scholarly journals A Phase 1 Study of Nivolumab in Combination with Ipilimumab for Relapsed or Refractory Hematologic Malignancies (CheckMate 039)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 183-183 ◽  
Author(s):  
Stephen Ansell ◽  
Martin E Gutierrez ◽  
Margaret A. Shipp ◽  
Douglas Gladstone ◽  
Alison Moskowitz ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Clinical Activity ◽  
Food And Beverage

Abstract Introduction: Nivolumab (nivo) is a fully human IgG4 monoclonal antibody (mAb) targeting programmed death receptor-1 (PD-1). Nivo has demonstrated clinical activity and an acceptable safety profile in a phase 1b study (NCT01592370; CheckMate 039) in patients (pts) with relapsed/refractory hematologic malignancies. In pts diagnosed with Hodgkin lymphoma (HL), after a median 86 weeks of follow-up, 7/20 responders maintained a response for >1.5 years (Ansell S et al. Blood 2015;126:583), and after a median follow-up of 67 weeks, clinical activity (investigator-assessed objective response rate) was demonstrated in follicular lymphoma (FL; 40%), diffuse large B-cell lymphoma (DLBCL; 36%), mycosis fungoides (15%), and peripheral T-cell lymphoma (PTCL; 40%) (Lesokhin AM et al. J Clin Oncol 2016;34:2698). CheckMate 039 also included a cohort of pts who had received nivo in combination with ipilimumab (ipi), a fully human mAb targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4). Combination of CTLA-4 and PD-1 blockade has shown superior efficacy compared with nivo or ipi alone in preclinical studies and solid tumor malignancies (Wolchok JD et al. N Engl J Med 2013;369:122; Larkin JM et al. N Engl J Med 2015;373:22; Antonia SJ et al. Lancet Oncol 2016;17:883). The aim of this cohort study was to evaluate the safety and efficacy of combined immune checkpoint blockade (nivo+ipi) in pts with the following hematologic malignancies: HL, B-cell non-Hodgkin lymphoma (B-NHL; FL and DLBCL), T-cell NHL (T-NHL; cutaneous T-cell lymphoma [CTCL] and PTCL]), and multiple myeloma (MM). Methods: Nivo+ipi were given at 3 mg/kg IV and 1 mg/kg IV, respectively, every 3 weeks for 4 doses, followed by nivo monotherapy (3 mg/kg) every 2 weeks for up to 2 years. Pts with any of the above histologies, relapsed or refractory disease after ≥2 prior lines of therapy, and adequate organ function were included in the study. Prior systemic therapy may have included chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT). Prior anti-PD-1 therapy and allogeneic (allo)-HSCT were not permitted. The primary endpoint was safety. Secondary endpoints included investigator-assessed objective response rate (ORR), best overall response, duration of response (DOR), and progression-free survival (PFS). Results: In total, 65 pts were treated with nivo+ipi (31 HL, 15 B-NHL, 11 T-NHL, 7 MM, and 1 with primary mediastinal B-cell lymphoma [PMBL] who was included in the overall safety cohort only). Median (range) number of prior systemic therapies was 4 (2, 10; HL), 3, (1, 16; B-NHL), 4 (1, 11; T-NHL), and 5 (2, 20; MM). Among patients with HL, only 13% (4/31) had prior auto-HSCT. 2 pts with HL and 1 with T-NHL proceeded to allo-HSCT after stopping study therapy. Across all cohorts, median follow-up was 11.4 months. 5 pts (8%) discontinued due to a drug-related adverse event (AE). The most common drug-related AEs of any grade were fatigue (17 pts [26%]), pyrexia (15 [23%]), and diarrhea (12 [18%]). 19 pts (29%) had a drug-related AE of grade ≥3. 31 pts (48%) had a serious AE. 24 pts (37%) died: HL 2 pts, B-NHL 11, T-NHL 6, MM 4, PMBL 1. Among those pts, 22 (34%) were from disease progression (HL 2 pts, B-NHL 10, T-NHL 5, MM 4, PMBL 1); no deaths were due to an AE. Clinical outcome data are presented (Table). Conclusions: These are the first reported data of combination checkpoint blockade therapy in hematologic malignancies. Overall, the combination of nivo+ipi in these heavily pretreated patients demonstrated a safety and efficacy profile similar to that previously reported for nivo monotherapy in HL, NHL, and MM. Additional follow-up may further clarify the role of ipi in this cohort of patients. In this predominantly transplant-naïve group of patients with HL, the efficacy of nivo+ipi was similar to that seen in patients with relapsed/refractory HL treated with nivo alone. Funding: Bristol-Myers Squibb (BMS). Medical writing: S Addison, Caudex, funded by BMS Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Gutierrez:Bayer Health Care Pharmaceuticals, Inc.: Other: Traveling and Lodging- Food and Beverage; E.R. Squibb & Sons, LLC (Bristol Myers Squibb): Consultancy, Other: Travel and Lodging; Incyte Corporation: Consultancy; Pfizer Inc: Consultancy; Merck Sharp & Dohme Corporation: Consultancy, Other: Travel and Lodging; Pharmacyclics LLC, An AbbVie Company: Other: Food and Beverage. Shipp:Cell Signaling: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Bayer: Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board. Moskowitz:Seattle Genetics: Research Funding; Seattle Genetics, Merck: Consultancy. Borello:Bristol-Myers Squibb: Research Funding, Speakers Bureau. Popa-Mckiver:Bristol-Myers Squibb: Employment, Equity Ownership. Farsaci:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment. Armand:Sequenta Inc: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Roche: Research Funding; Merck: Consultancy, Research Funding.

