The Combination of Brentuximab Vedotin (Bv) and Bendamustine (B) Demonstrates Marked Activity in Heavily Treated Patients with Relapsed or Refractory Hodgkin Lymphoma (HL) and Anaplastic Large T-Cell Lymphoma (ALCL): Results of an International Multi Center Phase I/II Experience

Abstract Introduction Patients with HL or ALCL who have relapsed post or are ineligible for autologous stem cell transplant (ASCT) remain incurable with standard therapies. The CD30 immunoconjugate Brentuximab vedotin has become the preferred treatment for such patients. Bendamustine has also demonstrated good activity and tolerability in several lymphoma subtypes including HL. This ongoing phase I/II study was designed to evaluate the safety and efficacy of the combination of brentuximab vedotin with bendamustine for the treatment of patients with relapsed or refractory HL or ALCL. We provide the phase I and II data. (ClinicalTrials.gov #NCT01657331). Methods Patients received an outpatient IV infusion of brentuximab vedotin on Day 1 with bendamustine on Days 1 and 2 of a 3-week cycle for up to 6 cycles. In the Phase 1 portion 4 dose levels were evaluated: (1) Bv = 1.2mg/kg; B = 70mg/m2; (2) Bv = 1.2mg/kg; B = 80mg/m2; (3) Bv = 1.8mg/kg; B = 80mg/m2; and (4) Bv = 1.8mg/kg; B = 90. Accrual followed a classic Fibonacci dose escalation, with 3 patients being treated at each dose level. Dose Limiting Toxicity (DLT), defined as any CTC version 4 Grade 3 or 4 toxicity led to expansion of the dose cohort. The recommended phase II dose was Bv 1.8 mg/kg on Day 1 and B 90 mg/m2 on Days 1 and 2. Response was assessed by the investigator per Cheson 2007 after cycles 2 and 6. Enrollment is ongoing of the Phase 2 portion of the study, where an additional 24 patients will be accrued. In addition, plasma and serum biomarkers are being prospectively collected for correlation with toxicity and response. Results Forty-two patients (55% male) with a median age of 37 years (range, 30-70) were enrolled. Forty-one patients had HL and 1 ALCL; the median number of prior systemic therapies was 5 (range 1-16); with 26 patients having had prior ASCT and 14 patients receiving prior radiation therapy. The predominant all grade toxicity observed with the combination was nausea (62%, grade 1-2). The observed grade 3-4 toxicities in the phase I were: neutropenia (19%), thrombocytopenia (19%), anemia (15%) and rash (11%). The observed phase II grade 3-4 toxicities were neutropenia (14%) and pneumonia (14%). No DLT was observed at dose level 4 (Bv 1.8 mg/m2 and B 90 mg/m2). The maximum tolerated dose (MTD) was not reached. A decision was made not to explore further doses that exceeded the standard single agent doses of both drugs. Patient's received a median of 6 cycles (range, 1-6). To date, 36/39 patients are evaluable for response. The overall response rate was 67%, with 7 patients (19%) attaining a complete response (CR). Eight patients had stable disease. Among the 11 patients who received prior Bv, 6 responded (55%) (CR= 2, PR=4, SD=3, PD=2), and of the 4 patients who had prior B, 2 responded (50%) (PR=2, SD=1, PD=1). Two patients had received both Bv and B as single agents prior to initiation of study; one patient achieved a PR and the other experienced PD. The ALCL patient achieved a PR. Conclusion In this heavily treated population of HL and ALCL, the combination of brentuximab vedotin 1.8 mg/kg on Day 1 with bendamustine 90 mg/m2 on Days 1 and 2 of 3-week cycles represents a very effective and tolerable outpatient regimen. The regimen has an ORR of 67% with responses ≥ 50% in patients who had received either agent separately supporting the potential clinical synergy of the combination. Table. Dose Cohort No. Patients Responses Complete Response Dose Cohort 1Bv = 1.2 mg/kg B = 70 mg/m2 7 4 1 Dose Cohort 2Bv = 1.2 mg/kg B = 80 mg/m2 3 3 0 Dose Cohort 3Bv = 1.8 mg/kg B = 80 mg/m2 7 5 1 Dose Cohort 4Bv = 1.8 mg/kg B = 90 mg/m2 11 5 1 Phase IIBv = 1.8 mg/kg B = 90 mg/m2 11 7 4 Total 39 (36 evaluable) 24 (67%) 7 (19%) Disclosures Sawas: Seattle Genetics: Research Funding; Gilead Sciences: Honoraria. Off Label Use: Bendamustine is not approved for the treatment of Hodgkin lymphoma or anaplastic large T- cell lymphoma. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Kuruvilla:Karyopharm: Honoraria, Research Funding; Roche Canada: Honoraria; Seattle Genetics: Honoraria, Research Funding. Neylon:Genentech: Speakers Bureau; Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau; Gilead: Speakers Bureau. Deng:TG Therapeutics, Inc.: Honoraria, Research Funding; Seattle Genetics: Research Funding. Amengual:Acetylon Pharmaceuticals, INC: Consultancy, Research Funding. Villa:Roche: Research Funding. Crump:Sanofi: Honoraria; Celgene: Honoraria; Seattle Genetics: Honoraria. O'Connor:Spectrum: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding; Seattle Genetics: Research Funding.

Download Full-text

Oral HDAC Inhibitor HBI8000 in Japanese Patients with Non-Hodgkin Lymphoma (NHL): Phase I Safety and Efficacy Results

Blood ◽

10.1182/blood.v128.22.1827.1827 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1827-1827 ◽

Cited By ~ 2

Author(s):

Makoto Onizuka ◽

Kiyoshi Ando ◽

Makoto Yoshimitsu ◽

Takashi Ishida ◽

S Yoshida ◽

...

