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

Blood ◽  
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.

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

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1537-1537 ◽  
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.

Event-Free Survival at 12 Months and Subsequent Overall Survival in Patients with Peripheral T-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1501-1501
Author(s):  
Matthew J Maurer ◽  
Fredrik Ellin ◽  
James Cerhan ◽  
Stephen Ansell ◽  
Brian K Link ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
T Cell Lymphomas

Abstract Background: Peripheral T-Cell lymphomas (PTCLs) constitute approximately 10% of lymphoid malignancies and consist of several distinct entities based on pathologic and clinical characteristics. With the exception of a few subtypes (e.g., ALK-positive anaplastic large cell lymphoma (ALCL) and some primary cutaneous or leukemic forms of PTCL), a majority of PTCLs are aggressive as characterized by poor treatment response, rapid disease progression and poor overall survival. We have shown that landmark timepoints of event-free survival after diagnosis can stratify subsequent overall survival (OS) in diffuse large B-cell and follicular lymphoma. Here we evaluate this approach in newly diagnosed aggressive PTCLs treated with anthracyline-based or related chemotherapy. Methods. Newly diagnosed PTCL patients were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2012. Clinical data were abstracted from medical records using a standard protocol. For this analysis, we included patients receiving anthracycline-based or other multiagent chemotherapy for the following PTCL subtypes: ALK-negative ALCL (N=24); angioimmunoblastic T-cell lymphoma (AITL, N=34); PTCL, not otherwise specified (NOS; N=60); enteropathy-associated T-cell lymphoma (EATL, N=8); extranodal NK/T-cell lymphoma, nasal type (ENKTL, N=11); and hepatosplenic T-cell lymphoma (HSTCL, N=1). Patients were prospectively followed, and event-free survival (EFS) was defined as time from diagnosis to progression, re-treatment, or death due to any cause. Landmark EFS timepoints were assessed at 12 (EFS12) and 24 (EFS24) months after the date of diagnosis. Subsequent OS was defined as time from a specific endpoint (diagnosis, event or EFS landmark). Replication was performed in a population-based cohort of T-cell lymphomas diagnosed from 2000-2009 from the Swedish Lymphoma Registry. Results. 138 eligible patients were enrolled in the MER from 2002-2012, the median age at diagnosis was 58 years (range, 19-88), 66% were male, 73% had Stage III-IV disease, and 33% had IPI 0-1. At a median follow-up of 47 months (range 11-120), 87 patients (63%) had an event and 70 patients (51%) had died. From diagnosis, only 60 patients were event-free at 12 months (EFS12 45%). Patients who failed to achieve EFS12 had a poor subsequent OS from event (median OS = 6.8 months, 95% CI: 5.3-14.0, figure 1). In contrast, patients who achieved EFS12 had a favorable subsequent OS (median unreached, figure 2). Of the 427 eligible patients in the Swedish registry, the median age at diagnosis was 66 years (range, 18-88), 63% were male, 68% had Stage III-IV disease, and 25% had IPI 0-1. PTCL subtypes were: ALK-negative ALCL (N=89); AITL (N=80); PTCL, NOS (N=183); EATL (N=44); ENKTL (N=24); and HSTCL (N=7). At a median follow-up of 86 months (range 40-158), 333 patients (79%) had an event and 316 patients (74%) had died. From diagnosis, 183 patients were event-free at 12 months (EFS12 44%). Similar to the MER cohort, Swedish patients failing EFS12 had poor subsequent survival (median OS = 3.7 months, 95% CI: 2.9-5.3, figure 1). Swedish patients achieving EFS12 had a favorable subsequent OS (median OS = 89 months, figure 2). Similar results were obtained when conducting landmark analysis at 24 months after diagnosis (EFS24). Conclusion. Relapse and re-treatment events within the first 12 months of diagnosis are associated with very poor OS in PTCL treated with anthracyclines or related chemotherapy, while patients achieving EFS12 have encouraging subsequent OS. Stratifying patients into prognostically distinct subsets using EFS12 may help focus biologic and biomarker studies. EFS12 has potential as an early endpoint for studies of newly diagnosed PTCL. Further investigation of determinants related to post-EFS12 survival is needed. Disclosures Maurer: Kite Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding. Relander:Respiratorius: Patents & Royalties: valproate for DLBCL.

scholarly journals Central Nervous System Involvement in Peripheral T-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5293-5293
Author(s):  
Sangeetha Gandhi ◽  
N. Nora Bennani ◽  
Sonia Fortin ◽  
Thomas M. Habermann ◽  
Patrick Johnston ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Advisory Board ◽  
T Cell Lymphoma ◽  
High Dose ◽  
Cns Involvement ◽  
Advisory Committees ◽  
Genetics Research