Safety and Clinical Activity of Temsirolimus in Combination with Rituximab and DHAP in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma - Results of the Part I Cohort of the STORM Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2727-2727 ◽  
Author(s):  
Mathias Witzens-Harig ◽  
Ulrich Keller ◽  
Andreas Viardot ◽  
Christian Buske ◽  
Anne Crombé ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Mtor Inhibitor ◽  
Cell Lymphoma ◽  
Central Venous Access ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Open Label ◽  
Salvage Regimen

Abstract Purpose. To evaluate the safety, tolerability and efficacy of the combination of the mTOR inhibitor Temsirolimus and a standard salvage regimen (R-DHAP) in patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL). Patients and Methods. This is a prospective, multicenter, phase II, open-label study. Patients with relapsed or refractory DLBCL with a maximum of two prior treatment lines were eligible. The STORM regimen consisted of Rituximab 375 mg/m² (day 2) and DHAP (Dexamethasone 40mg day 3-6, Cisplatine 100 mg/m² day 3, Cytarabine 2x2 g/m² day 4) with Temsirolimus added on day 1 and 8 of a 21 d cycle, with 2-4 cycles planned. In part I, dose levels for the mTOR inhibitor Temsirolimus from 25, 50, 75 and 100 mg were predefined. Results. Here we report on the preliminary results of part I of this clinical trial. 15 patients were included - 8 patients in the 25 mg cohort and 7 patients in the 50 mg cohort. Median age was 70 (range 49-76) years and median number of prior regimen was 1. Two DLTs (one venous thrombosis in the 25 mg cohort, one esophagus infection in the 50 mg cohort) were observed. The most frequent non-hematologic side effects were nausea (9 pts, 60%), epistaxis (7 pts, 47%), fatigue (6 pts, 40%), increased ALT (6 pts, 40%) and increased creatinine (6 pts, 40%). Frequent grade 3/4 events (n>2) in both cohorts (25mg|50mg) included leukopenia (11 pts, 73% - with a mean duration of 4.4 days | 6.7 days ), thrombocytopenia (11 pts, 73% - with a mean duration of 4.6 days | 11.9 days), lymphopenia (6pts, 40%), anemia (5 pts, 33%), neutropenia (3 pts, 20%), renal failure (3 pts, 20%) and infections (4 pts, 27%, bladder infection, esophagus infection, central venous access infection, soft tissue infection, mucositis). Based on the observed toxicity profile, the independent data safety committee recommended a Temsirolimus dose of 25 mg given on day 1 and 8 for the part II extension cohort of the trial. All but one evaluable patient responded (10/11 pts, 91%), with two CRs and one CRu (27%). Four patients could not be evaluated for response at the time of this report. After a median follow up of 12 (range 5-22) months, no relapse has been documented so far (1 pt lost to follow up). Conclusion. Temsirolimus can be safely added to DHAP and Rituximab with promising activity. Recruitment into part II is ongoing and updated results will be presented. Disclosures Witzens-Harig: Pfizer: Honoraria, Research Funding; Roche: Honoraria. Keller:Roche: Consultancy, Honoraria; Pfizer: Consultancy. Viardot:Roche: Honoraria; CTI: Consultancy; Pfizer: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy. Buske:Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria. Ho:Sanofi: Research Funding. Hess:Janssen, Roche, Celgene, Novartis: Consultancy; Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding.

scholarly journals Long-Term Follow-Up of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy

2020 ◽  
Vol 38 (32) ◽  
pp. 3805-3815
Author(s):  
Kathryn M. Cappell ◽  
Richard M. Sherry ◽  
James C. Yang ◽  
Stephanie L. Goff ◽  
Danielle A. Vanasse ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T

PURPOSE Anti-CD19 chimeric antigen receptors (CARs) are artificial fusion proteins that cause CD19-specific T-cell activation. Durability of remissions and incidence of long-term adverse events are critical factors determining the utility of anti-CD19 CAR T-cell therapy, but long-term follow-up of patients treated with anti-CD19 CAR T cells is limited. This work provides the longest follow-up of patients in remission after anti-CD19 CAR T-cell therapy. METHODS Between 2009 and 2015, we administered 46 CAR T-cell treatments to 43 patients (ClinicalTrials.gov identifier: NCT00924326 ). Patients had relapsed B-cell malignancies of the following types: diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma (DLBCL/PMBCL; n = 28), low-grade B-cell lymphoma (n = 8), or chronic lymphocytic leukemia (CLL; n = 7). This report focuses on long-term outcomes of these patients. The CAR used was FMC63-28Z; axicabtagene ciloleucel uses the same CAR. Cyclophosphamide plus fludarabine conditioning chemotherapy was administered before CAR T cells. RESULTS The percentages of CAR T-cell treatments resulting in a > 3-year duration of response (DOR) were 51% (95% CI, 35% to 67%) for all evaluable treatments, 48% (95% CI, 28% to 69%) for DLBCL/PMBCL, 63% (95% CI, 25% to 92%) for low-grade lymphoma, and 50% (95% CI, 16% to 84%) for CLL. The median event-free survival of all 45 evaluable treatments was 55 months. Long-term adverse effects were rare, except for B-cell depletion and hypogammaglobulinemia. Median peak blood CAR-positive cell levels were higher among patients with a DOR of > 3 years (98/µL; range, 9-1,217/µL) than among patients with a DOR of < 3 years (18/µL; range, 0-308/μL, P = .0051). CONCLUSION Complete remissions of a variety of B-cell malignancies lasting ≥ 3 years occurred after 51% of evaluable anti-CD19 CAR T-cell treatments. Remissions of up to 9 years are ongoing. Late adverse events were rare.

scholarly journals Impact of Interim FDG-PET (iPET) in the Outcomes of Patients with Aggressive B-Cell Lymphomas Receiving DA-EPOCH-R

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2898-2898
Author(s):  
Vania Phuoc ◽  
Leidy Isenalumhe ◽  
Hayder Saeed ◽  
Celeste Bello ◽  
Bijal Shah ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Fdg Pet ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
End Of Treatment

