Ofatumumab and Bendamustine in Previously Treated CLL and SLL

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4615-4615
Author(s):  
Chaitra S. Ujjani ◽  
Edmund A Gehan ◽  
Pari Ramzi ◽  
Catherine Broome ◽  
Bruce D. Cheson
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Brain Mri ◽  
Viral Reactivation ◽  
Multiple Infections ◽  
Advisory Committees ◽  
Richter’S Transformation ◽  
Richter's Transformation ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 4615 Background: Despite response rates of 85–95% with fludarabine and rituximab (R)-based therapies in multicenter trials, patients (pts) with CLL invariably relapse. Ofatumumab (O) and Bendamustine (B) have each shown efficacy in relapsed/refractory CLL with ORRs of 68–78% and 44–58%, respectively. While excellent responses have been seen with BR in CLL (77-91%), the combination of O and B has yet to be investigated. In this phase II study, we are combining O and B in previously treated CLL and SLL in order to investigate the efficacy and tolerability of this regimen. We report our experience with the first 5 pts here. Methods: Pts with relapsed/refractory CLL/SLL with adequate performance status and organ function were eligible as long as they had not received B previously. Pts received O 300 mg IV on D −7, followed by O 1000 mg IV on D1 and B 70 mg/m2 on D1, 2 of each cycle (C). Premedications included acetaminophen 650 mg PO, diphenhydramine 50 mg PO, and hydrocortisone 100 mg IV prior to O and Ondansetron 8 mg IV prior to B. Pts received 6 cycles of OB as long as tolerated or until disease progression. The target enrollment is 40 pts. Results: Of the 5 pts on study, the median age was 62 years, 4 were male, and 3 were Rai Stage III/IV. One pt had sole del 13q, 3 had del 11q, and 1 had del 17p cytogenetics. Pts received a mean of 2 prior therapies (range, 1–4). The first 3 pts developed Grade 2 infusion-related reactions with O during C1. Thus, the protocol was amended to increase acetaminophen to 1000 mg and hydrocortisone to 200 mg for O premedication. Three patients developed > Grade 3 neutropenia which delayed C2 treatment in 2 pts. Two pts experienced > Grade 3 anemia requiring transfusion. In addition, multiple infections arose on study. Pt 1 had a Grade 1 URI requiring hospitalization during C1. Pt 2 had a Grade 2 pneumonia with Grade 3 NTP during C1 and a Grade 2 UTI during C2. Pt 4 developed a Grade 3 pneumonia, Grade 3 hepatosplenic fungal infection, and Grade 3 bacteremia after C1. Pt 5 had a Grade 2 URI during C1 and Grade 2 sinusitis during C3. The protocol was amended so that pegfilgrastim was to be given with each cycle. After C1, Pts 1 and 4 developed a systemic neurotoxicity, characterized by blunted affect, weakness, fatigue, and failure to thrive requiring hospitalization. Complete infectious, metabolic, psychological, and neurologic evaluation was negative for Pt 1. Due to his ongoing weakness, he was removed from study after C2 and discharged to rehab. At 3 months he was only able to walk 3 blocks and his affect remained blunted. Pt 4 was found to have pneumonia on admission. With antibiotics, his functional status improved, but his affect remained mildly altered. Proposed etiologies for this neurotoxicity included infection such as viral reactivation or cytokine release storm. The protocol was amended to exclude pts with history of neurologic deficit and to perform a thorough neurologic evaluation including brain MRI, lumbar puncture, and serum and CSF viral serologies and cytokines levels at onset of concerning symptoms. Pts received a median of 2 cycles of therapy (range, 1–6). All showed evidence of response after C1. Pt 1 achieved a clinical CR with C1 but was removed from study after C2 and had recurrent disease at 5 months. Pt 2 achieved a CR after C3 and remains progression-free 5 months after completing C6. Pts 3 and 4 initially showed a response after C1 but developed Richter’s transformation during C2. Pt 5 had a response after C1 and is currently in C4. The most common reasons for stopping therapy were toxicity and Richter’s transformation. Conclusion: OB has significant efficacy in pts with multiply-relapsed and highly-refractory CLL/SLL. However, toxicity is considerable, particularly in terms of infection. In addition, despite an initial response, Richter’s transformation has been reported in two patients. As this is a small cohort with multiple confounding factors, further evaluation is needed. Disclosures: Broome: Alexion: Honoraria, Speakers Bureau. Cheson:Cephalon: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Bendamustine and Lenalidomide in Relapsed/Refractory CLL

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4618-4618
Author(s):  
Chaitra S. Ujjani ◽  
Syed M. Karim ◽  
Trishna Goswami ◽  
Jenny Crawford ◽  
Edmund A Gehan ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase I Study ◽  
Tumor Lysis Syndrome ◽  
Stage I ◽  
Advisory Committees ◽  
Richter’S Transformation ◽  
Richter's Transformation ◽  
Grade 3

Abstract Abstract 4618 Background: Front-line regimens for CLL typically include Fludarabine and Rituximab (R), producing ORRs of 90–95% (CR 44–47%) in multicenter trials. Despite these significant responses, patients (pts) invariably relapse and newer regimens are necessary for this relapsed/refractory population. Bendamustine (B) and Lenalidomide (L) have both shown efficacy as single agents in CLL with ORRs of 68–78% and 32–47%, respectively. The combination of these agents, however, has yet to be investigated. In this 2-stage phase I study, we are combining B and L in relapsed/refractory CLL (Stage I) in order to determine the MTD of L for future combination of BLR in CLL (Stage II). We report the preliminary results of the Stage I here. Methods: Pts with relapsed/refractory CLL with adequate performance status and organ function were eligible. This phase I study utilized a standard 3 + 3 dose-escalation design. In Stage I all pts received L 5 mg po daily D-7 through D-1 and allopurinol 300 mg po daily D-2 to D14 of Cycle 1 to minimize the risk of tumor lysis syndrome (TLS). For each 28-day cycle, pts received B 90 mg/m2 IV on D1, 2 with escalating doses of L po daily. Dose levels were 5 mg every other day (Cohort −1), 5 mg daily (Cohort 1), 10 mg daily (Cohort 2), 15 mg daily (Cohort 3), and 20 mg daily (Cohort 4). Pts in Cohorts 2 and higher received L 5 mg po daily during Cycle 1 followed by their respective cohort L doses in subsequent cycles. Pts received 6 cycles of BL followed by 6 cycles of L as long as tolerated or until disease progression. Results: For the 7 pts on study, the median age was 71 years, 100% were male, 43% were Rai Stage III/IV, 43% were CD38+, and 14% had a B-2 microglobulin level > 4. Two pts had sole del 13q, 3 had del 11q, and 1 had del 17p cytogenetics. Pts received a median of 1 prior therapy (range, 1–3). One pt had Richter’s transformation and one pt had PLL. The first pt (Richter’s transformation) in Cohort 1 had a DLT of Grade 3 rash. As rash is a common toxicity with L, the protocol was amended so that only Grade 3 rash that did not resolve to < Grade 2 within 10 days despite steroids or any Grade 4 rash were to be considered DLTs. In addition, L administration was reduced to only 21 days of each 28-day cycle. The trial was reinitiated after these amendments, and 3 new pts were enrolled into Cohort 1. There were no DLTs or Grade 3/4 rash found in this cohort. Three pts were enrolled into Cohort 2, but one suffered fatal septic shock during Cycle 2. No MTD has been reached for L. Common > Grade 3 toxicities included neutropenia (71%) and thrombocytopenia (29%). Pts completed a median of 5 cycles of therapy (range, 2–12). The most common reason for discontinuing therapy was toxicity. The ORR was 57% (CR of 14%). Responses were seen in pts with both sole del 13q and del 11q. The median time to response was 6 mos (range, 3–6 mos). Among the responders, the median length of response was 14 months (range, 13–23+ mo). Cohorts 1 and 2 have been completed. Conclusion: BL demonstrates promising efficacy and tolerability in pts with relapsed/refractory CLL. Further evaluation is needed. Disclosures: Cheson: Celphalon: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celegen: Membership on an entity’s Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Research Funding.