Keyword(s):

T Cell ◽

Phase I ◽

Phase Ii ◽

Research Funding ◽

Phase I Trial ◽

Cell Lymphoma ◽

Japanese Patients ◽

Dose Cohort ◽

Grade 3 ◽

Anti Tumor Activity

Abstract Background: HBI-8000 is an orally bioavailable member of the benzamide class of histone deacetylase inhibitors (HDACi), that inhibits cancer-associated HDAC enzymes (Class I and IIb). HBI-8000 has anti-tumor activity through various mechanisms of action, including epigenetic reprogramming and immunomodulation. It was recently approved by the Chinese FDA under the name chidamide (Epidaza) for relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) with a recommended dose of 30 mg twice weekly (BIW). HBI-8000 is also being manufactured in the USA for clinical development outside of China. The preliminary results of a phase I trial of HBI-8000 to confirm the safety and maximum tolerated dose (MTD) in Japanese patients (pts) with advanced NHL are presented (NCT02697552). Methods: This is a multicenter, prospective phase I trial in Japan. Inclusion criteria: patients are eligible if they have histologically or cytologically proven NHL and no other standard therapy is available. The primary endpoint is the MTD based on the frequency of dose-limiting toxicities (DLTs) observed within 28 days of the first dose. Secondary endpoints include pharmacokinetic (PK) profile and anti-tumor activity. At the time of this abstract submission, the trial is still ongoing. Results: Thirteen out of 14 pts were eligible for the 1st cycle DLT assessment (6 pts in the 30 mg, 7 pts in the 40 mg cohort). Median age was 68 years, gender well balanced, and the majority of pts had ≥ 2 prior treatment regimens. Five pts had the diagnosis of adult T-cell leukemia-lymphoma (ATL), 2 pts presented with PTCL, 3 with diffuse large B-cell lymphoma (DLBLC), 2 with follicular lymphoma (FL), 1 with cutaneous T-cell lymphoma (CTCL), and 1 with marginal zone lymphoma. Overall, the treatment was well tolerated, and adverse drug reactions (ADRs) were predominantly hematologic, consistent with the previous experiences. There were 7 pts in the 40 mg dose cohort because one of the first 3 pts had to be replaced for incomplete dosing due to grade 3 hypertriglyceridemia which was not regarded as DLT by the Data Monitoring Safety Committee (DMC/SMC). In the 40 mg cohort, 2 pts were considered as DLTs by definition in the protocol: grade 4 neutropenia and grade 3 alanine transaminase (ALT) increase. Both pts were asymptomatic. The grade 4 neutropenia promptly resolved with the administration of G-CSF and the grade 3 ALT elevation resolved with dose interruption. The 30 mg dose cohort completed with no DLT after the 1st cycle in 6 pts. The following hematologic grade 3/4 toxicities were noted in the 40 mg dose cohort (N=7): leukopenia (2 pts, 29%), neutropenia (3 pts, 43%), and thrombocytopenia (3 pts, 43%). Non-hematologic ADRs included fatigue, nausea, diarrhea, decreased appetite, erythema and pyrexia. The preliminary pharmacokinetic (PK) results from the 3 patients in the 30 mg cohort, and 7 patients in the 40 mg dose cohort show inter-patient variability as expected of an oral agent. Mean half-life (t ½ ) was between16.5 and 20 hours (h) with a Tmax between 2.5 and 3.5h and consistent with previous findings. Mean Cmax and AUC increased with dose (30 mg: 210 ng/mL; 3660 h*ng/mL and 40 mg: 590 ng/mL; 7200 h*ng/mL). The patient with neutropenia as DLT presented with the highest exposure. Cardiovascular assessments including serial ECGs and troponin assessments did not reveal clinically relevant findings. Best overall response was noted in 40 mg BIW cohort (N=7): 1 CR (10%), 5 PR (30%), 1 SD (20%). Four of the partial responders were ATL patients. In the 30 mg BIW dose cohort, 4/6 patients had stable disease after the 1st cycle. Summary: In this phase l trial evaluating the safety of twice weekly 30 mg and 40 mg doses, HBI-8000 was well tolerated with expected toxicities that could be managed with dose interruptions/reductions. Tumor response results in pts who completed at least one cycle of treatment indicate some clinical benefit especially in pts who started with the 40 mg dose level. The DMC/SMC has provided an opinion that the 2 observed DLTs with HBI-8000 in the phase I trial were clinically manageable and that 40 mg BIW would be recommended as the dosage for subsequent phase II studies. Registration enabling phase II trials to evaluate efficacy and safety in R/R ATL pts (Japan) and R/R PTCL pts (Japan and Korea) are being initiated. Disclosures Ando: SymBio Pharmaceuticals: Research Funding. Yoshimitsu:HUYA Bioscience International: Research Funding. Ishida:Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Celgene KK: Research Funding; Bayer Pharma AG: Research Funding. Hidaka:Chugai-pharm: Research Funding. Nagashima:HUYA Bioscience International: Employment. Miyazato:HUYA Bioscience International: Employment. Schupp:HUYA Bioscience International: Employment. Rolland:HUYA Bioscience International: Employment. Gillings:HUYA Bioscience International: Employment. Lee:HUYA Bioscience International: Employment. Tobinai:Eisai: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; HUYA Bioscience: Honoraria; Janssen Pharmaceuticals: Honoraria, Research Funding; Kyowa Hakko Kirin: Research Funding; Mundipharma: Honoraria, Research Funding; Ono Pharmaceuticals: Research Funding; Servier: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Chugai Pharma: Research Funding; Celgene: Research Funding; Abbvie: Research Funding.

