ventricular ejection fraction < 40%. Carfilzomib was given once weekly 20 mg/m2 on C1D1 and thereafter 70 mg/m2 in 28-day cycles on day 1, 8, 15 in cycles 1-8, thereafter on day 1, 15 combined with weekly elotuzumab 10 mg/kg on day 1, 8, 15 in cycles 1-2, thereafter on day 1, 15; dexamethasone 40 mg on day 1, 8, 15, 22 in cycles 1-8, thereafter on day 1, 15. Treatment continued until progression (PD) or toxicity. The primary endpoint was overall response rate (ORR). If patients achieved at least very good partial remission (VGPR) the quality of response was assessed with high-sensitivity multicolour flow cytometry according to the 8-color EuroFlow protocol. Patients also completed health-related quality of life (QoL) questionnaires at day 1 and 15 through cycle 1-8. Results: The median age of patients was 69 (62-73) years, 80% (12/15) had received upfront autologous stem cell transplantation. The median number of prior lines was 2 (1-3). Proportion of Len or B refractory was 47% and 20% were double refractory. FISH, beside at diagnosis, was repeated and 73% (11/15) had at least one of following aberrations: del17p, t(4;14), t(14;16), t(14;20) or +1q. Del17 was found in 27% (4/15) of patients and +1q was frequent (67%). After the median follow-up of 18 months the ORR (at least partial response, PR) was 87% (13/15). Seven patients (47%) achieved VGPR, of these 6 patients continue in study, one was withdrawn due to thrombotic microangiopathy (TMA). The median measurable MRD level of VGPR patients was 0.005% (range 0.002-0.15%, one undetectable), and 0.003% (range 0.0007-0.26%) after one year, respectively. Regarding the rest of the patients 6 achieved PR, one minimal response and one was refractory. The median time to response was 7 (3-16) weeks. The estimated median PFS is 22 months (CI 95% 17.4-27.1). The OS has not been reached. Two (13%) grade 2 infusion reactions during first infusion were noticed. One patient developed autoimmune hemolytic anemia (AIHA), but recovered and continued KD without reappearance of AIHA. Grade 1-2 respiratory infections appeared in 66% of patients. Altogether 22 severe adverse events (SAE) grade 3-4 were reported in 60% (9/15) patients, one third were infections. Grade 3-4 neutropenia was found in 40% which is slightly more compared to reports when elotuzumab is combined with Len or pomalidomide. The overall QoL trajectory was kept steady throughout the 8 cycles. Diarrhea and dyspnoe were reported during treatment, but with full recovery before starting the next cycle which had no consequence for further treatment. Conclusion: The primary endpoint, at least PR, was reached in 87% of study patients. After a median follow-up of 18 months KED resulted in durable responses in 7 of these 15 patients (47%), despite the high frequency of adverse cytogenetics by FISH, 67% with +1q and 27% with del17p. The number of non-hematological SAEs was 60%. We noticed 2 serious unexpected adverse reactions, AIHA and TMA with convulsions, and an additional case of pulmonary embolism, in responding patients. We recommend careful monitoring for the signs of microangiopathy and hemolysis. In summary, KED resulted in a high ORR, which was durable in approximately 50% of the patients. Side effects were manageable and randomized trials with KED are warranted. Disclosures Silvennoinen: Cancer patients Finland: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Anttila:Janssen: Honoraria, Other: Advisory Board; BMS: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Lievonen:Amgen, Celgene, BMS, Sanofi, Takeda: Consultancy; Celgene, Janssen, Novartis, Amgen: Honoraria; Cancer Association Finland: Honoraria. Varmavuo:Abbvie, Roche, Celgene, Amgen, Sanofi: Consultancy. Säily:Boehringer Ingelheim: Honoraria; Janssen Cilag: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Celgene: Honoraria; Abbvie: Honoraria; Amgen: Honoraria. Partanen:Takeda: Other: Scientific Advisory Board Meeting; Behring: Honoraria; Abbvie: Honoraria, Other: Scientific Advisory Board Meeting. Sankelo:Celgene, Amgen, Sanofi: Other: Congress travel support. Luoma:Amgen, Janssen. Incyte: Other: Advisory Boards. Jantunen:Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Sanofi: Honoraria; TEVA: Other: Advisory Board; Takeda: Other: Advisory Board. Heckman:Celgene: Research Funding; Novartis: Research Funding; Oncopeptides: Research Funding; Orion Pharma: Research Funding; Innovative Mediicines Initiative project Harmony: Research Funding.