An Open-Label Phase 2 Study Of Ofatumumab In Combination With a Novel AKT Inhibitor (Afuresertib) In Previously Treated Patients With Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4175-4175
Author(s):  
Christine I. Chen ◽  
Susi Snitzler ◽  
Trina Wang ◽  
Harminder Paul ◽  
Lisa W Le ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Treatment Phase ◽  
Phase 2 ◽  
Akt Inhibitor ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Previously Treated ◽  
Grade 3

Abstract Introduction Ofatumumab is a novel anti-CD20 monoclonal antibody which led to impressive single-agent responses of 47-58% in a phase 2 study of CLL patients (pts) with refractory disease (Wierda et al 2010). Unfortunately, response durations were short (median 5.6-7.1 mos). In order to improve upon these results, we combined ofatumumab with a novel pan-AKT kinase inhibitor, afuresertib (GSK2110183). The AKT pathway plays a centralized role in tumor differentiation, migration, proliferation and survival and is frequently aberrantly activated in CLL (Longo et al 2007). Single agent afuresertib is very well-tolerated with minimal myelotoxicity in relapsed/refractory hematologic malignancies (Spencer et al ASH 2011). We present an interim analysis of the initial 19 of 31 planned pts in an ongoing trial of ofatumumab and afuresertib in relapsed/refractory CLL. Methods Previously treated CLL pts who have received at least one prior fludarabine-containing regimen with disease progression are eligible. During the initial 6 month Treatment Phase, ofatumumab 2000mg IV is administered weekly for 8 doses, then once every 4 week cycle for 4 doses (dose/schedule identical to the pivotal phase 2 trial) with afuresertib 125mg orally daily. An initial 10 day Lead-in Phase with afuresertib alone allows for evaluation of pharmacodynamic (PD) changes in phosphoproteins and pharmacokinetic (PK) studies. Pts are assessed for safety and response on day 1 of each cycle. Pts achieving SD, PR or CR by the end of the Treatment Phase proceed to the Maintenance Phase with single-agent afuresertib for a maximum of 12 mos (12 cycles). Results Demographics: To date, 19 pts have been enrolled. Median age is 65 yrs (range 43-76), baseline median Hb 108g/L (range 80-145), absolute lymphocytes 29.7 x109/L (range 1.0-464.9), β2M 4.42mg/L (range 1.42-3.21), bulky nodes ≥5cm in 5 pts (32%), organomegaly in 8 pts (42%), del17p/del11q on FISH in 9 pts (47%), and ZAP70+ in 13 pts (68%). Eight pts (42%) were fludarabine-refractory; only 2 pts had received prior alemtuzumab. The median number of prior therapies was 2 (range 1-6). Toxicity: Hematologic: 4 pts (21%) developed Gr 3-4 neutropenia during at least 1 cycle; 1 pt (5%) had a febrile neutropenia event. Only 2 pts (10.5%) have developed Gr 3-4 thrombocytopenia, without bleeding. Nonhematologic toxicity: Most common related grade 3-4 toxicities were GI: dyspepsia (53%), diarrhea (37%), nausea (21%), temporally related to oral afuresertib and easily managed symptomatically. Infusion reactions to ofatumumab were frequent (12 pts; 63%) with grade 3 reactions in 3 pts. Five pts (26%) developed non-infectious pneumonitis, with 3 pts requiring hospitalization. Two pts with preexisting atrial arrhythmias sustained exacerbation with weekly ofatumumab infusions. Most infections were mild, with only 1 grade 3 cellulitis. Efficacy: Of the 19 response-evaluable pts receiving a median of 6 cycles (range 1-9), 8 pts (42%) have achieved a PR, 11 SD (58%), and no CR. Response onset was rapid at a median 0.9 mos (range 0.8-2.8). At a median follow-up of 6.8 mos (range 0.3-12.9 mos), 5 pts (26%) have progressed and one patient has died after cycle 1 on therapy due to progressive CLL. PD Studies: CD19+ cells are assayed for phosphorylated AKT and its downstream targets RAS40 and GSK3 in addition to phospho-proteins of alternative pathways including ERK and pS6 by multiplexed phospho-flow cytometry. Peripheral blood samples are collected at screening and on cycle 1 day 10, after dosing with afuresertib. Of the 7 patients evaluated thus far, 5 demonstrated constitutive AKT phosphorylation at baseline. Partial inhibition of AKT signaling evidenced by increased phosphorylation of AKT and inhibition of GSK3 and/or RAS40 phosphorylation in response to BCR stimulation was observed post-treatment, indicating target engagement by afuresertib. PK Studies: Afuresertib exposure (Cmax and AUC) was similar when afuresertib was administered alone or in combination with ofatumumab. Conclusion Preliminary results from this phase 2 study suggests that a combination of ofatumumab plus a novel oral AKT inhibitor, afuresertib, has activity in previously treated CLL and is generally well-tolerated with minimal myelotoxicity. Response data are encouraging but whether durable responses can be achieved requires more mature follow-up. Disclosures: Chen: Johnson & Johnson: Consultancy, Research Funding; Lundbeck: Consultancy; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria. Off Label Use: Off-label use of ofatumumab and afuresertib for the treatment of relapsed/refractory CLL. Smith:GSK: Employment, Equity Ownership. Johnston:Roche: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Lundbeck: Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

scholarly journals Efficacy and Safety of Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 17p Deletion: Results from the Phase II RESONATE™-17 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 327-327 ◽  
Author(s):  
Susan O'Brien ◽  
Jeffrey A. Jones ◽  
Steven Coutre ◽  
Anthony R. Mato ◽  
Peter Hillmen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Previously Treated ◽  
Grade 3