Download Full-text

Brentuximab Vedotin in Combination with Multi-Agent Chemotherapy Is Well Tolerated and Shows Promising Activity As Frontline Treatment for Primary Mediastinal B-Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.2694.2694 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2694-2694 ◽

Cited By ~ 2

Author(s):

Jakub Svoboda ◽

Lauren E. Strelec ◽

Sunita Dwivedy Nasta ◽

Daniel J. Landsburg ◽

Anthony R. Mato ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Systemic Therapy ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Brentuximab Vedotin ◽

Genetics Research ◽

Frontline Treatment ◽

Grade 3

Abstract Background: Primary mediastinal B-cell lymphoma (PMBL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL) with distinctive clinical and immunophenotypic features. Most PMBL patients (pts) present at young age and with bulky mediastinal mass. Over 80% of PMBL cases are CD30 positive by immunohistochemistry (IHC). Standard frontline systemic therapy for PMBL remains controversial and the use of intensive regimens may be associated with increased toxicity. Brentuximab vedotin (BV) is a CD30-directed immunoconjugate with established efficacy in relapsed Hodgkin lymphoma and several other CD30 positive lymphoid malignancies, but this targeted agent has not been utilized in frontline combinations for PMBL. Methods: We designed an open label phase I/II trial using BV administered concurrently with rituximab, cyclophosphamide, doxorubicin, and prednisone (standard R-CHOP with the omission of vincristine to minimize risk of neuropathy) as frontline treatment for PMBL, grey zone lymphoma (GZL), and other CD30-positive DLBCLs. Pts with any Ann Arbor stage and at least equivocal CD30 expression on IHC were eligible. Consolidative radiation was allowed after completion of therapy at discretion of the treating physician. Phase I utilized a 3+3 de-escalation design with starting dose of BV 1.8 mg/kg on Day 1 in combination with rituximab 375 mg/m2 on Day 1, cyclophosphamide 750 mg/m2 on Day 1, doxorubicin 50 mg/m2 on Day 1, and prednisone 100 mg daily on Days 1-5 every 3 weeks for 6 cycles. The primary objective of phase I was assessment of safety and dose limiting toxicity (DLT) defined as any grade 3/4 non-hematologic toxicity observed in Cycle 1 requiring dose delay >14 days from the planned Day 1 of Cycle 2. Secondary end points included overall response rate (ORR), progression free survival (PFS), and overall survival (OS). The primary phase II objective was ORR with secondary endpoints of PFS, OS, safety, and correlation with CD30 expression. Revised Response Criteria for Malignant Lymphoma was used for response assessment (Cheson, 2007). Enrollment began in January 2014 and is reported through July 27, 2015. Results: Twelve pts including 9 PMBL (75%), 1 GZL (8%), and 2 DLBCL (17%) have been enrolled and treated; 11 patients are evaluable after completing protocol defined therapy. Median age was 37 years (range 25 - 58), 5 (45%) were female, 9 (82%) had elevated LDH, and 6 (55%) had stage III-IV disease. No DLT was observed during phase I and no BV dose de-escalation was required. There were no grade 3/4 non-hematologic adverse events (AEs). Hematologic grade 3/4 AEs included febrile neutropenia in 2 pts and afebrile neutropenia in 1 pt. Five pts had grade 2 non-hematologic AEs at least possibly related to BV including mucositis, nausea/vomiting, diarrhea, abdominal pain, anorexia, hypotension, and neuropathy. No study related deaths were observed. The ORR among evaluable pts was 100% (10 pts with CR, 1 pt with GZL with PR). The PFS and OS with median follow-up of 8 months (range: 4 -18 months) is 100%. Eight pts completed consolidative radiation therapy after systemic therapy. Conclusions: We established safety of administrating BV 1.8 mg/kg in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline therapy for PMBL, GZL and CD30-positive DLBCL. This outpatient regimen was well tolerated. Clinical outcomes observed in this initial cohort are very encouraging and will be validated in the ongoing phase II part of the trial. Disclosures Svoboda: Celgene: Research Funding; Immunomedics: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding. Off Label Use: Brentuximab is not FDA approved for front-line therapy in PMBL and CD30+ DLBCL. Nasta:Seattle Genetics: Research Funding; BMS: Research Funding. Mato:Celgene Corporation: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy. Pro:Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses. Barta:Seattle Genetics: Research Funding. Schuster:Janssen: Research Funding; Celgene: Consultancy, Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Phamacyclics: Consultancy, Research Funding; Hoffman-LaRoche: Research Funding; Novartis: Research Funding; Gilead: Research Funding.

Download Full-text

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

Blood ◽

10.1182/blood.v126.23.582.582 ◽

2015 ◽

Vol 126 (23) ◽

pp. 582-582 ◽

Cited By ~ 9

Author(s):

Ramon Garcia-Sanz ◽

Anna Sureda ◽

Sara Alonso-Alvarez ◽

Ana Pilar Gonzalez ◽

Antonia Rodriguez ◽

...

Keyword(s):

Stem Cell ◽

Phase I ◽

Hodgkin Lymphoma ◽

Complete Response ◽

Brentuximab Vedotin ◽

High Dose ◽

Hematologic Toxicity ◽

Pet Ct ◽

Grade 3 ◽

Dose Limiting Toxicity

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

Download Full-text

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

Blood ◽

10.1182/blood-2018-99-117172 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4185-4185 ◽

Cited By ~ 1

Author(s):

Kami J. Maddocks ◽

Farrukh T. Awan ◽

Ying Huang ◽

Sabarish Ayyappan ◽

Robert A Baiocchi ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Phase I Study ◽

Hematologic Toxicity ◽

Tumor Lysis ◽

Genetics Research ◽

Non Hodgkin Lymphoma ◽

Grade 3

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

Download Full-text

Real-World Characteristics of Patients with Peripheral T-Cell Lymphoma Receiving Frontline Brentuximab Vedotin with Chemotherapy: A Retrospective Analysis with Propensity Score Matching

Blood ◽

10.1182/blood-2020-140832 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 18-19

Author(s):

John M. Burke ◽

Nicholas Liu ◽

Kristina Yu-Isenberg ◽

Michelle A. Fanale ◽

Andy Surinach ◽

...