Introduction: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) remains the standard of care for baseline and end of treatment scans for aggressive non-Hodgkin lymphomas (NHLs). However, the role of interim FDG-PET remains not as well defined across aggressive NHLs, especially in the era of high-intensity chemoimmunotherapy. Interim FDG-PET (iPET) can serve as an early prognostic tool, and prior studies evaluating the utility of iPET-guided treatment strategies primarily focused on diffuse large B-cell lymphomas (DLBCL) and frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Classification criteria systems assessing response also differ between studies with no clear consensus between use of Deauville criteria (DC), International Harmonization Project (IHP), and the ΔSUVmax method. Methods: This study evaluates our institutional experience with iPET during treatment with DA-EPOCH ± R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with or without Rituximab) in aggressive NHLs. We retrospectively evaluated 70 patients at Moffitt Cancer Center who started on DA-EPOCH ± R between 1/1/2014 to 12/31/2018 for aggressive NHLs. Response on interim and end-of-treatment (EOT) scans were graded per DC, IHP, and ΔSUVmax methods, and progression free survival (PFS) probability estimates were calculated with chi-square testing and Kaplan Meier method. PFS outcomes were compared between interim negative and positive scans based on each scoring method. Outcomes were also compared between groups based on interim versus EOT positive or negative scans. Results: We identified 70 patients with aggressive NHLs who received DA-EPOCH ± R at our institute. The most common diagnoses were DLBCL (61%) followed by Burkitt's lymphoma (10%), primary mediastinal B-cell lymphoma (9%), plasmablastic lymphoma (7%), gray zone lymphoma (6%), primary cutaneous large B-cell lymphoma (1%), primary effusion lymphoma (1%), and other high-grade NHL not otherwise specified (3%). Of the 43 patients with DLBCL, 21/43 (49%) had double hit lymphoma (DHL) while 7/43 (16%) had triple hit lymphoma (THL), and 3/43 (7%) had MYC-rearranged DLBCL while 2/43 (5%) had double expressor DLBCL. Thirty nine out of 70 (56%) were female, and median age at diagnosis was 58.39 years (range 22.99 - 86.86 years). Most patients had stage IV disease (49/70, 70%), and 43/70 (61%) had more than one extranodal site while 45/70 (64%) had IPI score ≥ 3. Forty-six out of 70 (66%) received central nervous system prophylaxis, most with intrathecal chemotherapy (44/70, 63%). Fifty-five out of 70 (79%) had iPET available while 6/70 (9%) had interim computerized tomography (CT) scans. Fifty-six out of 70 (80%) had EOT PET, and 4/70 (6%) had EOT CT scans. Sustained complete remission occurred in 46/70 (66%) after frontline DA-EPOCH ± R (CR1), and 12/70 (17%) were primary refractory while 5/70 (7%) had relapse after CR1. Four of 70 (6%) died before cycle 3, and 3/70 (4%) did not have long-term follow-up due to transition of care elsewhere. Median follow-up was 15.29 months (range 0.85 - 60.09 months). There was significantly better PFS observed if iPET showed DC 1-3 compared to DC 4-5 (Χ2=5.707, p=0.0169), and PFS was better if iPET was negative by IHP criteria (Χ2=4.254, p=0.0392) or ΔSUVmax method (Χ2=6.411, p=0.0113). Comparing iPET to EOT PET, there was significantly better PFS if iPET was negative with EOT PET negative (iPET-/EOT-) compared to iPET positive with EOT negative (iPET+/EOT-), and iPET+/EOT+ and iPET-/EOT+ had worse PFS after iPET-/EOT- and iPET+/EOT- respectively. This pattern in iPET/EOT PFS probability remained consistent when comparing DC (Χ2=30.041, p<0.0001), IHP (Χ2=49.078, p<0.0001), and ΔSUVmax method (Χ2=9.126, p=0.0104). These findings fit clinical expectations with positive EOT scans indicating primary refractory disease. There was no significant difference in PFS when comparing DLBCL versus non-DLBCL (Χ2=3.461, p=0.0628) or DHL/THL versus non-DHL/THL diagnoses (Χ2=2.850, p=0.0914). Conclusion: Our findings indicate a prognostic role of iPET during treatment with DA-EPOCH ± R for aggressive NHLs. Significant differences in PFS were seen when graded by DC, IHP, and ΔSUVmax methods used in prior studies and when comparing interim versus EOT response. Larger studies are needed to confirm these findings. Disclosures Bello: Celgene: Speakers Bureau. Shah:Novartis: Honoraria; AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Sokol:EUSA: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Systematic Literature Review of the Clinical Evidence in Relapsed/Refractory (R/R) Large B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5821-5821
Author(s):  
David G. Maloney ◽  
Fei Fei Liu ◽  
Lisette Nientker ◽  
Cathelijne Alleman ◽  
Brian Hutton ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