Abstract Background: Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years in the relapsed/refractory (R/R) setting. Ibrutinib (ImbruvicaTM), a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for previously treated patients with CLL and for patients with del 17p CLL. We report results from the primary analysis of the Phase II RESONATETM-17 (PCYC-1117-CA) study, designed to evaluate the efficacy and safety of single-agent ibrutinib for treatment of patients with R/R del 17p CLL or small lymphocytic leukemia (SLL). Methods: Patients with del 17p CLL or SLL who failed at least one therapy were enrolled to receive 420 mg oral ibrutinib once daily until progression. All patients receiving at least one dose of ibrutinib were included in the analysis. The primary endpoint was overall response rate (ORR) per an independent review committee (IRC). Other endpoints included duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib. Results: Among 144 treated patients (137 with CLL, 7 with SLL), the median age was 64 (48% 65 years or older) and all had del 17p. Baseline characteristics included 63% of patients with Rai Stage III or IV disease, 49% with bulky lymphadenopathy of at least 5 cm, and 10% with lymphadenopathy of least 10 cm. The median baseline absolute lymphocyte count (ALC) was 32.9 x 109/L with 57% of patients with a baseline ALC at least 25.0 x 109/L. Baseline beta-2 microglobulin levels were at least 3.5 mg/L in 78% of patients (range 1.8-19.8 mg/L), and lactate dehydrogenase levels were at least 350 U/L in 24% of patients (range 127-1979 U/L). A median of 2 prior therapies (range 1-7) was reported. Investigator-assessed ORR was 82.6% including 17.4% partial response with lymphocytosis (PR-L). Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) were reported in 3 patients. IRC-assessed ORR is pending. At a median follow up of 13.0 months (range 0.5-16.7 months), the median PFS (Figure 1) and DOR by investigator determination had not been reached. At 12 months, 79.3% were alive and progression-free, and 88.3% of responders were progression-free. Progressive disease was reported in 20 patients (13.9%). Richter transformation was reported in 11 of these patients (7.6%), 7 of the cases occurring within the first 24 weeks of treatment. Prolymphocytic leukemia was reported in 1 patient. The most frequently reported adverse events (AE) of any grade were diarrhea (36%; 2% Grade 3-4), fatigue (30%; 1% Grade 3-4), cough (24%; 1% Grade 3-4), and arthralgia (22%; 1% Grade 3-4). Atrial fibrillation of any grade was reported in 11 patients (7.6%; 3.5% Grade 3-4). Seven patients reported basal or squamous cell skin cancer and 1 patient had plasma cell myeloma. Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients (4.9%, all Grade 2 or 3). Study treatment was discontinued in 16 patients (11.1%) due to AEs with 8 eventually having fatal events (pneumonia, sepsis, myocardial or renal infarction, health deterioration). At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib. Conclusions: In the largest prospective trial dedicated to the study of del 17p CLL/SLL, ibrutinib demonstrated marked efficacy in terms of ORR, DOR, and PFS, with a favorable risk-benefit profile. At a median follow up of 13 months, the median DOR had not yet been reached; 79.3% of patients remained progression-free at 12 months, consistent with efficacy observed in earlier studies (Byrd, NEJM 2013;369:32-42). The PFS in this previously treated population compares favorably to that of treatment-naïve del 17p CLL patients receiving fludarabine, cyclophosphamide, and rituximab (FCR) (Hallek, Lancet 2010;376:1164-74) or alemtuzumab (Hillmen, J Clin Oncol 2007;10:5616-23) with median PFS of 11 months. The AEs are consistent with those previously reported for ibrutinib (Byrd, NEJM 2014;371:213-23). These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL. Figure 1 Figure 1. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Jones:Pharmacyclics: Consultancy, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siddiqi:Janssen: Speakers Bureau. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Stevens-Brogan:Pharmacyclics: Employment. Li:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Clow:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Chu:Pharmacyclics: Employment, Equity Ownership. Hallek:Janssen, Pharmacyclics: Consultancy, Research Funding. Stilgenbauer:Pharmacyclics, Janssen Cilag: Consultancy, Honoraria, Research Funding.

scholarly journals Ritumixab in Combination with Adapted-Dose of Ifosfamide and Etoposide As Salvage Treatment in Elderly Refractory/Relapsed Diffuse Large B-Cell Lymphoma Patients Non-Candidate for High Dose Therapy: A Retrospective Study of Lyon Hospital University

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4215-4215
Author(s):  
Guillaume Aussedat ◽  
Delphine Maucort-Boulch ◽  
Philippe Rey ◽  
Violaine Safar ◽  
Lionel Karlin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
High Dose ◽  
First Line ◽  
Advisory Committees ◽  
Previously Treated ◽  
Grade 3