Keyword(s):

T Cell ◽

Real World ◽

Research Funding ◽

Cell Lymphoma ◽

Primary Prophylaxis ◽

Brentuximab Vedotin ◽

Publicly Traded ◽

Genetics Research ◽

T Cell Lymphomas

Introduction: In the phase 3 ECHELON-2 study (NCT01777152), treatment with brentuximab vedotin (BV) + cyclophosphamide, doxorubicin, and prednisone (A+CHP) demonstrated significantly longer progression-free and overall survival compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the frontline (FL) treatment of patients with systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL). This study supported the November 2018 US FDA approval of A+CHP as FL therapy for adults with sALCL or other CD30-expressing PTCL. The current analysis describes patient characteristics, PTCL subtypes, and supportive care use of FL A+CHP and CHOP outside of the clinical trial setting in the US. Methods: Using medical and pharmacy claims data in the Symphony Health Solutions database, a retrospective cohort analysis of patients with PTCL treated with FL A+CHP or CHOP was conducted to compare treatment and utilization characteristics. Patients ≥18 years with 1 inpatient or 2 outpatient ICD-9/10 PTCL diagnosis codes, newly initiated on A+CHP or CHOP (index date) between November 2018 and January 2020, and with ≥6 months continuous activity before and ≥3 months after the index date were included. To adjust for confounding factors, a 1:1 propensity score matching analysis was performed based on age, gender, baseline comorbidities, geographic region and length of follow-up. Results: A total of 755 patients met inclusion criteria (335 A+CHP; 420 CHOP) with a median follow-up period of 10.1 and 10.6 months, respectively. In the unmatched cohorts, 61% were male, and median age at index was 62 and 69 years for A+CHP and CHOP, respectively. The prevalence of comorbidities based on the Charlson Comorbidity Index was similar between the cohorts; prevalent conditions included diabetes, chronic pulmonary disease, congestive heart failure, and liver disease (Table 1). PTCL subtypes treated with A+CHP included sALCL (54%), PTCL-not otherwise specified (NOS; 27%), and angioimmunoblastic T-cell lymphoma (AITL; 13%); subtypes treated with CHOP included PTCL-NOS (35%), adult T-cell leukemia/lymphoma (ATLL; 35%), and AITL (11%) (Table 2). After matching, the proportion of patients who received granulocyte-colony stimulating factor (G-CSF; A+CHP: 91%, CHOP: 86%, p=0.1) and the incidence rate of neutropenia (A+CHP: 45%, CHOP: 42%, p=0.4) during FL treatment for both study cohorts was similar. Of patients who received G-CSF, the majority received it as primary prophylaxis given within the first 5 days of FL treatment initiation (A+CHP: 89%, CHOP: 85%, p=0.2). The rate of subsequent therapy (ie, therapy change after FL), was similar between A+CHP and CHOP (18% vs 21%; p=0.3) and for the sALCL subtype (16% vs 26%, p=0.2). Of the A+CHP patients who received subsequent therapy, 32% were retreated with a BV-containing regimen and 19% of CHOP patients received a BV-containing regimen. Conclusions: In this real-world analysis, US patients with PTCL newly initiated on A+CHP or CHOP were older (67 vs 58 years) than those in ECHELON-2. There was a high comorbidity burden; over half of the patients in both cohorts had 1+ comorbidities, a potential reflection of the older population. As would be expected due to a high rate of CD30-positivity in the disease, A+CHP was more commonly used than CHOP in sALCL. In PTCL subtypes in which CD30 is more variably expressed, A+CHP and CHOP were used with similar frequencies. Although clinical trials in ATLL have demonstrated improved outcomes with more complex and intensive regimens than CHOP, CHOP remains commonly used in ATLL. A+CHP was also used in PTCL subtypes not included in ECHELON-2, such as NK/T cell lymphomas. G-CSF was used as primary prophylaxis in the large majority of patients in both cohorts. The use of a BV-containing regimen as subsequent therapy was more common in A+CHP vs CHOP, probably because the tumors of A+CHP patients were more likely to have expressed CD30. Confounding by unmeasured characteristics cannot be ruled out due to inherent limitations in claims data (eg, lack of disease stage, CD30 testing and response outcomes). Characteristics and management of this real-world population with PTCL differed from those in the ECHELON-2 trial, demonstrating the importance of retrospective studies to assess the impact of new regimens on clinical practice and to identify areas for further education of practitioners. Disclosures Burke: Seattle Genetics: Speakers Bureau; Gilead: Consultancy; Bristol Myers Squibb: Consultancy; Roche: Consultancy; Epizyme: Consultancy; Adaptive: Consultancy; Kura: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Consultancy; Verastem: Consultancy; Astra Zeneca: Consultancy; Bayer: Consultancy; AbbVie: Consultancy. Liu:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Yu-Isenberg:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Fanale:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Surinach:Seattle Genetics: Research Funding. Flores:Seattle Genetics: Research Funding. Lisano:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Phillips:Beigene: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy; Bayer: Consultancy, Research Funding; Lymphoma Connect: Other; Incyte: Consultancy, Research Funding; Cardinal Health: Consultancy; University of Michigan: Current Employment; Pharmacyclics: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy.

Download Full-text

FDG-PET Adapted Sequential Therapy With Brentuximab Vedotin and Augmented ICE Followed By Autologous Stem Cell Transplant For Relapsed and Refractory Hodgkin Lymphoma

Blood ◽

10.1182/blood.v122.21.2099.2099 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2099-2099 ◽

Cited By ~ 5

Author(s):

Alison Moskowitz ◽

Heiko Schoder ◽

John F. Gerecitano ◽

Paul Hamlin ◽

Steven M. Horwitz ◽

...