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Incidence and Outcomes of Toxoplasma Reactivation in Patients with Hematologic Diseases after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2021-151474 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1779-1779

Author(s):

Taha Al-Juhaishi ◽

Alexandre Elias Malek ◽

Denái R. Milton ◽

Jeremy L. Ramdial ◽

May Daher ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Antimicrobial Prophylaxis ◽

Advisory Board ◽

License Agreement ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Scientific Advisory Board ◽

Scientific Advisory

Abstract Introduction: Toxoplasmosis is a rare complication of allogeneic hematopoietic stem cell transplantation (AlloHSCT) usually through reactivation in a previously seropositive recipient, and is associated with mortality as high as 60% (Paccoud et al. BMT 2020). Seroprevalence in the population varies ranging from 5% or lower in North America to over 50% in France. Risk factors for reactivation include immune suppression, seronegative donors, cord blood grafts, and lack of adequate antimicrobial prophylaxis (Robin et al. BBMT 2019). We sought to evaluate the outcomes of patients with toxoplasma reactivation after undergoing AlloHSCT in the modern era. Methods: This study was a retrospective single center analysis of all patients who underwent AlloHSCT between January 2012 and June 2021 at our center. Primary objectives were to assess the incidence of toxoplasma reactivation and the effects of reactivation on survival. Patients were identified in the department database and relevant demographic and clinical data were extracted. Results of toxoplasma testing [IgG serology and polymerase chain reaction (PCR)] were collected and verified by manual chart review. Patients with negative toxoplasma serology and/or missing serology or PCR data were excluded from analysis. Reactivation was defined as positive PCR in a seropositive patient. Toxoplasma reactivation associations were assessed by logistic regression models. Overall Survival (OS) was estimated using the Kaplan-Meier method and differences compared using the log-rank test. Cox proportional hazards models were used for survival associations. Cumulative incidence of non-relapse mortality (NRM) was determined using competing risks method. This study was approved by the institutional board review (IRB) committee at our center. Results: A total of 370 patients who received AlloHSCT and had a positive toxoplasma IgG were identified. Fifty-two patients had missing toxoplasma PCR and 4 did not meet eligibility criteria and were excluded. Twenty-two (7%) out of the remaining 314 seropositive patients experienced toxoplasma reactivation as confirmed by positive PCR. Median age in the reactivation group was 55 years, and patients were mostly white males with myeloid neoplasms who underwent AlloHSCT in first complete remission using nonmyeloablative conditioning and a matched unrelated donor (table 1). No significant differences in baseline characteristics were seen between the seropositive only and the reactivation groups, except for antimicrobial prophylaxis use (P <0.001). Fifty-nine percent of patients (13 out of 22) in the reactivation group were on toxoplasma prophylaxis compared to 93% (273 out of 292) in the seropositive patients without reactivation. Sixteen out of the 22 (73%) patients with reactivation developed clinical symptoms while 6 (27%) had asymptomatic reactivation. Antimicrobial prophylaxis only with either pentamidine, atovaquone, trimethoprim/sulfamethoxazole but not dapsone, was associated with lower risk of developing reactivation (table 2). With a median follow up of 15.4 months (0.3-98.9), the median OS was 9.6 months in patients with reactivation versus 58.5 months in seropositive patients without reactivation [HR, 2.06; (95% CI, 1.21 to 3.52); P=0.008] (figure 1). NRM was also higher in the reactivation group [HR, 2.61; (95% CI, 1.34 to 5.11); P=0.005] (figure 2). Specifically, day 100, 1-year and 2-year NRM were higher in the reactivation group versus (vs) seropositive patients (36% vs 10%, 41% vs 18%, and 47% vs 20% respectively). Toxoplasma reactivation was associated with worse OS and increased NRM in univariable analysis however this did not reach statistical significance in multivariable analysis. Conclusion: Toxoplasma reactivation in seropositive AlloSCT patients remains low at our center at around 7%. Toxoplasma reactivation is associated with worse outcomes after AlloHSCT and reactivation could be mitigated by improved compliance with antimicrobial prophylaxis. Figure 1 Figure 1. Disclosures Mehta: Kadmon: Research Funding; Incyte: Research Funding; CSLBehring: Research Funding; Syndax: Research Funding. Shah: Amgen: Consultancy; Bluebird Bio: Research Funding; BMS/Celgene: Research Funding; CareDx: Consultancy; CSL Behring: Consultancy; GSK: Consultancy; Indapta Therapeutics: Consultancy; Janssen: Research Funding; Karyopharm: Consultancy; Kite: Consultancy; Nektar: Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Precision Biosciences: Research Funding; Sanofi: Consultancy; Sutro Biopharma: Research Funding; Teneobio: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Rezvani: Pharmacyclics: Other: Educational grant, Research Funding; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding; Takeda: Other: License agreement and research agreement, Patents & Royalties; GSK: Other: Scientific Advisory Board ; Caribou: Other: Scientific Advisory Board; GemoAb: Other: Scientific Advisory Board ; AvengeBio: Other: Scientific Advisory Board ; Virogin: Other: Scientific Advisory Board ; Navan Technologies: Other: Scientific Advisory Board; Bayer: Other: Scientific Advisory Board . Qazilbash: Janssen: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; Angiocrine: Research Funding; Amgen: Research Funding; Oncopeptides: Other: Advisory Board; Biolline: Research Funding; NexImmune: Research Funding. Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Shpall: Takeda: Patents & Royalties; Navan: Consultancy; Novartis: Honoraria; Magenta: Honoraria; Affimed: Patents & Royalties; Novartis: Consultancy; Magenta: Consultancy; Adaptimmune: Consultancy; Axio: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria. Ahmed: Seagen: Research Funding; Xencor: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding.