Abstract Introduction: standard treatment for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT) but this strategy is not appropriate for elderly DLBCL patients (pts) related to a high risk of toxicities. Multiple chemotherapy regimens had been developed for heavily pretreated elderly DLBCL patients such as R-bendamustine, R-gemcitabine-oxaliplatin (R-GEMOX) and pixantrone; the median progression free survival (PFS) of these regimens were 2, 4 and 3.5 months, respectively in prospective phase II studies for patients previously treated with R (Sehn 2017, Mounier 2013, Pettengel 2016). Adapted dose of ifosfamide and etoposide was firstly developed as sequential consolidation regimen after high-dose CHOP (ACVBP regimen) in first line therapy of young DLBCL patients (Tilly 2003). This regimen with a safe toxicity profile was then used in combination with R in Lyon University Hospital in elderly R/R DLBCL ineligible to intensive strategy. Methods: we retrospectively reviewed the efficacy and the safety profile of this regimen performed in two Lyon University Hospitals (Centre Hospitalier Lyon Sud and Leon Berard Cancer Center). Between June 2004 and March 2017, 75 pts with R/R DLBCL (63 de novo DLBCL, 12 transformed DLBCL) received R (375 mg/m2) in combination etoposide (300 mg/m2) and ifosfamide (1500 mg/m2) on day 1 (N=72, 96%) and on days 1-2 (N=3, 4%) at 2 (N=46, 61%) or 3-week (N=29, 39%) intervals. All medical records were reviewed for clinical and biological characteristics, modality of treatment and supportive care, toxicities, responses and outcome. Results: the median age was 79 years (range, 64-92) at the beginning of R-ifosfamide/VP16 treatment with 46% of the patients over 80 years. 13% of pts had a CIRS-G grade 3 or 4 >2 categories and 35% had a cumulative CIRS-G score more than 6. The performance status according to EORTC scale was 2-4 in 37% of the pts and 93% had III-IV Ann Arbor stages. Age-adjusted IPI were 0-1 in 20 pts (27%) and 2-3 in 55 pts (73%). All patients were previously treated in first-line therapy by R in combination with chemotherapy (CHOP, N=56, 75%, low-dose CHOP, N=14, 19%, other, N=5, 6%). The patients received a median number of 1 previous line (range, 1-8) and no patient was previously treated by ASCT. The median time between initial diagnosis and R-ifosfamide/VP16 was 20 months (range 4-187). The median time between the last treatment and R-ifosfamide/VP16 was 5 months (range 0-181). A refractory disease to first-line treatment was showed in 14 pts (19%). 31% of the patients had a refractory disease to the last regimen performed before R-ifosfamide/VP16. Patients received a median of 6 cycles (1-12). At the end of treatment, the overall response rate (ORR), defined by the rate of complete response (CR) and partial response (PR) was 37%, with 18% of CR. Evaluations were assessed for 29% of the pts by TEP scanner. For toxicity, among the 387 cycles, 10 patients developed febrile neutropenia (2.6%); 15 (20%) a grade 3-4 neutropenia; 7 (9%) a grade 3-4 thrombocytopenia; 5 patients needed platelet units and 16 patients received packed red blood cell units. No grade 3-4 non-hematological toxicity was observed and no toxic death occurred. With a median follow up of 31.3 months (range, 5.0-202.8), the median progression-free survival (PFS) was 4.3 months with a 1-year PFS rate of 26.0% (95%CI, 17.7-38.3) (Figure 1A). The median overall survival (OS) was 8.2 months with a 1-year OS rate of 40.8% (95%CI, 30.9-54.0) (Figure 1B). The median duration of response was 4 months (range 1-97). The median PFS was adversely affected by response (refractory versus CR/PR) to the last treatment (3.0 months versus 5.5 months, P=0.001) (Figure 1C). Conclusions: in this retrospective study, R-Ifosfamide/VP16 regimen provided effective results in R/R DLBCL transplant-ineligible pts with 37% of ORR and a median of PFS of 4.3 months with a safe toxicity profile. This regimen could also be considered as a platform for combinations with novel targeted agents in these categories of patients. Disclosures Karlin: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sarkozy:ROCHE: Consultancy. Bachy:Gilead Sciences: Honoraria; Takeda: Research Funding; Sandoz: Consultancy; Amgen: Honoraria; Roche: Research Funding; Celgene: Consultancy; Janssen: Honoraria. Salles:Abbvie: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Other: Advisory Board; Acerta: Honoraria; Novartis: Consultancy, Honoraria; Servier: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria; BMS: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria. Ghesquieres:Sanofi: Consultancy; Gilead: Consultancy; Celgene: Consultancy.

scholarly journals Near-Tetraploidy Is Strongly Associated with Development of Richter's Transformation in Chronic Lymphocytic Leukemia Patients Receiving Ibrutinib

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3198-3198
Author(s):  
Cecelia R. Miller ◽  
Amy S. Ruppert ◽  
Nyla A. Heerema ◽  
Kami J. Maddocks ◽  
Jadwiga Labanowska ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Complex Karyotype ◽  
Advisory Committees ◽  
Data Set ◽  
Richter’S Transformation ◽  
Richter's Transformation

Abstract Ibrutinib is a promising targeted therapy for chronic lymphocytic leukemia (CLL). However, a small subset of patients progress on ibrutinib either through progressive CLL or Richter's transformation. Patients responding to ibrutinib and then progressing with Richter's transformation do so most commonly within the first 2 years of treatment and have an extremely poor prognosis. Identifying biomarkers associated with this transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas; however, its incidence in CLL has not been described. We investigated the prevalence of near-tetraploidy in CLL patients prior to starting ibrutinib and identified it as a pre-treatment biomarker for Richter's transformation. We examined near-tetraploidy in a large series of CLL patients enrolled across four ibrutinib clinical trials at the Ohio State University, for which extensive correlative studies and follow up data are available (previously described by Maddocks et al., JAMA Oncol, 2015). We identified this abnormality in 9 of 300 patients (3.0%, 95% CI: 1.4-5.6) in blood or bone marrow samples taken prior to starting therapy. Near-tetraploidy was detected by the presence of four signals with four or more fluorescence in situ hybridization (FISH) probes and confirmed in the metaphase karyotype of each patient in at least one cell. Near-tetraploidy was associated with aggressive disease characteristics including: Rai stage 3/4 (p=0.03), deletion 17p (p=0.03), and complex karyotype (p=0.01), as well as trisomy 12 (p=0.05). With a median follow-up time of 40.5 months, in patients positive with near-tetraploidy, one patient (11%) progressed with CLL on ibrutinib, six patients (67%) progressed with Richter's transformation, and two patients (22%) were still on treatment. Cumulative incidence of Richter's transformation was significantly higher in patients with near-tetraploidy (Figure; p<0.0001). Notably, near-tetraploidy was not associated with progression with CLL alone (p=0.53). In a multivariable model, both near-tetraploidy (HR 8.66, 95% CI 3.83-19.59, p<0.0001) and complex karyotype (HR 4.78, 95% CI 1.42-15.94, p=0.01) were independent risk factors for discontinuing ibrutinib due to Richter's transformation. Our results suggest that near-tetraploidy is a distinct biomarker to assess in patients initiating ibrutinib which would predict a high risk for Richter's transformation. As a biomarker it will be important to confirm this association in a second independent data set as well as interrogate the distinct pathophysiology of this genomic subset of CLL. Figure Figure. Disclosures Lozanski: Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding; Genentech: Research Funding; Beckman Coulter: Research Funding. Jones:Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Andritsos:Hairy Cell Leukemia Foundation: Research Funding. Awan:Novartis Oncology: Consultancy; Pharmacyclics: Consultancy; Innate Pharma: Research Funding. Blum:Pharmacyclics: Research Funding. Woyach:Acerta: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding.