Keyword(s):

Stem Cell ◽

Hodgkin Lymphoma ◽

Salvage Therapy ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Brentuximab Vedotin ◽

Cell Transplant ◽

Genetics Research ◽

Grade 3

Abstract Background Pre-transplant FDG-PET (PET) normalization is the strongest predictor of outcome following autologous stem cell transplant (ASCT) for patients with relapsed or refractory (rel/ref) Hodgkin lymphoma (HL) (Moskowitz, AJ. Blood. 2010 Dec 2;116(23):4934-7). Due to its high efficacy in ASCT failures, we aimed to determine whether brentuximab vedotin (BV) can replace ICE (ifosfamide, carboplatin, etoposide) salvage therapy, increase rate of PET normalization, and enhance referral to ASCT for patients (pts) who fail front-line HL therapy. Here we present our phase II study evaluating a novel salvage strategy for rel/ref HL, an intent-to-treat study of PET-adapted sequential therapy with BV and augmented ICE (augICE) prior to ASCT. Methods Patients with rel/ref HL who have failed 1 prior regimen are enrolling on this phase II clinical trial. Patients receive weekly brentuximab vedotin (BV) administered at 1.2mg/Kg IV weekly for 3 weeks on and 1 week off for 2 cycles, followed by PET. Patients who achieve normalization of PET (Deauville 2 or less) proceed to ASCT. Patients with PET scores of Deauville 3 or higher receive 2 cycles of augICE prior to consideration for ASCT. Results 41 of planned 46 patients have enrolled; 34 pts completed salvage therapy, of whom 33 proceeded to ASCT. 28 pts are at least 90 days post-ASCT and represent the focus of this report. These 28 pts include 20 (71%) males, 21 (75%) pts with primary refractory or relapse within 1 year of initial treatment, 11 (39%) with B symptoms at enrollment and 11 (39%) with extranodal disease. Median number CD34+ cells/kg collected were 7.44x 10^6 (2.96 - 31.43x10^6). Disease status prior to ASCT was CR (Deauville 2) for 27 pts and PR (Deauville 3) for 1 pt. Salvage therapy for pts in CR prior to ASCT include BV alone (9), BV followed by augICE (16), and BV followed by augICE (with Deauville 4 response) followed by involved field radiation to achieve CR (2). The 1 patient in PR prior to ASCT received BV followed by augICE. Conditioning regimens included BEAM (9), CBV( 9), and high dose chemoradiotherapy (10). Early (within 90 days) transplant-related toxicities include grade 2 pneumonitis (3pts) and grade 3 acute kidney injury (1pt); late toxicities include grade 3 esophageal stenosis (1pt), grade 3 acute kidney injury (1pt), and 1 death (7 months post ASCT) due to progressive multifocal leukoencephalopathy. After a median follow-up of 9.5 months post-ASCT (range 3.3-15.6 months), 2 of 28 pts have progressed (at 2.7 and 4.3 months post ASCT respectively). One achieved a second CR with BV and proceeded to allogeneic stem cell transplant (alloSCT); the second achieved near CR following GND (gemcitabine, vinorelbine, Doxil) and proceeded to alloSCT. Conclusion PET-adapted sequential salvage therapy with BV followed by augICE produces high CR rates, adequate stem cell collection, and facilitates referral to ASCT for virtually all pts. Updated results will be presented at the meeting. Disclosures: Moskowitz: Seattle Genetics: Research Funding. Off Label Use: Brentuximab vedotin is approved for treatment of Hodgkin lymphoma following failure of 2 multi-agent regimens or autologous stem cell transplant. This study is evaluating the use of brentuximab vedotin in the pre-transplant setting for Hodgkin lymphoma. Schoder:Seattle Genetics: Research Funding. Hamlin:Seattle Genetics : Consultancy, Honoraria. Horwitz:Millennium: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Moskowitz:Seattle Genetics: Research Funding.

Download Full-text

The Pralatrexate - Romidepsin Doublet: A Well Tolerated and Highly Effective Combination for Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.1824.1824 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1824-1824 ◽

Cited By ~ 3

Author(s):

Jennifer E Amengual ◽

Renee Lichtenstein ◽

Celeste Rojas ◽

Ahmed Sawas ◽

Changchun Deng ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Median Number ◽