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CC-486 in Patients with Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML), or Chronic Myelomonocytic Leukemia (CMML): Safety, Tolerability, and Response

Blood ◽

10.1182/blood.v124.21.4638.4638 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4638-4638

Author(s):

Michael R. Savona ◽

Kathryn Kolibaba ◽

Paul Conkling ◽

Edwin C. Kingsley ◽

Carlos Becerra ◽

...

Keyword(s):

Research Funding ◽

Performance Status ◽

Advisory Board ◽

Extension Phase ◽

Employment Equity ◽

Scientific Advisory Board ◽

Hematological Cancers ◽

Scientific Advisory ◽

Equity Ownership ◽

Grade 3

Abstract Background: CC-486 is an oral formulation of the epigenetic modifier, azacitidine, in clinical development for treatment (Tx) of hematological cancers. Part 1 of this phase I, multicenter study showed no effect on pharmacokinetics (PK) of CC-486 when taken with food or with a proton-pump inhibitor (Laille, 2014). A prospective extension phase of this study is ongoing to assess the safety and efficacy of CC-486. Objectives: To assess safety, tolerability, and hematological response associated with an extended CC-486 dosing schedule in patients (pts) with MDS, AML, or CMML. Methods: Eligible pts were age ≥18 years, had confirmed WHO-defined MDS, CMML, or AML based on bone marrow (BM) aspirate and biopsy, and an ECOG performance status score 0-2. In the PK phase, pts received 2 to 3 single CC-486 doses and in the extension phase, pts received CC-486 300 mg QD for the first 21 days of repeated 28-day cycles. Tx-emergent adverse events (TEAEs) were coded by MedDRA v15.0 and graded using NCI-CTCAE v4.0. In addition to TEAEs for all pts, because PK-phase exposure was quite limited, TEAEs of interest are reported for the subset of pts who entered the extension phase (21-day dosing). Responses (complete or partial remission [CR, PR], CR with incomplete blood count recovery [CRi], marrow CR [mCR], hematologic improvement [HI], and transfusion independence [TI]) were defined by IWG 2006 (MDS) or IWG 2003 (AML) criteria. Baseline transfusion dependence (TD) was defined as ≥4 red blood cell (RBC) units or ≥2 platelet transfusions, in the 56 days before first dose. TI was defined as no transfusion for 56 consecutive days. The safety-evaluable cohort included all pts who received ≥1 CC-486 dose. Efficacy-evaluable pts had ≥1 post-baseline efficacy measurement during the extension phase as of data cut-off (June 6, 2014). Efficacy results are reported for the combined MDS and CMML pt population and separately for pts with AML. Results: A total of 32 pts (MDS n=19 [59%], CMML n=4 [13%], and AML n=9 [28%]) received ≥1 CC-486 dose and are evaluated for safety. Median (range) age of all pts was 72 (53-93) years, with 44% of pts age ≥75 years. Most pts were male (69%) and all were Caucasian. Median number of CC-486 Tx cycles for all pts was 4 (range 1-18), and within the MDS, CMML, and AML groups was 5 (1-18), 4 (2-17), and 1 (1-9), respectively. The mean ±SD Tx cycle length was 30 ±9.0 days overall (by group: 33 ±8.3 