Bortezomib May Be Safely Combined with Y-90 Ibritumomab Tiuxetan In Patients with Relapsed/Refractory Follicular or Transformed Non-Hodgkin Lymphoma: A Phase I Trial of Combined Induction Therapy and Bortezomib Consolidation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1749-1749
Author(s):  
Rupali Roy ◽  
Andrew M Evens ◽  
David P. Patton ◽  
Annette Larsen ◽  
Alfred Rademaker ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Induction Therapy ◽  
Research Funding ◽  
Phase I Trial ◽  
Ibritumomab Tiuxetan ◽  
Advisory Committees ◽  
Non Hodgkin Lymphoma ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 1749 Background: Preclinical studies suggest that bortezomib, through inhibition of NF-kB activation, may act as a radiosensitizer and enhance the effects of radioimmunotherapy. Methods: This phase I trial was designed to determine the maximum tolerated dose (MTD) of weekly bortezomib induction combined with Y-90-ibritumomab tiuxetan in patients 18 years or older with relapsed/refractory follicular or transformed non-Hodgkin lymphoma. In addition, we assessed the tolerability of weekly bortezomib consolidation following induction therapy. Cohorts consisting of three patients each were treated with bortezomib induction at doses of 1.0, 1.3, or 1.6 mg/m2 on days 1, 8, 15, and 22, rituximab 250 mg/m2 on days 8 and 15, and Y-90 ibritumomab tiuxetan 0.4 mCi/kg on day 15. Consolidation, consisting of bortezomib 1.6 mg/m2 weekly on days 1, 8, and 15 of three 28 day cycles, was initiated on day 71 after recovery of the platelet count to 100,000/uL and ANC> 1,000/uL. At least three patients per cohort were followed for 7 weeks or had recovery of blood counts without dose-limiting toxicities (DLTs) before dose escalation was allowed. MTD was defined as the dose previous to that in which two patients had DLTs. To be evaluable, patients were required to have received at least two doses of bortezomib and the Y-90-ibritumomab tiuxetan therapeutic dose. Response was assessed by CT scanning following induction therapy and PET/CT and diagnostic CT scans after completion of consolidation. Results: Nine patients with a median age of 55 (range: 29–71) were treated with bortezomib combined with Y-90-ibritumomab tiuxetan. Eight patients had FL and one had evidence of a transformation to diffuse, large B-cell lymphoma. All had a performance status of 0 or 1, and all had been previously treated with rituximab either as a single agent or in combination with chemotherapy. All but one had received prior chemotherapy [R-CHOP (n=7), chlorambucil (n=1), or R-CVP (n=2)], and three had received radiotherapy. Only one had bone marrow involvement. The median number of prior therapies was one (range: 1–3). Grade 3 or 4 toxicities were observed in all but one of the patients and as expected, all but one of these toxicities were hematologic (leukopenia, lymphopenia, neutropenia, and/or thrombocytopenia). One patient had grade 3 cardiotoxicity characterized by palpitations and shortness of breath on day 15 of her first consolidation, with PVC's noted on subsequent EKG. Though uncommon, cardiotoxicity has been reported in association with bortezomib in the form of systolic heart failure, arrhythmias, and angina. It should be noted that this patient was previously treated with an anthracycline as have the majority of patients reported to have experienced cardiotoxicity in association with bortezomib. A DLT of grade 4 thrombocytopenia lasting more than ten days was observed in two of three patients treated with bortezomib at 1.6 mg/m2. One of these two patients was the only one to receive .3 mCi/kg rather than .4 mCi/kg of the radioisotope because of thrombocytopenia on the day of treatment. Thus, the MTD of bortezomib was 1.3 mg/m2. All patients are alive, and the median followup for those patients who have not progressed is 6.5 months (range: 3 – 15 mo.). All but one patient responded to therapy (4 CR/CRu, 4PR, 1 SD). The four complete responders remain in remission at 3.0, 5.0, 5.0 and 15.0 months. All of the partial responders have progressed (3.5, 3.5, 11.5, and 17.5 months), as has the patient with stable disease (5.0 months). Conclusions: The MTD for weekly bortezomib combined with Y-90 ibritumomab tiuxetan induction therapy is 1.3 mg/m2. Consolidation with bortezomib at 1.6 mg/m2 was well tolerated in this group of relapsed/refractory follicular and transformed non-Hodgkin lymphoma patients. Nearly all patients responded. A phase II trial at the MTD is underway to better define the toxicity and effectiveness of this regimen in patients with relapsed/refractory FL. Disclosures: Evens: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrm: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ziopharm: Membership on an entity's Board of Directors or advisory committees; Lilly: Research Funding; Ortho- Biotec: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Gordon:Cure Tech, Ltd: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, Inc: Research Funding; Genentech: Speakers Bureau; Millenium: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees. Winter:Millenium: Consultancy, Research Funding; Pfizer/Wyeth: Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Spectrum: Honoraria.

scholarly journals Updated Preliminary Results of a Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib Alone or in Combination with Idelalisib or Entospletinib in Patients with Previously Treated Chronic Lymphocytic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3135-3135 ◽  
Author(s):  
Alexey V Danilov ◽  
Charles Herbaux ◽  
Martin J.S. Dyer ◽  
Peter Hillmen ◽  
Simon Rule ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Duration Of Treatment ◽  
Advisory Committees ◽  
Overall Response ◽  
Previously Treated ◽  
Grade 3 ◽  
Dose Levels ◽  
Common Teaes