Peripheral T Cell Lymphoma ◽

Advisory Committees ◽

Genetics Research ◽

The Mean ◽

Grade 3

Abstract Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphomas in which only ~25% of patients experience long-term survival with CHOP chemotherapy. Recently several drugs have been approved for this entity including pralatrexate (P), romidepsin (R), and belinostat which have response rates ranging from 26%-29% as single agents. Based on our demonstration of synergy of P+R in preclinical models of TCL, we initiated a study on the safety and efficacy of P+R in a phase I-II study for relapsed or refractory lymphomas (NCT01947140) and sought to evaluate biological mechanisms of synergy. A 3+3 dose-escalation study started at P 10mg/m2 and R 12mg/m2 with escalation to P 25 mg/m2 and R 14 mg/m2. Patients were treated on 1 of 3 dosing schedules (weekly x 3 Q28D; weekly x 2 Q21D and QOW Q28D). The primary objective was to determine MTD and DLT; the secondary objective included describing ORR (CR+PR). Patients were required to have relapsed lymphoma of any subtype, ECOG PS ≤2, and adequate organ and marrow function. There was no upper limit to the number of prior therapies or transplantation. Twenty-six patients were enrolled and were evaluable for toxicity. Median age was 52 yrs (23-73) and 58% were male. The median number of prior therapies was 3 (range 1-16). Histologies included HL (N=3), B-cell (N=10 of which FL=4) and T-cell (N=13). The median number of cycles completed was 4 (range 1-12). There were 3 DLTs in cohort 4 (P 20mg/m2 & R 12mg/m2given weekly x 2 Q21D) consisting of 2 Grade 3 oral mucositis and 1 Grade 4 sepsis. The QOW Q28D schedule had no mucositis at all dose levels. Patients dosed at the MTD (P 25 mg/m2 & R 12mg/m2 QOW) did not experience any toxicities. The grade 3/4 toxicities reported in >5% of patients were: neutropenia (31%), thrombocytopenia (31%), anemia (23%), oral mucositis (15%), hyponatremia (8%), pneumonia (8%) and sepsis (8%). Twenty-two patients were evaluable for response, 1 patient is currently on therapy. The ORR in the total, non-PTCL and PTCL populations was 59%; 33% (no CR) and 77% respectively. Of the PTCL patients 4/13 (31%) achieved a CR, 6/13 (46%) achieved a PR, and 1 patient had stable disease. The mean duration of response (DOR) for all patients on the study (N=13) was 6.1 months (1.1 - 26.5), for the non-PTCL population (N=3) was 4.8 m (1.1-11) and for the PTCL population (N=10) was 6.55 months (range 1.6 - 26.5 +ongoing). The mean progression free survival (PFS) for all patients on study (N=26) was 4.8 m (.3 - 30.2), for the non-PTCL population (N=13) was 2.8 m (0.3-14.5), and for the PTCL population was 6.13 months (range 1.5 - 30.2 +ongoing). Pharmacokinetic studies were performed for P and R and data for the first 15 patients is presently available for reporting. PK analyses were performed using WinNonLin® to determine Cmax and AUC. Preliminary Cmax results for P 10 mg/m2 and P 15 mg/m2 are 1810+/-1063 ng/mL and 2748+/-995 ng/mL, respectively. Preliminary Cmax results for R 12 mg/m2 and R 14 mg/m2 are 420+/-198 ng/mL and 552+/- 346 ng/mL, respectively. After infusion with P 10 mg/m2 or 15 mg/m2 PK analysis indicate AUC0-24.08h of 3616+/-1543 h*ng/mL and 4104+/-2124 h*ng/mL, respectively. AUC0-28h after treatment with R 12 mg/m2or 14 mg/m2 was 1503+/-1286 h*ng/ml and 2535+/-2560 h*ng/mL. These values are consistent with that observed for both of these drugs in previous studies. Results from the phase I study conclude that the combination of P + R given on the QOW schedule is safe and very well tolerated. These data support the lineage specific activity of the P+R combination, which is currently being expanded to a multicenter Phase II for PTCL. Figure Figure. Disclosures Amengual: Bristol-Myers Squibb: Research Funding; Acetylon Pharmaceuticals, Inc: Research Funding. Sawas:Seattle Genetics: Honoraria; Gilead Sciences: Speakers Bureau. O'Connor:Spectrum: Research Funding; Seattle Genetics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Spectrum: Research Funding; TG Therapeutics: Research Funding; TG Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Celgene: Research Funding.

Download Full-text

Preclinical and Clinical Binding Properties, Internalization Kinetics, and Clinicopathological Activity of Brentuximab Vedotin (SGN-35): A Novel Antibody Drug Conjugate for Anaplastic Large Cell Lymphoma and Classical Hodgkin Lymphoma

Blood ◽

10.1182/blood.v116.21.1789.1789 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1789-1789 ◽

Cited By ~ 5

Author(s):

Jonathan R Fromm ◽

Julie A. McEarchern ◽

Dana Kennedy ◽

Thomas Anju ◽

Andrei R Shustov ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Large Cell ◽

Brentuximab Vedotin ◽

Post Treatment ◽

Binding Properties ◽

Genetics Research ◽

Internalization Kinetics ◽

Cd30 Antigen

Abstract Abstract 1789 Background: Brentuximab vedotin (SGN-35) is a novel anti-CD30 antibody conjugated to the cytotoxic drug monomethyl auristatin E (MMAE) designed to selectively target and kill CD30 expressing neoplasms. This agent has demonstrated antitumor activity in classical Hodgkin lymphoma and CD30-positive T cell lymphoma, yet the binding properties, internalization kinetics, and clinicopathological findings have not been described in tumor specimens derived from treated patients. Therefore, we investigated the activity of SGN-35 on a patient with cutaneous manifestations of systemic ALK-negative anaplastic large cell lymphoma (ALCL), and correlated these results with studies of the activity of SGN-35 on cultured CD30-positive cells lines. Methods and Results: First, we confirmed (using flow cytometry) that SGN-35 and the anti-CD30 antibody clone BerH83 do not compete for binding to CD30. Next, in Karpas 299 (ALCL cell line) and KM-H2 (cell line derived from Hodgkin lymphoma) cells, we quantitatively monitored CD30 expression and cell-surface SGN-35 over time (measured as antigen binding capacity [ABC]/cell), demonstrating maximum antigen expression at 24–48 hours of incubation with 15 μg/ml SGN-35 followed by decrease at 120 hours, consistent with SGN-35-induced internalization (Table). Similar studies were performed on sequential tumor biopsies from a 68 year old male with a 5-year history of ALK-negative ALCL relapsing after 4 prior systemic regimens and radiation, now presenting with multiple pink ulcerated tumorous lesions on his lower extremities as well as bone and nodal involvement. H&E and anti-CD30 immunohistochemical stains of both pretreatment and 24 hrs post-treatment (after the first dose of SGN-35 (1.8mg/kg)-ClinicalTrials.gov identifier NCT01026415) skin punch biopsies showed a dense dermal infiltrate of large CD30-positive neoplastic cells. Biopsy at 48 hrs post-treatment demonstrated numerous apoptotic cells. Antigen density experiments on the patient biopsy specimens and clinical findings correlated with these morphologic results. CD30 antigen density was highest on the patient's cells pretreatment biopsy (1.01 × 105 ABC units/cell) and then decreased after 24 hrs (7.83 × 104 ABC units/cell) and 48 hrs (5.08 × 104 ABC units/cell). Bound SGN-35 was greatest at 24 hrs (2.26 × 103 ABC units/cell) and decreased at 48 hrs (1.40 × 103 ABC units/cell) (Table). The corresponding measured blood concentrations of SGN-35 at 24 hr, 48 hr, and 21 days were 10 μg/mL, 7 μg/mL, and 1 μg/mL, respectively. No CD30 positive cells were present in the day 21 biopsy, precluding evaluation of CD30 antigen density and bound SGN-35. Clinically, the size and prominence of the skin lesions were reduced at day 21 post treatment and biopsy at this time point showed no morphologic or immunohistochemical evidence of the neoplastic population (pathologic complete remission). After the second dose of SGN-35 the patient achieved an 81% reduction in all radiographically measurable lesions (partial response) and achieved a radiographic and cutaneous complete remission after the 5th infusion of this agent. Conclusion: These data are the first to suggest in both cell lines and patient-derived tissues that the internalization kinetics of SGN-35 is rapid with resultant reduction in CD30 expression within the first 48 hours and concurrent apoptosis induction within the targeted cells. While the measured SGN-35 occupancy of CD30 binding sites in the patient is lower than with the cell lines, these data highlight the potential antitumor activity of this agent. The results from the single patient need to be confirmed in a cohort of patients. Nevertheless, such results imply that even with subsaturating occupancy of CD30, thousands of molecules of SGN-35 (each with approximately 4 molecules of MMAE) are likely to be internalized by and potentially kill each targeted cell and may be sufficient to yield pathologic remissions and clinical activity. Disclosures: Fromm: Seattle Genetics: Research Funding. McEarchern:Seattle Genetics: Employment. Kennedy:Seattle Genetics: Employment. Shustov:Seattle Genetics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Gopal:Seattle Genetics: Research Funding.