Introduction: Large B-cell lymphoma (LBCL) is the most common subtype of non-Hodgkin lymphoma. Frontline treatment is curative in ~60% of patients (pts); however, ~30% of pts relapse and ~10% are refractory to frontline treatment. Treatment options for pts with relapsed/refractory (R/R) disease, especially in the third-line or greater (3L+) setting, have been primarily salvage chemotherapies (CTs). Recently, 2 CAR T cell products, axicabtagene ciloleucel (Yescarta®) and tisagenlecleucel (Kymriah®), and the antibody-drug conjugate, polatuzumab vedotin (Polivy®), were approved in the 3L setting. A systematic literature review (SLR) of R/R LBCL was conducted to identify relevant evidence on clinical outcomes in LBCL pts, including these new therapies, within the second-line and greater (2L+) or 3L+ setting, and to define the unmet medical need. Methods: This SLR was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and European Union Health Technology Assessment requirements. The review identified randomized and nonrandomized/observational studies within R/R LBCL, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma grade 3B (FL3B), primary mediastinal large B-cell lymphoma (PMBCL), DLBCL transformed from indolent lymphomas, and R/R DLBCL with secondary central nervous system (SCNS) involvement. Sources were EMBASE, MEDLINE, The Cochrane Library, and clinical conferences (ASCO, ESMO, EHA, ASH, ICML, AACR, and EORTC) from Jan 2000 to Apr 2019. Results : Following screening of 8683 database records and additional sources, 103 publications covering 78 unique studies were identified. Studies identified were characterized by line of treatment and R/R LBCL subtype (Figure). OS, PFS, DOR, OR, and safety observed from the identified studies were described. Disease subtypes, pt eligibility criteria, and length of follow-up varied notably across studies. In the 3L+ population, 11 salvage CT and 2 CAR T cell therapy studies reported survival outcomes. With salvage CT, the reported ORR across studies ranged from 0% to 54%, while CR ranged from 5.6%-31%. Median OS (mOS) ranged between 3-9 months, with one outlying study reporting mOS at 20 months. Median PFS (mPFS) reported within the salvage CT studies ranged from 2-6 months. Among CAR T cell therapies, pts treated with axicabtagene ciloleucel (n=101) reported a CR rate of 58% and median DOR (mDOR) was 11.1 months after a median follow-up of 27.1 months. mPFS was 5.9 months and mOS was not reached. At a median follow-up of 19.3 months, pts treated with tisagenlecleucel (n=115) had a CR of 40% but the mDOR was not reached. mOS was 11.1 months for all infused patients. In the 2L+ transplant-eligible population (36 studies), pts who received high-dose CT + HSCT achieved mOS between 9 months to 5 years. In the transplant noneligible population, 16 studies reported mOS between 3-20 months. Studies involving mixed transplant-eligible and noneligible populations (30 studies) reported mOS of 1-17 months. A few studies with limited sample sizes were found to report outcomes in LBCL subtypes (eg, PMBCL, SCNS lymphoma, DLBCL transformed from non-FL indolent lymphoma, FL3B). In the 3L+ setting, 1 study reported that mOS was not reached after a median of 6.6 months. In the 2L+ setting, 4 studies reported mPFS and mOS outcomes ranging between 2-9 months and 10-16 months, respectively. Among studies assessing safety of salvage CTs in R/R LBCL, neutropenia, leukocytopenia, thrombocytopenia, and infections were the most commonly reported adverse events (AEs), with neutropenia being the most reported. Among the 3 studies reporting safety outcomes of CAR T cell therapy, data suggest that hematologic AEs (possibly related to lymphodepleting CT), cytokine release syndrome, and neurotoxicity are the most reported. Conclusions : Despite the availability of new therapies for 2L+ and 3L + LBCL, examination of the current evidence has shown that there exists a high unmet need for additional therapeutic options that provide favorable benefit/risk and durable response for these patients. Furthermore, limited data are available for the rarer subtypes of LBCL. Both findings represent important treatment gaps for R/R LBCL that must be addressed in future research geared toward improvement of the current treatment landscape. Disclosures Maloney: Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria; A2 Biotherapeutics: Honoraria, Other: Stock options . Liu:Celgene Corporation: Employment. Nientker:Celgene Corporation: Consultancy; Pharmerit Cöoperatief U.A.: Employment. Alleman:Pharmerit Cöoperatief U.A.: Employment; Celgene Corporation: Consultancy. Garcia:Celgene: Employment, Equity Ownership.

Other Tumours in Primary Cutaneous Lymphomas.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4417-4417
Author(s):  
Serena Rupoli ◽  
G. Goteri ◽  
P. Picardi ◽  
S. Pulini ◽  
A. Tassetti ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Skin Carcinoma ◽  
B Cell Lymphomas ◽  
T Cell Lymphomas ◽  
Cutaneous Lymphomas ◽  
Other Neoplasms

Abstract Patients with primary cutaneous lymphomas (PCLs) are treated with multiple therapeutic regimens, which may increase the risk of subsequent solid and haematological neoplasms. The aim of our study was to assess the incidence of other malignancies in our series of PCLs. From March 1994 to January 2007, 272 patients with PCLs (179 M, 93 F, median age 65 yr, range 14–88) were referred to our center for staging, treatment and follow-up. The clinical charts were reviewed to detect the incidence of malignancies occurred before or after the diagnosis of PCL or concomitantly. The series was composed by 228 patients (150 M, 78 F, median age 66 yrs) with T-cell lymphomas (202 Mycosis Fungoides/MF, 10 Sézary Syndrome/SS, 9 CD30+ PCL, 7 non MF/non CD30+ T cell PCL); 43 patients (28 M, 15 F, median age 60 yrs) with B-cell lymphomas (25 Follicular/FL, 14 marginal/MZL, 3 Leg-type, 1 Lymphoblastic) and one patient with CD4+/CD56+ hematodermic neoplasm. Chemotherapy was administered to 48 patients. During follow-up 12 patients died for the disease and 24 for other causes. A second tumor was observed in 41 patients (15%): 6 of them experienced more than one neoplasms: overall we observed 48 malignancies, 38 solid and 10 haematological. The other neoplasms appeared similarly before (20) and after (21) the diagnosis of PCL; in 7 cases they were diagnosed simultaneously. Solid tumours (17 preceding, 4 concurrent, 17 subsequent) were diagnosed in: skin (11), colon (5), lung (4), breast (3), CNS (3), bladder (2), liver (2), kidney (2), uterus (2), testis (1), prostate (1), stomach (1), thyroid (1). The haematological malignancies (3 preceding, 3 concurrent, 4 subsequent) were: B-cell lymphomas (4), acute myeloid leukemias (3), plasmocytoma (1), T-cell lymphoma (1), Hodgkin’s lymphoma (1). Among the six patients with more than one adjunctive neoplasms one patient had lung and kidney carcinoma preceding PCL; two patients a preceding carcinoma (skin and bladder, respectively) and subsequently a lung carcinoma; other two patients showed both a preceding and a concurrent neoplasm (skin and colon carcinoma, B-cell lymphoma and skin carcinoma, respectively). Finally a patient had a preceding skin carcinoma, a concurrent nodal Hodgkin’s lymphoma and a subsequent nodal B-cell lymphoma. So we have reported 48 other neoplasms in 41 patients within 272 PCLs (15%). The occurrence of the other malignancy was not related to the B/T phenotype of PCLs, as it was observed in 35/228 (15.4%) T-cell lymphomas (32 MF, 2 SS, 1 non MF/non CD30+ T cell lymphoma) and in 6/43 (14%) B-cell lymphomas (3 FL, 3 MZL; χ2 test: P=0.88). The interval of occurrence was longer for tumors preceding (median 60 mo.s, range 8–180) than for tumors following PCL (median 45, range 6–122). The administration of chemotherapy for PCL was not associated with an increased incidence of second neoplasm(χ2 test, P=0.77). Multicentric studies might help in elucidating the role of genetic and immunitary factors in the pathogenesis of multiple neoplasms in patients with PCLs.