Abstract Introduction: Tirabrutinib (TIRA; GS/ONO-4059) is a Bruton's tyrosine kinase (BTK) inhibitor. Idelalisib (IDELA), a first-in-class phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor, is approved for the treatment of CLL. Entospletinib (ENTO) is a selective inhibitor of spleen tyrosine kinase (SYK). All three have single agent activity in CLL and updated results from TIRA monotherapy and the combinations of TIRA+IDELA and TIRA+ENTO from this ongoing phase 1b study (NCT02457598) are reported here. Methods: Patients with previously treated CLL and no prior exposure to targeted inhibitors were eligible for enrollment. For the TIRA+IDELA combination, patients were treated with dose levels in a 3+3 approach combining either idelalisib 50 mg BID or 100mg QD and TIRA ranging from 20mg to 80mg QD. For the TIRA+ENTO combination, patients were treated with entospletinib at either 200mg or 400mg QD and tirabrutinib ranging from 40mg to 80mg QD in dose levels with a 3+3 approach. TIRA monotherapy was with 80mg QD. Results: As of March 5, 2018, total of 50 CLL patients have been enrolled, 26 patients in the TIRA monotherapy group, 14 in the TIRA + IDELA group, and 10 patients in the TIRA + ENTO group. The median number of prior therapies is 1 (range 1-6). No MTD was identified for either combination at the doses evaluated and activity was high at all dose levels. For the 25 patients who have received at least one dose of TIRA monotherapy, the median duration of treatment is 28 weeks (range 0.3-54.1), and 22 patients are still on treatment. All 12 patients evaluable for response per IWCLL2008 criteria achieved a partial response on study with best overall response shown in table 1. Treatment-emergent adverse events (TEAE) were reported in 92% patients, with 28% having a ≥grade 3 TEAE. The most common TEAEs (any grade/≥grade 3) were diarrhoea (24%/0), constipation (20%/0), neutropenia (16%/12%), contusion (12%/0), asthenia (12%/0), ecchymosis (12%/0), and nausea (12%/0). AEs led to treatment interruption in 3 patients and discontinuation in 2 patients and there were no deaths in this group on study. For the 14 patients in the TIRA+IDELA group, the median duration of treatment is 100 weeks (range 36-134.9), and 11 patients are still on treatment. 12/13 evaluable patients achieved a response on study with best overall response shown in table 1. TEAEs were reported in all patients with 64% of patients having a ≥grade 3 TEAE. The most common TEAEs (any grade/≥grade 3) were diarrhoea (43%/7%), neutropenia (36%/36%), bronchitis (36%/0), rash (36%/0), back pain (29%/0), dyspepsia (29%/0), nausea (29%/0), cough (29%/0), constipation (29%/0), arthralgia (29%/0), pruritus (29%/0). AEs led to interruption or discontinuation of all study treatment in 5 and 1 patients, respectively. One patient died due to sudden respiratory difficulty not believed to be related to study treatment. For the 10 patients in the TIRA+ENTO group, the median duration of treatment is 82 weeks (range 57.1-93.9) and all patients are still on treatment. All patients achieved a partial response on study with best overall response shown in table 1. TEAEs were reported in all patients with 60% having a ≥grade 3 TEAE. The most common TEAEs (any grade/≥grade 3) were contusion (50%/0), fatigue (50%/0), diarrhoea (40%/0), upper respiratory tract infection (40%/10%), rhinitis (30%/0), alanine aminotransferase increased (30%/10%), cough (30%/0), and dyspepsia (30%/0%). AEs led to interruption or discontinuation of all study treatment in 4 and 0 patients respectively. Conclusion: Tirabrutinib in combination with idelalisib or entospletinib at the doses evaluated was tolerable with no significant potentiation of already characterized side effects from the single agents such as bleeding, diarrhea or cytopenias. Both combinations showed a high level of activity in CLL and are currently being evaluated in Phase 2 studies. Disclosures Danilov: Bayer Oncology: Consultancy, Research Funding; Aptose Biosciences: Research Funding; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Astra Zeneca: Consultancy; Genentech: Consultancy, Research Funding; Takeda Oncology: Research Funding; Gilead Sciences: Consultancy, Research Funding. Herbaux:Gilead Sciences, Inc.: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Dyer:Gilead Sciences, Inc.: Honoraria, Research Funding. Hillmen:Celgene: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Pharmacyclics: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rule:Kite: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Huang:Gilead Sciences, Inc.: Employment. Mitra:Gilead Sciences, Inc.: Employment. Karlin:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Fegan:Napp: Honoraria; Abbvie: Honoraria; Gilead Sciences, Inc.: Honoraria; Roche: Honoraria; Janssen: Honoraria.

scholarly journals Dynamo: A Phase 2 Study Demonstrating the Clinical Activity of Duvelisib in Patients with Relapsed Refractory Indolent Non-Hodgkin Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1218-1218 ◽  
Author(s):  
Ian W. Flinn ◽  
Carole B. Miller ◽  
Kirit M Ardeshna ◽  
Scott Tetreault ◽  
Sarit E. Assouline ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Clinical Activity ◽  
Phase 2 ◽  
Advisory Committees ◽  
Non Hodgkin Lymphoma ◽  
Phase 2 Study ◽  
Previously Treated ◽  
Grade 3

Abstract DYNAMO: A Phase 2 Study Demonstrating the Clinical Activity of Duvelisib in Patients with Relapsed Refractory Indolent Non-Hodgkin Lymphoma Introduction: Indolent non-Hodgkin lymphoma (iNHL) is characterized by a relapsing clinical course with shorter responses to therapy after each relapse. Duvelisib is an oral dual inhibitor of PI3K-d,γ in development for the treatment of hematologic malignancies, including previously-treated iNHL. Data from a Phase 1 study of duvelisib indicate the potential for duvelisib to be an effective treatment for previously-treated iNHL, with an acceptable safety profile. DYNAMO is a Phase 2 study designed to evaluate the safety and efficacy of duvelisib in a previously-treated, refractory iNHL population. Methods: DYNAMO is an ongoing, open-label, single-arm, safety and efficacy study that includes adult patients (pts) diagnosed with follicular lymphoma (FL), small lymphocytic lymphoma (SLL), or marginal zone lymphoma (MZL) whose disease is refractory to rituximab and to a chemotherapy regimen (containing an alkylator or purine analogue) or radioimmunotherapy. Pts received duvelisib 25 mg twice daily (BID) in 28-day treatment cycles until disease progression or unacceptable tolerability. The primary endpoint of the study is overall response rate (ORR) as assessed by an independent review committee, according to the revised IWG criteria. Secondary endpoints include duration of response (DoR), progression-free survival (PFS), overall survival (OS), time to response (TTR), adverse events (AEs), and changes in safety laboratory values. Pneumocystis jirovecii pneumonia (PJP) prophylaxis was mandated for all patients. Here we present the results from the final analysis, with a data cut-off of 07 April 2016. Results: 129 iNHL pts received at least 1 dose of duvelisib, including 83 pts with FL, 28 with SLL, and 18 with MZL. The median duration of exposure was 6 months (range 0.4 - 23.8). The median age was 65 years, and 68% were male. The median time from initial diagnosis to the first dose of duvelisib was 4.5 years, and from last anticancer therapy was 3.5 months. Pts had received a median of 3 prior regimens (range 1 - 18), with 40% having received ≥ 4 regimens. 77% of patients had disease refractory to ≥ 2 regimens and 96% were refractory to their most recent regimen. 64% of patients previously received bendamustine, 80% of whom were refractory. The ORR was 46% (all PRs, 95% CI 37 - 55), with a median DoR of 9.9 months (95% CI 4.5 - 10.3). The median TTR was 1.9 months (range 1.4 - 11.7). With a median follow-up of 11.5 months, the median PFS was 8.4 months (95% CI 5.8 - 11.3) with a 60% estimated probability of being alive and event-free at 6 months, and the median OS was 18.4 months (95% CI 15.7 - NE) with an estimated probability of survival of 74% at 12 months. 83% of pts experienced a reduction in tumor burden following treatment with duvelisib. The response rate across the disease subtypes was: 41% FL, 68% SLL, and 33% MZL (see Table). AEs were predominantly Grade 1-2. The most common ≥ Grade 3 AEs were transient cytopenias (neutropenia [28%], anemia [12%], and thrombocytopenia [13%]), and diarrhea (15%). 63% of pts had dose modifications (interruptions or reductions) due to AEs and 17% of pts discontinued due to an AE. AEs leading to duvelisib discontinuation in ≥ 2 pts included pneumonitis (n = 3), pneumonia (n = 2), and rash generalized (n = 2). Six pts had an AE with an outcome of death, four assessed as related to duvelisib (suspected viral infection, septic shock, and 2 severe cutaneous reactions [TEN and DRESS]). The incidence of ≥ Grade 3 infection was 20%. The incidence of pneumocystis was 0.8% (1 patient) and the incidence of CMV was 2.3% (3 subjects), none of which were fatal. Conclusions: In the Phase 2 DYNAMO study, duvelisib achieved meaningful clinical activity in a heavily pretreated and highly refractory iNHL population. The safety profile was acceptable, with the majority of AEs low grade (≤ Grade 2) and the majority of pts able to remain on duvelisib. These results suggest duvelisib has a favorable benefit-risk profile in this patient population and further development is ongoing. Table 1 Table 1. Disclosures Flinn: Janssen: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Miller:Infinity: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Ardeshna:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses, Research Funding. Assouline:BMS: Speakers Bureau; Pfizer: Speakers Bureau. Zinzani:Infinity: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: 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; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding. Pettitt:Roche: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Infinity: Research Funding. Tournilhac:Roche: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Amgen: Research Funding; Celgene: Honoraria, Research Funding; GSK: Research Funding; Novartis: Research Funding; Mundipharma: Honoraria, Research Funding. Crump:Roche: Consultancy; Seattle Genetics: Consultancy; Janssen-Ortho: Consultancy; Celgene: Consultancy. Santabarbara:Infinity: Consultancy. Shi:Infinity: Employment. Steelman:Infinity: Employment. Wagner-Johnston:Pharmacyclics: Speakers Bureau.