days in MDS, 25 ±5.4 in CMML, and 27 ±10.7 in AML pts). The most frequent types of TEAE were gastrointestinal (GI) and hematological (Table 1). CC-486 dose was adjusted due to GI TEAEs for 5 pts (16%), and due to hematological TEAEs for 8 pts (25%). Of all 32 pts, 30 pts (94%) entered the 21-day dosing extension phase. Of these pts, GI TEAEs (grade ≥2) were reported for 23 pts (77%). Of these, only 4 grade 3 (vomiting and diarrhea, 2 each) and no grade 4 TEAEs were observed. Hematological TEAEs (grade ≥3) were reported for 19 pts (63%). Neutropenic grade ≥2 TEAEs occurred in 12 (40%) of 30 pts, of which 29% were grade 2, 38% grade 3, and 32% grade 4. Febrile neutropenia occurred in 3 pts and grade 4 thrombocytopenia in 3. Most TEAEs occurred during the first 2 Tx cycles: GI, 73% and hematological, 55%. The efficacy-evaluable population at data cut-off included 27 pts (84%): 20 pts with MDS or CMML, and 7 pts with AML (Table 2). One pt with MDS achieved CR, 1 pt with AML achieved CRi, and 1 pt with AML achieved PR (pt was to proceed to transplant). Of HI-evaluable pts in the MDS+CMML and AML groups, respectively, 6/18 (33%) and 2/7 (29%) attained an HI response. Few pts were TD at baseline. Of pts who were RBC TD at baseline, 1/5 pts (20%) in the MDS+CMML group and 1/5 pts (20%) in the AML group attained RBC TI. Of 3 pts who were platelet TD at baseline, 1 pt with AML attained platelet TI. Conclusions: CC-486 can provide the flexibility to adjust dose or dosing regimen to improve tolerability or efficacy as needed. The safety and tolerability of CC-486 300 mg QD taken for the first 21 days of repeated 28-day cycles were consistent with the known safety profile of injectable azacitidine in these pts with MDS, CMML, and AML. Grade 3-4 gastrointestinal TEAEs were infrequent (<20% of all pts). Grade 3-4 neutropenias were observed and deserve scrutiny, especially in the first 2 Tx cycles, and in some cases may warrant initiation of prophylactic antibiotics, particularly in pts with prolonged grade 4 neutropenia. HI rates of ~30% observed in this trial were similar to previous reports of CC-486. Disclosures Savona: Karyopharm: Consultancy, Equity Ownership; Celgene: Consultancy; Gilead: Consultancy; Incyte: Consultancy. Kolibaba:Celgene: Research Funding. Conkling:Celgene: Research Funding. Rifkin:Celgene: Scientific Advisory Board Other; Millennium/Takeda: Scientific Advisory Board, Scientific Advisory Board Other; Onyx/Amgen: Scientific Advisory Board, Scientific Advisory Board Other. Laille:Celgene: Employment, Equity Ownership. Kellerman:Celgene: Employment. Ukrainskyj:Celgene: Employment, Equity Ownership. Dong:Celgene: Employment. Skikne:Celgene: Employment, Equity Ownership.

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Secreted Factors Determine Resistance to Idelalisib in Marginal Zone Lymphoma Models of Resistance

Blood ◽

10.1182/blood-2019-124299 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2569-2569

Author(s):

Alberto J Arribas ◽

Sara Napoli ◽

Eugenio Gaudio ◽

Luciano Cascione ◽

Alessandra Di Veroli ◽

...

Keyword(s):