Outcomes of Nodular Lymphocyte Predominant Hodgkin's Lymphoma (NLPHL) Patients Treated with R-CHOP.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2812-2812 ◽  
Author(s):  
Michelle A. Fanale ◽  
Chao-Ming Lai ◽  
Peter McLaughlin ◽  
Jorge Romaguera ◽  
Luis Fayad ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Hodgkin’S Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Stage I ◽  
Hodgkin's Lymphoma ◽  
Stage Iii ◽  
Field Radiation

Abstract Abstract 2812 Introduction: Nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) constitutes 5% of Hodgkin's lymphoma (HL) diagnoses. Recently gene expression profiling has shown significant overlap between NLPHL, T-cell-rich B cell lymphoma (TCRBCL), and classical HL (Brune, V et al, J Exp Med, 2008). NLPHL patients also have an approximate 7% risk of transformation at 10 years to diffuse large B-cell lymphoma (DLBCL) and TCRBCL (Al-Mansour, M et al, JCO, 2010). Data from multiple groups (Nogova, L et al, Ann Onc, 2005, Chen, RC et al, JCO, 2010, Wirth, A et al, Cancer, 2005) support extended progression-free survivals (PFS) for stage IA/IIA patients treated with radiation alone. While chemotherapy is generally recommended for patients with stage IB/IIB or III/IV disease, there is lack of guidelines on whether classical HL-directed regimens, such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), or B-cell lymphoma-directed regimens, such as R-CHOP (rituximab, cychlophosphamide, doxorubicin, vincristine, prednisone) should be used. Given the similarities between NLPHL and indolent CD20+ B-cell non-Hodgkin's lymphoma (NHL), our group started using the R-CHOP regimen for patients with NLPHL requiring systemic therapy. In order to examine the potential efficacy of this approach, we conducted a retrospective analysis of treatment outcomes in patients who received R-CHOP versus other regimens treated at UT MDACC from 1995 to 2010. Results: 83 patients were referred. 6 patients were found to have NLPHL with transformation to DLBCL or TCRBCL. 3 had alternative diagnoses. 11 lacked full immunophenotyping to confirm diagnosis. 63 patients had confirmed diagnoses of NLPHL (39 stage I/II and 24 stage III/IV). 52 NLPHL patients were evaluable (10 did not complete full treatment planning or were lost to follow-up and 1 is currently completing therapy). 7 patients had extranodal disease (thyroid, breast, lung, liver, bone marrow/cortex) and 8 had spleen involvement. Overall their median age at diagnosis was 40, male:female ratio was 2.5, and median follow-up is 46 months (range 8–149 months). 6 patients had relapse of NLPHL, 2 patients had transformation at a median of 39 months (1 to DLBCL, 1 to TCRBCL), 4 patients died (1 from acute myelogenous leukemia with deletion 7, 1 from DLBCL, 2 from unrelated causes while in remission), and 2 patients underwent autologous stem cell transplant (1 for relapsed NLPHL in 3rd complete remission and 1 for transformation to TCRBCL). Therapies for stage I/II NLPHL included: surgical excision alone (2 patients with stage IA disease declined radiation treatment), subtotal nodal irradiation (STNI), mantle field radiation, involved field radiation (IFRT), rituximab (R) alone and plus IFRT, ABVD plus STNI, R-ABVD, COPP (cyclophosphamide, vincristine, procarbazine, prednisone) plus IFRT, and R-CHOP alone and plus IFRT. Therapies for stage III/IV included: mantle field radiation (1 patient who declined chemotherapy), NOVP (mitoxantrone, vincristine, vinblastine, prednisone) plus mantle field radiation, ABVD, R-ABVD, R-CHOP alone and plus IFRT. A total of 15 patients received R-CHOP alone (4 stage I/II, 11 stage III/IV) and 5 patients received R-CHOP plus IFRT (4 stage I/II, 1 stage III/IV). Response to R-CHOP as assessed by CT scan criteria was 100% overall response rate (ORR) with 90% complete remissions (CR). No R-CHOP patients have had relapses or transformation with a median follow-up of 42 months (range 8–111 months). One patient treated with R-CHOP died of unrelated causes while in remission. However, with other therapies 19% have relapsed after median remissions of 38 months (range 4 to 72 months). R-CHOP when compared to other treatments has a trend towards improved PFS (Figures 1, 2, and 3). Survival rates for NLPHL patients at 5 years with 95% confidence intervals are: R-CHOP: PFS 0.95 (0.86, 1), OS (overall survival) 0.95 (0.86, 1) and other therapies: PFS 0.71 (0.55, 0.92), OS 0.91 (0.8, 1). Conclusions: Our data demonstrates that RCHOP is an effective regimen for the treatment of patients with NLPHL. A prospective evaluation of R-CHOP as a front-line treatment of NLPHL is under consideration. Disclosures: Fanale: Seattle Genetics: Research Funding; Novartis: Honoraria, Research Funding; Millenium: Research Funding; Genentech: Research Funding. Off Label Use: Given the CD20 positivity of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) rituximab has been evaluated previously for relapsed NLPHL and was shown to be efficacious. Rituximab however is not FDA approved for NLPHL. This is a retrospective study that evaluates the use of R-CHOP and other therapies for NLPHL. Current NCCN guidelines support consideration of R-CHOP for NLPHL treatment, and given the rarity of the disease there is no one defined preferred chemotherapy regimen. This information will be disclosed to the audience. Fayad:Genentech: Research Funding. Rodriguez:Genentech: Research Funding. Shah:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Novartis: Research Funding. Younes:Genentech: Honoraria, Research Funding; SBIO: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding.