Download Full-text

Pancreatitis In Patients Treated With Brentuximab Vedotin: A Previously Unrecognized Serious Adverse Event

Blood ◽

10.1182/blood.v122.21.4380.4380 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4380-4380 ◽

Cited By ~ 3

Author(s):

Mitul Gandhi ◽

Andrew M Evens ◽

Timothy S. Fenske ◽

Paul Hamlin ◽

Bertrand Coiffier ◽

...

Keyword(s):

Adverse Event ◽

Abdominal Pain ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Large Cell ◽

Brentuximab Vedotin ◽

Normal Pancreas ◽

Genetics Research ◽

Grade 3

Abstract Background Brentuximab vedotin (BV) is a novel antibody drug conjugate consisting of an anti- CD30 IgG1 antibody, cAC10, linked to monomethylauristatin E, a potent inhibitor of microtubule polymerization. It is approved for treatment of relapsed classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) in the US (FDA; 8/2011) and Europe (EMA; 10/2012). Peripheral neuropathy was the most frequent treatment-related adverse event (AE) in phase II trials, and the most common Grade 3 or higher toxicity apart from cytopenias. Although abdominal pain has been observed in up to 25% of all patients, pancreatitis is a previously unrecognized AE. We now report 8 cases of BV-associated pancreatitis, 2 of them fatal. Methods Following a grade 5 AE from pancreatitis in a patient receiving single-agent BV on an ongoing clinical trial (NCT01476410), collaborating investigators examined their collective cases of pancreatitis associated with BV. Lymphoma specialists at other centers were solicited for additional events. IRB or Ethics Committee approval as required was obtained in all cases. AE's reported to the FDA Adverse Event Report Systems (FAERS) from 6/2011-7/2013 were also examined. Data was collected and analyzed through the Research on Adverse Drug Events and Reports Project. Immunohistochemical staining with the anti-CD30 antibody BER-H2 (DAKO) was performed on residual normal pancreas from one of the fatal cases and normal control pancreas. Results Eight cases of BV-associated pancreatitis were identified by collaborators, and one additional report with limited information was listed in FAERS. Demographic, treatment and AE information for the eight complete cases is detailed in Table 1. In all cases, BV was administered as a single agent. In seven cases, the dosing was 1.8 mg/kg every 21 days with a maximum of 180 mg; in one case, BV was administered weekly at 1.2 mg/kg (days 1,8,15, q 28). Two patients were retreated with BV after resolution of pancreatitis; one had no further evidence of pancreatitis and proceeded to a stem cell transplant, whereas the other patient, having recovered from Grade 4 pancreatitis, experienced a second episode (Grade 3). All patients demonstrated clinical evidence of pancreatitis as manifested by severe abdominal pain and nausea. In addition, all patients had biochemical and radiologic evidence of pancreatitis. Notably, no patient had an antecedent history of excess alcohol use or radiologic evidence of biliary pathology. Two patients developed progressive and fatal multiorgan dysfunction as a consequence of acute pancreatitis. An autopsy performed on one of the two fatalities showed evidence of acute necrotizing pancreatitis as the cause of death; diffuse pancreatic parenchymal necrosis and fat necrosis were seen but no cholelithiasis. Although the anti-CD30 antibody BER-H2 was previously reported to stain normal pancreas (BLOOD 1989 74:1678), routine immunohistochemical staining for CD30 on both the patient pancreas and normal pancreas controls were negative. Conclusion This is the first series describing pancreatitis as a rare, but serious and potentially fatal toxicity related to BV. Pancreatitis has been previously reported with other microtubule inhibitors such as taxanes and vinca alkaloids, but the mechanism, as with BV, remains unclear. Genetic factors that predispose to both acute and chronic pancreatitis have been reported and may underlie a susceptibility to this uncommon complication of treatment with BV. Clinicians prescribing BV should evaluate patients who present with abdominal pain for pancreatitis, and should consider pre-treatment biochemical assessments with serum lipase and/or amylase. Disclosures: Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Evens:Seattle Genetics : Consultancy, Honoraria. Fenske:Seattle Genetics: Consultancy. Hamlin:Seattle Genetics : Consultancy, Honoraria. Coiffier:Millennium Pharmaceuticals : Consultancy. Engert:Millennium Pharmaceuticals : Consultancy. Moskowitz:Seattle Genetics : Research Funding. Ghosh:Millennium Pharmaceuticals : Membership on an entity’s Board of Directors or advisory committees. Petrich:Seattle Genetics : Consultancy, Honoraria, Research Funding. Gordon:Seattle Genetics : Research Funding. Winter:Seattle Genetics : Research Funding.