B Cell ◽

Cell Lines ◽

Research Funding ◽

Advisory Board ◽

Institutional Research ◽

Rna Seq ◽

Scientific Advisory Board ◽

Scientific Advisory ◽

Erbb Signaling ◽

Travel Grant

Background . PI3Kδ is expressed in B-cells and has a central role in the B-cell receptor signaling in B-cell derived malignancies. Idelalisib was the first-in-class PI3Kδ inhibitors and several second-generation compounds are undergoing clinical investigation as single agents and in combinations. To identify modalities to overcome the resistance that develops to this class of agents, we have developed two idelalisib-resistant models derived from splenic marginal zone lymphoma (SMZL) cell lines. Materials and Methods. Cells were kept under idelalisib (IC90) until acquisition of resistance (RES) or with no drug (parental, PAR). Stable resistance was confirmed by MTT assay after 2-weeks of drug-free culture. Multi-drug resistance phenotype was ruled out. Cells underwent transcriptome and miRNA profiling by RNA-Seq, whole exome sequencing (WES), lipidomics profiling, pharmacological screening (348 compounds), and FACS analysis. Cytokines and growth factor secretion was performed by ELISA. Results. Two RES models were obtained from VL51 and Karpas1718 with 7-10 fold times higher IC50s than PAR counterparts. In both models, conditioned media from RES cells transferred the resistance in the PAR cells. While WES did not identify somatic mutations associated with resistance, RNA-Seq and lipidomics analyses showed that the two cell lines had developed resistance activating different modalities. The VL51 RES model showed an enrichment in BCR-TLR-NFkB (TLR4, CD19, SYK), IL6-STAT3 (IL6, CD44), chemokines (CXCL10, CXCR4, CXCR3) and PDGFR (PDGFRA, PRKCE) signatures, paired with increased p-AKT and p-BTK levels, decreased cardiolipins and sphingomyelins levels, and increased levels of specific triacylglycerols and glycerophosphocholines. In particular, there was an over-expression of surface expression of PDGFRA and secretion of IL6 in the medium. Silencing of both IL6and PDGFRA by siRNAs reverted the resistance, while the silencing of the individual genes had only a partial effect. These data were paired with the acquired sensitivity to the PDGFR inhibitor masitinib, identified in the pharmacologic screening. In the Karpas1718 model, we observed an increased p-AKT activity with an enrichment for B-cell activation signatures (RAG1, RAG2, TCL1A), proliferation (E2F2, MKI67), ERBB signaling (HBEGF, NRG2, ERRB4), increased levels of some triacylglycerols and repressed levels for specific glycerophosphocholines. HBEGF secretion was confirmed by ELISA. The addition of recombinant HBEGF to the medium induced resistance in the PAR cells. Combination with the pan ERBB inhibitor lapatinib was beneficial in the K1718 RES. Recombinant HBEGF also induced resistance to the BTK inhibitor ibrutinib in the PAR cells and in the mantle cell lymphoma SP-53 cell line. Specific members of the let-7 family of miRNAs were repressed in the RES lines derived from both cell lines, indicating the involvement of miRNA deregulation in the mechanism of resistance. Indeed, let-7 members are known to directly target IL6-STAT3 and cytokine signaling cascade, as well PI3K-AKT network. In solid tumors, let-7 members are also expressed at low levels in tumors with constitutive active ERBB signaling, in accordance with the activation of ERBB pathway and p-AKT we observed in our Karpas1718model. Experiments with a LIN28B inhibitor are now on-going. Finally, we validated the findings across a panel of 34 B-cell lymphoma cell lines, in which IL6, PDGFRA, HBEGF and LIN28 expression levels were negatively correlated with idelalisib sensitivity, while the latter was positively correlated with let-7 levels (P <0.05). Conclusions. We developed two distinct models derived from MZL of secondary resistance to the PI3Kδ inhibitor idelalisib. We identified treatments that might overcome resistance to idelalisib and are worth of further investigations. The two models, driven by different biologic processes, will allow the evaluation of further alternative therapeutic approaches. Disclosures Stathis: PharmaMar: Other: Renumeration; ADC Therapeutics: Other: Institutional research funding; Abbvie: Other: Renumeration; Bayer: Other: Institutional research funding; Novartis: Other: Institutional research funding; MEI-Pharma: Other: Institutional research funding; Roche: Other: Institutional research funding; Pfizer: Other: Institutional research funding; Merck: Other: Institutional research funding. Stuessi:Gilead: Speakers Bureau. Zucca:Gilead: Honoraria, Other: travel grant. Rossi:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Other: Scientific advisory board; Janseen: Honoraria, Other: Scientific advisory board; Roche: Honoraria, Other: Scientific advisory board; Astra Zeneca: Honoraria, Other: Scientific advisory board. Bertoni:Nordic Nanovector ASA: Research Funding; Acerta: Research Funding; Jazz Pharmaceuticals: Other: travel grants; ADC Therapeutics: Research Funding; Bayer AG: Research Funding; Cellestia: Research Funding; CTI Life Sciences: Research Funding; EMD Serono: Research Funding; Helsinn: Consultancy, Research Funding; ImmunoGen: Research Funding; Menarini Ricerche: Consultancy, Research Funding; NEOMED Therapeutics 1: Research Funding; Oncology Therapeutic Development: Research Funding; PIQUR Therapeutics AG: Other: travel grant, Research Funding; HTG: Other: Expert Statements ; Amgen: Other: travel grants; Astra Zeneca: Other: travel grants.

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