A Phase II Trial of Ofatumumab In Subjects with Waldenstrom's Macroglobulinemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1795-1795 ◽  
Author(s):  
Richard R. Furman ◽  
Herbert Eradat ◽  
Julie C. Switzky ◽  
Suzanne R. Hayman ◽  
Craig C. Hofmeister ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Cell Lymphoma ◽  
International Workshop ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Rapid Rise ◽  
Grade 3

Abstract Abstract 1795 Background: Waldenstrom's macroglobulinemia (WM) is an indolent B-cell lymphoma characterized by a heterogeneous population of lymphocytes, plasmacytoid lymphocytes and plasma cells with variable CD20 expression. Rituximab (R) achieves an overall response rate (ORR) of 25–50% in relapsed/refractory WM and is associated with IgM flares, manifested by a rapid rise in IgM, potentially leading to complications of hyperviscosity. Ofatumumab (OFA) is a fully human monoclonal antibody that targets an epitope encompassing both the large and small extracellular loops of CD20 and effectively induces complement-dependent cytotoxicity of B-lymphoma cells. OFA is approved for the treatment of fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia (CLL) and has demonstrated clinical activity in non-Hodgkin's lymphoma. Given the efficacy of OFA in CLL, with its decreased CD20 antigen density, similar to WM where CD20 is down-regulated with differentiation of cells into plasma cells, a Phase II, open-label, single-arm trial of OFA in patients (pts) with WM was initiated to examine the safety and efficacy of OFA in this population. We report data from a planned interim analysis, which was performed to examine IgM flare, toxicity and response data. Methods: Pts (age ≥18 years) with WM requiring therapy by 2nd International Workshop on WM criteria were eligible. Pts received OFA 300 mg week 1 and 1000 mg weeks 2–4. Premedication included acetaminophen and antihistamine (all infusions) and glucocorticoid (infusions 1 and 2). Pts who experienced grade 3–4 infusion-related adverse events (AEs) during weeks 1 and 2 also received glucocorticoid during weeks 3 and 4. The primary endpoint was ORR assessed by 3rd International Workshop on WM criteria, and toxicity was assessed according to NCI-CTCAE, v3.0. Results: Fifteen pts were enrolled between March 2009 and January 2010. Median age was 59 years (range 43–85), and 9 pts were male. Pts had a median IgM level of 3.70 g/dL (range 1.21–6.62) and median hemoglobin (hgb) of 9.8 g/dL (range 5.3–11.7). Three pts were previously untreated; 12 pts had received a median of 3 therapies (range 2–5), including 11 pts who had received R, and 7 pts who had received a purine analog. Fourteen pts completed all 4 infusions of OFA. One pt withdrew from study after infusion 3 due to a drug-related serious AE (SAE). One pt had cryoglobulinemia, which interfered with IgM assessment. Of the 14 pts with evaluable IgM levels, 3 achieved partial response (PR), and 3 achieved minor response (ORR=43%) 8 weeks to 5 months after start of OFA therapy. One of 3 previously untreated pts and 5 of 12 relapsed pts responded. Four of 11 pts who had received prior R and 2 of 4 R-naïve pts responded. Five of 9 pts with IgM <4 g/dL and 1 of 5 pts with IgM >4 g/dL responded. Four pts with a median hgb of 8.0 g/dL (range 5.3–9.2) experienced ≥2.8 g/dL increase in hgb, including 3 pts who had >5 g/dL increase; median time to reach hgb ≥11.0 was 4 weeks. Infusion-related events occurred with dose 1 (300 mg) in 12 pts and with dose 2 (1000 mg) in 7 pts; all infusion events were grade 1–2 except 2 grade 3 events (rash, serum sickness). Nine pts developed 11 infections: 7 URI, 2 UTI, 1 sinusitis, 1 oral candidiasis (all grade 2). One pt developed grade 3 febrile neutropenia. Two pts developed SAEs possibly related to OFA. One pt developed grade 3 Coombs-negative hemolytic anemia after infusion 3 resulting in study withdrawal, and 1 pt with a baseline IgM level of 6.62 g/dL developed grade 3 renal insufficiency due to a rapid rise in IgM and cast nephropathy 6 weeks after starting OFA. One additional pt, with a baseline IgM level of 4.69 g/dL, developed a rapid rise in IgM and hyperviscosity symptoms. Both pts with a rapid rise in IgM underwent plasmapheresis with resolution of symptoms. No other OFA-related hematologic toxicity was observed. Conclusions: OFA has an acceptable toxicity profile, although a rapid rise in IgM requiring plasmapheresis was observed in 2 pts with high baseline IgM levels. OFA shows clinical activity in pts with WM, including those who relapse after R therapy, with rapid improvement in hgb and slower reduction of IgM levels. Based on the acceptable safety profile in this study and the dose of OFA approved for refractory CLL, the study was amended to increase the OFA dose to 2000 mg and allow a 2nd cycle of therapy for pts who do not attain PR after cycle 1. Accrual to the amended study is ongoing. Disclosures: Furman: GlaxoSmithKline: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Cephalon, Inc.: Speakers Bureau; Celegene: Consultancy; Calistoga: Consultancy. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Switzky:GlaxoSmithKline: Employment, Research Funding; Genmab: Employment, Research Funding. Leonard:GlaxoSmithKline: Consultancy. Liao:GSK: Employment. Shah:GlaxoSmithKline: Employment; Genmab: Research Funding. Brownell-Buttich:GlaxoSmithKline: Employment. Lisby:Genmab A/S: Employment. Lin:GlaxoSmithKline: Consultancy, Employment.

Outcome Of Patients With Double-Hit Lymphomas Treated With CODOX-M/IVAC + R Followed By Hematopoietic Stem Cell Transplantation In British Columbia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1788-1788 ◽  
Author(s):  
Haowei (Linda) Sun ◽  
Kerry J. Savage ◽  
Aly Karsan ◽  
Graham W. Slack ◽  
Cynthia L. Toze ◽  
...  
Keyword(s):  
British Columbia ◽  
B Cell ◽  
Cell Transplantation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Definitive Treatment ◽  
High Grade ◽  
Double Hit