Download Full-text

Frontline Treatment of CD30+ Peripheral T-Cell Lymphomas with Brentuximab Vedotin in Combination with CHP: 3-Year Durability and Survival Follow-up

Blood ◽

10.1182/blood.v126.23.1537.1537 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1537-1537 ◽

Cited By ~ 4

Author(s):

Steven M Horwitz ◽

Andrei R. Shustov ◽

Andres Forero-Torres ◽

Nancy L Bartlett ◽

Ranjana Advani ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Brentuximab Vedotin ◽

Advisory Committees ◽

Genetics Research ◽

Frontline Treatment ◽

Multi Agent

Abstract Background: Peripheral T-cell lymphomas (PTCL) encompass a subset of aggressive non-Hodgkin lymphomas. Many PTCL tumor cells express the surface marker CD30, including systemic anaplastic large cell lymphoma (ALCL) where CD30 is uniformly expressed. Multi-agent chemotherapy regimens provide inadequate long-term outcomes: complete remission (CR) rates range from 39-53% and 5-year overall survival (OS) rates are 12-49%, depending on subtype. Three-year progression-free survival (PFS) and OS rates are approximately 30% and <40% (excluding anaplastic lymphoma kinase [ALK] -positive), respectively (Vose 2008; Reimer 2009; D'Amore 2012). A phase 1 trial evaluated brentuximab vedotin (ADCETRIS®; BV), a CD30-directed antibody-drug conjugate, in sequence with CHOP or in combination with CHP (CHOP without vincristine) in treatment-naive pts with PTCL, including systemic ALCL (Fanale 2014; ClinicalTrials.gov NCT01309789). We are presenting updated durability data and peripheral neuropathy resolution from the combination-therapy arm of this trial. Methods: The analysis set consisted of patients who received the combination treatment (tx) regimen (BV+CHP; 6 cycles, q3wk, IV). Patients who achieved at least a partial remission (PR) following BV + CHP could subsequently receive up to 10 additional cycles of single-agent BV (1.8 mg/kg q3wk). ALK+ systemic ALCL pts must have had an International Prognostic Index (IPI) score ≥2. Antitumor response assessments were per investigator according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Efficacy endpoints included PFS and OS, which were estimated using Kaplan-Meier methodology. Results: Twenty-six pts received BV + CHP combination treatment. Diagnoses included systemic ALCL (n=19; 3ALK+, 16 ALK-), peripheral T-cell lymphoma-NOS (n=2), angioimmunoblastic T-cell lymphoma (n=2), adult T-cell leukemia/lymphoma (n=2), and enteropathy-associated T-cell lymphoma (n=1). The objective response rate to tx was 100% and CR rate was 88%. Treatment-emergent adverse events (TEAEs) with a severity of at least Grade 3 (≥10% incidence) were febrile neutropenia, neutropenia, anemia and pulmonary embolism with 73% reporting any grade peripheral neuropathy. At the time of this analysis, 20 pts remained on study for long term follow-up (LTFU). The median observation time from first dose was 38.7 months (range, 4.6 to 44.3). The 3-year OS rate was 80% (95% CI: 59, 91 months) and the median PFS was not reached (95% CI: 12.3, -). Twenty one pts received a median of 10 doses (range, 1 to 10) of BV post BV-CHP. Nine/19 (47%) ALCL and 5/7 (71%) non-ALCL pts have not experienced disease progression or death. A Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) was performed for peripheral neuropathy (PN). Eighteen of 19 (95%) patients who received combination therapy experienced either complete resolution (n=7, 37%) or improvement by at least 1 grade level (n=11, 58%) in neuropathy symptoms. There were a total of 44 PN events of which 23 (52%) resolved and 14 (32%) improved. Five pts (19%) who experienced disease progression after completing treatment received subsequent treatment with BV in LTFU, and 3 patients received stem cell transplants (1 autologous, 2 allogenic). There were no patients who received a consolidative stem cell transplant in first remission. Conclusions: Durable remissions were observed with BV in combination with CHP in newly diagnosed pts with PTCL. After over 3 years of follow-up, clinical outcomes compare favorably with historical data in PTCL pts. An ongoing randomized trial with 450 pts is comparing BV+CHP with CHOP for the frontline treatment of CD30+ PTCL (ClinicalTrials.gov NCT01777152). Final resultsfrom this trial are expected in 2017 to 2018. Progression-Free Survival: Brentuximab Vedotin in Combination with CHP Figure 1. Figure 1. Disclosures Off Label Use: Brentuximab vedotin (BV) is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. This study evaluates the use of brentuximab vedotin as a frontline treatment in patients with systemic ALCL or CD30-positive mature T-cell and NK-cell neoplasms in combination with multiagent chemotherapy.. Shustov:Seattle Genetics: Research Funding. Forero-Torres:Seattle Genetics: Research Funding. Bartlett:Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Advani:Genetech: Consultancy; Seattle Genetics, Inc.: Research Funding. Pro:Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses. Chen:Genentech: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau. Davies:Takeda: Honoraria; Seattle Genetics: Research Funding. Illidge:Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Kennedy:Seattle Genetics,Inc: Employment, Equity Ownership, Honoraria, Speakers Bureau. Fanale:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding.

Download Full-text