Efficacy and Safety Of Fedratinib (SAR302503/TG101348) In Patients With Intermediate- Or High-Risk Myelofibrosis (MF), Post-Polycythemia Vera (PV) MF, Or Post-Essential Thrombocythemia (ET) MF Previously Treated With Ruxolitinib: Interim Results From a Phase II Study (JAKARTA-2)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 661-661 ◽  
Author(s):  
Claire N Harrison ◽  
Nicolaas PM Schaap ◽  
Sonja Zweegman ◽  
Eric Jourdan ◽  
Jean-Jacques Kiladjian ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Interim Analysis ◽  
Research Funding ◽  
Symptom Burden ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Once Daily ◽  
Previously Treated ◽  
Grade 3

Abstract Background The JAK1/JAK2 inhibitor ruxolitinib (RUX) is approved for treatment of myelofibrosis (MF). However, some patients do not respond to RUX, while others lose responsiveness or develop intolerance to RUX over time. Preclinical data also suggest that certain JAK2 mutations (eg the gatekeeper mutation M929I) may confer resistance to RUX (Leukemia 2012;26:708). Options for these RUX resistant/intolerant patients, particularly with regard to further JAK inhibitor therapy, are unclear. Fedratinib (SAR302503) is a JAK2-selective inhibitor which has demonstrated clinically meaningful reductions in splenomegaly and symptom burden in patients with MF, with an acceptable and consistent safety profile (J Clin Oncol 2011;29:789. Haematologica 2013;98:S1113). Fedratinib sensitivity in vitro is unaffected by the M929I mutation. This pre-specified interim analysis of the JAKARTA-2 study (NCT01523171) investigated the efficacy and safety of fedratinib in MF patients previously treated with RUX. Methods JAKARTA-2 is a Phase II, multicenter, open-label, single-arm study of patients who previously received RUX for MF. Patients ≥18 yrs with splenomegaly and platelet count ≥50 ×109/L received fedratinib 400 mg orally, once daily for consecutive 4-wk cycles (permitted dose adjustment to 200–600 mg daily). Eligible patients had received ≥14 d RUX treatment, and had discontinued RUX for ≥14 d prior to starting fedratinib. Although there is no consensus definition of RUX resistance/intolerance, for the purpose of this study patients were classed (investigator assessment) as resistant (lack or loss of response) or intolerant to RUX. Primary endpoint for the interim analysis: spleen response rate (RR) (≥35% reduction in spleen volume from baseline at Wk 12 [MRI/CT blinded central review]) in the per-protocol (PP) population. Secondary endpoints: symptom RR (≥50% reduction in total symptom score [TSS: modified Myelofibrosis Symptom Assessment Form] from baseline to Wk 12) and safety. Results At the cut-off date for this interim analysis, 27 patients had received fedratinib treatment (median RUX exposure 10.7 months [range 1.9–34.4]): median age 69 yrs; 56% male; 67% primary MF; 63% high-risk MF; 67% JAK2V617F positive; 41% platelet count <100 × 109/L; baseline median spleen volume 3190 mL [1072–7815]; baseline median TSS 19.6 [4.9–46.0]. Eighteen patients were considered resistant by the treating physician (8 lack of response, 3 disease progression, 7 loss of response; median RUX exposure 11.1 months [range 1.9–34.4]) and 9 intolerant (6 hematologic, 3 non-hematologic toxicity; median RUX exposure 9.2 months [2.9–33.2]) to RUX. Median fedratinib exposure to cut-off date: 4 cycles (range 1–10); 19 patients remain on treatment. Spleen RRs were 40% (8/20 PP patients) and 43% (3/7) in patients with baseline platelet count <100 ×109/L. Overall, 19% (5/26 evaluable patients) had a symptom response by Wk 12 (Table). The majority of patients had a reduction in TSS at Wk 12 (Figure). The most common non-hematologic treatment-emergent adverse events (AEs) were gastrointestinal (nausea 67%; diarrhea 56%; vomiting 48%). Grade 3/4 diarrhea occurred in 2 patients; no Grade 3/4 vomiting or nausea. Anemia was the most common hematologic AE (all grades, 93%; Grade 3, 41%; Grade 4, 0%). Thrombocytopenia (all grades) occurred in 19 (70%) patients; Grade 3 in 6 patients and Grade 4 in 2 patients. One patient had Grade 3 AST elevations and 1 patient had Grade 3 hyperbilirubinemia. Seven patients (26%) discontinued treatment due to AEs. There were 2 deaths on study, both due to disease progression. Conclusions Interim results from the JAKARTA-2 study indicate that once-daily fedratinib provides clinical benefit, through reduced splenomegaly and symptom burden, in MF patients previously treated with RUX. The safety profile was acceptable and manageable, with safety results to date consistent with those reported in previous trials of fedratinib. Sponsored by Sanofi. Disclosures: Harrison: Novartis: Research Funding; Novartis, Sanofi, YM Bioscience, Celgene, SBio, Gilead: Honoraria; Novartis, Sanofi, Shire: Speakers Bureau; Novartis, Sanofi, YM Bioscience, SBio, Gilead: Membership on an entity’s Board of Directors or advisory committees. Jourdan:Sanofi: Honoraria. Kiladjian:Novartis, Celgene, AOP Orphan: Research Funding; Novartis, Sanofi, AOP Orphan: Honoraria; Novartis, Sanofi, AOP Orphan: Membership on an entity’s Board of Directors or advisory committees. Cervantes:Novartis: Speakers Bureau; Novartis and Sanofi: Membership on an entity’s Board of Directors or advisory committees. Niederwieser:Novartis Pharma: Consultancy. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Passamonti:Novartis, Celgene, Incyte, Sanofi, Roche: Honoraria. Reiter:Sanofi: Honoraria. Heidel:Novartis Inc.: Honoraria; Novartis Inc.: Research Funding; Novartis Inc.: Membership on an entity’s Board of Directors or advisory committees. Silver:Sanofi: Consultancy; Sanofi: Research Funding; Sanofi: Honoraria. Winton:Sanofi: Research Funding. Gupta:Incyte, Novartis: Consultancy; Incyte, Novartis: Research Funding; Novartis: Honoraria. Gisslinger:AOP Orphan Pharmaceuticals, Novartis, Sanofi, Shire, Celgene, Janssen: Membership on an entity’s Board of Directors or advisory committees; AOP Orphan Pharmaceuticals, Novartis, Sanofi, Shire, Celgene, Janssen: Honoraria. Vannucchi:Novartis: Membership on an entity’s Board of Directors or advisory committees. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Zhang:Sanofi: Employment. Shi:Sanofi: Employment. Mesa:Incyte, Genentech, Lilly, MS Pharma, Gilead: Research Funding.