Abstract Background Double-hit (DHIT) lymphoma is a heterogeneous group of non-Hodgkin lymphomas characterized by concurrent translocations involving MYC and BCL2 and typified by aggressive behavior and poor prognosis with only rare long-term survivors. There is no established treatment for DHIT lymphoma. Since 2003, the British Columbia Cancer Agency (BCCA) has adopted the use of intensive chemotherapy CODOX-M/IVAC combined with rituximab (R) followed by high-dose chemotherapy and hematopoietic cell transplantation (HSCT) as definitive treatment for DHIT lymphoma. In younger patients, an ablative matched sibling donor allotransplant (AlloSCT) is preferred over an autotransplant (AutoSCT). For all patients over the age of 60 years only AutoSCT is offered. Total Body Irradiation (TBI) is used as a part of the conditioning regimen for patients younger than 60 years of age. Here we report our provincial experience with this strategy, focusing on the ability to deliver this treatment and survival outcomes. Methods The Leukemia/BMT Program of British Columbia database and the BCCA Lymphoid Cancer Database were searched to identify all patients diagnosed with non-Hodgkin lymphomas with concurrent translocation of MYC and BCL2 (DHIT lymphoma) diagnosed between January 2003-September 2012. Results 27 cases of DHIT lymphoma were identified with the following characteristics: median age at diagnosis was 55.8 years (range 35.5-70.9 years); 19 (70%) were male; 26 (96%) patients had stage 3/4 disease; 16 (59%) had bone marrow involvement. All cases were HIV negative. Histological diagnosis based on the WHO 2008 classification were: diffuse large B-cell lymphoma (DLBCL) n=8 (30%); B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCL-U) n=17 (63%); B-cell acute lymphoblastic lymphoma (ALL) n=1; high-grade B-cell lymphoma, not otherwise specified (NOS) n=1. 13 cases (48%) were transformed from an underlying indolent B-cell lymphoma (12 follicular lymphoma, 1 low-grade B-cell lymphoma NOS). CODOX-M/IVAC + R was administered in 20 patients (74%). 7 patients received alternative chemotherapy regimen (5 R-CHOP, 1 R-CVP, 1 R-ICE) due to patient and/or physician preference. 14 patients (52%) underwent HSCT (7 AutoSCT, 7 AlloSCT), including 11 patients treated CODOX-M/IVAC + R pre-transplant, and 3 patients who received other therapy. 13 patients did not undergo HSCT: primary refractory disease n=7; patient preference n=2; deconditioning n=1; age > 65 and poor performance status n=3. The clinical status at time of transplantation was CR in 5 patients (19%), PR in 8 (30%), progressive disease in 1 (4%). The conditioning regimens included: cyclophosphamide/TBI n=6, VP-16/cyclophosphamide/TBI n=4, BEAM n=3, busulfan/cyclophosphamide n=1. At last follow-up, 15 (56%) patients have died, 14 from disease progression and 1 from complications of AlloSCT. 10 (37%) patients are alive and in remission and 2 patients are alive but have relapsed. 8 of 14 HSCT recipients (6 AutoSCT, 2 AlloSCT) remain alive and free of disease compared with 2 of 13 patients who did not receive HSCT; both disease free survivors received CODOX-M/IVAC + R. Median follow-up for living patients was 31 months (range 6.5-67.3 months). 2-year EFS and OS from the diagnosis of all DHIT lymphoma patients were 35% (95% CI 16%-54%) and 45% (95% CI 20%-65%), respectively. For patients who received CODOX-M/IVAC + R, the 2-year EFS was 37%. For patients who received CODOX-M/IVAC + R followed by SCT, the 2-year EFS was 43%. Patients with BCLU/ALL/High-grade lymphoma NOS had a 2-year EFS of 27% and patients with DLBL had a 2 –year EFS of 50%. Conclusion Patients with DHIT lymphoma treated with CODOX-M/IVAC + R followed by SCT can have durable remissions. Regardless, progression during initial therapy prior to SCT remains a significant problem. Patients with DLBCL histology may have a more favorable outcome than those with BCLU. Disclosures: Savage: Eli-Lilly: Consultancy. Toze:Roche Canada: Research Funding; F Hoffmann-La Roche: Research Funding. Sehn:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Connors:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Gerrie:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Sutherland:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Villa:Roche: Honoraria, Research Funding; Lundbeck: Honoraria; Celgene: Honoraria. Song:Roche: Research Funding.

Phase II Study Of Anti-CD19 Antibody Drug Conjugate (SAR3419) In Combination With Rituximab: Clinical Activity and Safety In Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (NCT01470456)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4395-4395 ◽  
Author(s):  
Bertrand Coiffier ◽  
Catherine Thieblemont ◽  
Sophie de Guibert ◽  
Jehan Dupuis ◽  
Vincent Ribrag ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Duration Of Response ◽  
Grade 3

Abstract Background SAR3419 is a humanized anti-CD19 antibody conjugated to maytansin DM4, a potent cytotoxic agent. SAR3419 targets CD19, an antigen expressed in the majority of B cell non-Hodgkin lymphomas (NHL). The recommended dose for single agent SAR3419 was previously determined to be 55 mg/m2 administered IV every week for 4 weeks, then bi-weekly. In phase I, clinical activity was shown mainly in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). (Trial funded by Sanofi). Methods Patients (pts) with a CD20+ and CD19+ DLBCL relapsing or refractory (R/R) after at least 1 standard treatment including rituximab and not candidate for or who already underwent transplantation, were eligible. Refractory disease was defined as unresponsive to or progressing within 6 months of regimen completion. Fresh (or recent formalin-fixed, paraffin-embedded) biopsy was required before SAR3419 start. Pts received 375 mg/m2 of rituximab (R) IV and 55 mg/m² of SAR3419 on day 1, 8, 15, 22 (35-day cycle 1), followed by bi-weekly R and SAR3419 at the same doses for 2 additional 28-day cycles, provided there was no disease progression or other study discontinuation criteria met. The primary objective was the overall response rate (ORR) following Cheson 2007 criteria, with the first tumor assessment being done 42 days after the last study treatment administration. Secondary objectives were: safety, pharmacokinetics (PK), duration of response (DOR), progression free survival (PFS), overall survival (OS) and correlation of the antitumor and biological activity of the combination with tumor biomarker status. Results Fifty-three pts were enrolled, 52 treated. Median age was 66.5 years (range 38-85), 50% were male; 23%, 33% and 40% of patients had received 1, 2 or ≥3 prior chemo/immunotherapy regimens for DLBCL, respectively. Of the enrolled patients, 3.8% had received no prior regimen for DLBCL and therefore were excluded from primary analysis for efficacy. Seventy-three percent had stage III/IV disease, 59% had elevated lactate dehydrogenase (LDH), and 63% had bulky disease. Sixty percent were refractory to first regimen (primary refractory), 16% were refractory to last regimen and 24% were relapsed pts. The ORR in the per-protocol population (n=45) was 31.1% (80% confidence interval (CI): 22.0% to 41.6%). Among the 14 responders, 5 had progressed at the time of analysis, with duration of response beyond 6 months for 3 of them. The ORR was 58.3% (80% CI: 36.2% to 78.1%) for patients with relapsed DLBCL (n=12), 42.9% (80% CI: 17.0% to 72.1%) for pts refractory to last regimen (n=7) and 15.4% (80% CI: 6.9% to 28.4%) for primary refractory pts (n=26). Overall survival and PFS data are not yet mature. Biomarkers and PK data will be presented at the meeting. The most common (≥10%) all grades non-hematologic treatment-emergent adverse events (TEAEs) were asthenia (25.0%), nausea (21.2%), cough (19.2%), diarrhea (17.3%), weight decrease (17.3%), vomiting (15.4%), dyspnea (15.4%), abdominal pain (13.5%), back pain (13.5%), pyrexia (13.5%) and constipation (11.5%). Related grade 3-4 TEAEs were: 1 syncope, 1 bronchospasm, 2 neutropenia and 1 anemia. No TEAEs led to treatment discontinuation, no grade 3-4 peripheral neuropathy or grade 3-4 ocular events were observed. Two pts experienced grade 2 keratitis, both rapidly recovered with local treatment. Hematological toxicity was moderate, with grade 3-4 neutropenia and thrombocytopenia in 15.7% and 9.8% pts, respectively. No complications related to neutropenia were reported. Grade 3 transaminase increase was observed in 1 patient. Conclusions The combination of SAR3419 plus R showed moderate ORR in R/R DLBCL; however the study population was of poor prognosis (60% refractory to first line therapy). In the relapsed DLBCL patients a higher ORR was observed. SAR3419 plus R presented with a favorable safety profile. Further investigations on biomarker expression are ongoing to identify a sub-group of pts who could have better benefited from this combination. Disclosures: Coiffier: Sanofi: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Phase II of SAR3419. Ribrag:Johnson & Johnson: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cartron:LFB: Honoraria; GSK: Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Casasnovas:Roche: Consultancy, Honoraria, Research Funding. Hatteville:Sanofi: Employment. Zilocchi:Sanofi: Employment. Oprea:Sanofi: Employment. Tilly:Amgen: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Takeda: Membership on an entity’s Board of Directors or advisory committees; Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

TGR-1202, a Novel Once Daily PI3Kδ Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile, Lacking Hepatotoxicity, in Patients with Chronic Lymphocytic Leukemia and B-Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1984-1984 ◽  
Author(s):  
Howard A. Burris ◽  
Manish R. Patel ◽  
Danielle M. Brander ◽  
Owen A. O'Connor ◽  
Changchun Deng ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Tumor Burden ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Employment Equity ◽  
Previous Formulation ◽  
Equity Ownership

Abstract Background: TGR-1202 is a novel oral, next generation PI3Kδ inhibitor which notably lacks the hepatotoxicity associated with other PI3Kδ inhibitors. Preliminary data from an ongoing Ph I study of TGR-1202 demonstrated clinical activity in patients with advanced hematologic malignancies (ASCO 2014). Herein we present updated results from this Phase I, first in human study of TGR-1202 in patients with relapsed and/or refractory CLL and B-cell lymphoma. Methods: TGR-1202 is administered orally once daily following a 3+3 dose escalation design. Previously treated patients with an ECOG PS ≤ 2 and confirmed diagnosis of B-cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or other lymphoproliferative disorders are eligible. Endpoints include safety, PK/PD, and efficacy. Results: 49 patients have been enrolled to date of various lymphoma subtypes including CLL, follicular lymphoma (FL), Hodgkin’s lymphoma (HL), DLBCL, mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Demographics: 76% male, ECOG 0/1/2: 17/31/1, median age of 59 yrs (range: 22-85), median prior treatment regimens: 3 (range: 1-14), and 43% were refractory to prior treatment. 35 patients have been treated at doses ≥ 800 mg of a previous formulation where a threshold effect in activity was observed, and 6 have been treated with an improved micronized formulation (≥ 200 mg). TGR-1202 was well tolerated and no MTD has been reached to date. The only Gr≥3 AE occurring in >5% of patients was neutropenia (8%). AE’s of all grades occurring in >20% of patients were limited to diarrhea (24%), cough (22%), fatigue (20%), and nausea (20%). Notably, in comparison to other PI3Kδ inhibitors, no hepatotoxicity and no cases of colitis have been observed to date. Rates of infection and pneumonia have also been low (12% and 6%, respectively), and no cases of febrile neutropenia have been reported. Of the 41 patients treated at ≥ 800 mg of the previous formulation or with the micronized formulation, 32 are evaluable for efficacy (6 too early to evaluate, 2 non-compliant, 1 did not meet I/E criteria). Responses have been limited in patients with aggressive lymphoma and HL. Of the 9 evaluable CLL patients, 8 (89%) achieved a nodal PR (median nodal reduction of 71%), of which 5 achieved a PR per Hallek 2008 criteria with the remaining 4 having persistent lymphocytosis. The 1 CLL patient with SD had a >40% nodal reduction and remains on study. Of the 7 evaluable FL patients, all have shown clinical benefit with a reduction in tumor burden with 2 having achieved a PR, and the remaining 5 patients in SD. Additionally 2 MZL patients each achieved SD with >25% nodal reductions and remain on study. Notably, no patient with CLL or indolent lymphoma (FL & MZL) treated at ≥800 mg has progressed to date (median time on study of 20 weeks, range 6 – 73+), and no patient who achieved >50% reduction in tumor burden (including patients with CLL, FL, and HL) has progressed, with median time on study of 34 weeks (range 7 – 68+). Pharmacodynamic analysis in CLL patients indicates rapid suppression of pAKT at doses of 400 mg QD of the previous formulation. Conclusions: TGR-1202 is well tolerated in patients with relapsed and/or refractory hematologic malignancies with no reported hepatotoxicity or events of colitis and promising clinical activity. Enrollment continues in expansion cohorts and with the micronized formulation. Disclosures Brander: Celgene: Mentor received research funding Other. O'Connor:Celgene: Consultancy; Millennium Pharmaceuticals: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics: Employment, Equity Ownership. Vakkalanka:Rhizen: Employment, Equity Ownership. Flinn:Infinity Pharmaceuticals: Consultancy.

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