scholarly journals Loss of TOSO Promotes Richter's Transformation of TCL1A Driven CLL

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 354-354
Author(s):  
Alexandra da Palma Guerreiro ◽  
Cornelia Dorweiler ◽  
Laurent Kintzelé ◽  
Dunja Baatout ◽  
Malte Huelsemann ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Overall Survival ◽  
Board Of Directors ◽  
Germinal Center ◽  
Research Funding ◽  
Conditional Knockout ◽  
Advisory Committees ◽  
Richter’S Transformation ◽  
Richter's Transformation

Abstract Background: The immunoglobulin-like protein TOSO, which has been found to serve as Fc receptor for IgM (FcµR), was shown by us and others to be overexpressed on CLL cells and only weakly expressed on more aggressive B-NHL. However the functional role of TOSO on lymphomagenesis has not been explored so far. Methods: To determine the role of TOSO on lymphoma development, we took advantage of the Eµ-TCL1 transgenic mice, which usually end up with an aggressive (IgVH unmutated) CLL-like phenotype. We generated a novel B cell-specific conditional knockout (KO) mouse model in which EµTCL1 mice (TC or control in the following) were crossbred with TOSO-floxed mice, expressing Cre recombinase under the control of the CD19 promoter (EµTCL1;Tosofl/fl;Cd19cre/wtor TCT in the following). TCT mice were further compared with p53 conditional knockout (EµTCL1;Tp53fl/fl;Cd19cre/wt or TCP). Results: In this study, we compared kinetics, overall survival and phenotype of lymphoma/CLL in TC, TCT and TCP mice. Interestingly, TCTmice developed a very aggressive phenotype and resulted in significantly shorter overall survival compared to TC mice (TCT 274 days vs. TC 346 days; p<0.0001). As expected, mice lacking p53 (TCP) died even more rapidly than TCT mice (median survival: TCP 233 days). Initially, all three genotypes (TC, TCT, TCP) developed a CLL phenotype, exhibiting a CD19 and CD5 positive malignant clone. In the TCT mice, shorter overall survival is accompanied by a stronger increase of blood leukocytes. Flow cytometry analysis confirmed a strong increase of leukemic CD19/CD5-positive B cells in the blood of TCT mice. With only 20 weeks of age, leukemic cells already made up 37.5 % (SD ± 15.47; n=14) of lymphocytes (TC: 14.3 % SD ± 9.81; n=31). At the age of 36 weeks, TCT mice showed even a 3.6-fold elevated malignant cell count compared to control mice (n=35 TC, n=14 TCT; p=0.006). All TCT mice developed a splenomegaly, with spleen weight (p=0.01) and size (p=0.018) significantly increased in 36 week old TCT mice (n=7) compared to TC mice (n=7) and comparable to those from TCP mice. Interestingly, between week 28 and 36, we could observe that most of the TCT mice start losing CD19+ cells in the blood in contrast to TC and TCP mice. Immunohistochemistry revealed the expansion of malignant cells with pleomorphic nuclei and abundant cytoplasm in the spleen and bone marrow, as we know it from Richter`s transformation. To understand the rapid development of leukemia in TCT mice, we first determined the role of the BCR in this model. Interestingly, flow cytometry revealed a higher surface IgM expression (MFI: TCT 9,27; TC 2,05). In addition, in vitro assays revealed a significantly higher resistance of TCT cells towards PI3K inhibition (Idelalisib and Duvelisib) compared to TC cells. To further rule out the role of TOSO under "germinal-center conditions", we stimulated primary human CLL cells with CD40L expressing feeder cells and IL-4. Interestingly, both stimuli (either alone or in combination) resulted in almost complete loss of TOSO on CLL cells. Moreover, we uncovered, that the TOSO promoter is counteractively regulated by NF-κB and BCL6. Furthermore, our data illustrate that DNA hypomethylation of the TOSO promoter is a discriminating characteristic in CLL patients compared to healthy donors, thus explaining the significantly enhanced expression levels. Thus, both, epigenetic regulation and altered NF-κB/ BCL6 expression are critical pathogenetic steps in the development of CLL and aggressive B-NHL by regulating TOSO expression. Conclusion: The transformation of CLL into more aggressive malignancies is still not fully understood. Our data reveal that the loss of TOSO might play a major role in Richter's transformation by upregulation of the BCR and by mimicking the germinal-center phenotype. Disclosures Fingerle-Rowson: Roche: Employment. Wendtner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hallek:GSK: Research Funding; Mundipharma: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Gilead: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria.

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