Background: Central nervous system (CNS) involvement by peripheral T cell lymphoma (PTCL) is a rare condition. Among primary CNS lymphomas, only 2% are secondary to PTCL, while the risk of CNS relapse in all cases of PTCL is estimated at 2% to 6%. Little is known about the presentation and outcomes of PTCL patients with CNS involvement given the rarity of this entity. In this study, we describe patient characteristics, histology, and clinical course of patients with CNS involvement by PTCL. Methods: The Mayo Clinic Lymphoma Database was used to identify PTCL patients with primary or secondary CNS involvement seen at our institution between 2000 and 2018. A total of 12 patients were identified and their medical records were reviewed for patient and disease characteristics, CNS-directed treatment modality, and outcomes. The Kaplan-Meier method was used for time-to-event analysis. Results: The median age at CNS diagnosis was 63 years (range 41 to 76) and 11 (93%) patients were male. The histological diagnoses were PTCL, NOS in 9 (75%) patients, enteropathy-associated T-cell lymphoma in 2 (17%) patients, and angioimmunoblastic T-cell lymphoma in 1 (8%) patient. Five patients presented with primary T-cell CNS lymphoma (all with a PTCL, NOS histology), while the remaining 7 (58%) patients also had systemic involvement. All patients presented with neurologic symptoms at the time of CNS involvement diagnosis including: focal motor deficits in 6 patients (unilateral upper extremity weakness, gait impairments, and hemiparesis), cognitive decline in 5 patients (memory impairments, reduced attention, and confusion), headache in 4 patients, and seizure in 3 patients. The CNS disease location included the brain parenchyma in 9 (75%) patients, leptomeninges in 1 (8%) patient, and lumbar plexus in 1 (8%) patient. One patient (8%) had positive CSF finding only without radiologic evidence of involvement. CSF analysis was performed in 11 patients. Elevated protein levels were noted in 3 (27%) patients, malignant cells in 2 (18%), and no clear abnormalities in the remaining 6 (55%) patients. Concomitant bone marrow involvement was seen in only 1 patient. Elevated LDH was seen in 2 patients. The a median LDH was 195 U/L (range 139 to 4,360) The most common CNS-directed therapies were: high-dose methotrexate (MTX)-based regimens in 8 (67%) patients, including high-dose MTX in combination with temozolomide (n=2), or cytarabine and thiotepa (n=2). Intrathecal MTX, temozolomide and dexamethasone, lenalidomide, high-dose steroids, and surgical resection were the treatment modality used for one patient each. At a median follow up of 18 months, eight (75%) out of 12 patients were not alive at the time of last follow up. The median overall survival (OS) from diagnosis was 16 months (95% CI: 2.8-173). The median progression free survival (PFS) from initiation of CNS-directed therapy was 9 months (95% CI: 1.6-33) (figure). Four patients had a PFS longer than 12 months. These 4 patients were treated with: temozolomide/dexamethasone, high-dose MTX, lenalidomide, and high-dose MTX followed by cytarabine/thiothepa. Conclusion: CNS involvement by T-cell lymphoma is a rare complication that carries a poor prognosis. Early onset of neurologic symptoms should trigger prompt investigation of CNS involvement. Despite the short OS and PFS, some patients may achieve a relatively longer disease free interval. Disclosures Bennani: Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board. Cerhan:Celgene: Research Funding; NanoString: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Nowakowski:Celgene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Curis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; NanoString: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees. Ansell:Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding. Paludo:Celgene: Research Funding; Verily Life Sciences: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding.

scholarly journals Weekly Dosing Schedule of Brentuximab Vedotin in Mycosis Fungoides/Sezary Syndrome and Aggressive T Cell Lymphomas

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-22
Author(s):  
Megan Lee ◽  
Molly Schiffer ◽  
Iris Isufi ◽  
Scott F. Huntington ◽  
Mina L. Xu ◽  
...  
Keyword(s):  
T Cell ◽  
Clin Oncol ◽  
Mycosis Fungoides ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Brentuximab Vedotin ◽  
T Cell Lymphoma ◽  
Weekly Schedule ◽  
Dosing Schedule ◽  
T Cell Lymphomas

Introduction While the approved dose of brentuximab in T cell lymphomas has been every 3 weeks on a 1.8 mg/kg schedule, earlier studies exploring weekly dosing showed that a dose of 1.2 mg/kg on a weekly dosing (every 3 out of 4 weeks) in pts with Hodgkin's lymphoma and hematologic malignancies may improve cancer response rates while still having manageable side effects3. We explored the weekly dosing schedule in 37 pts (pts) with mycosis fungoides/Sezary syndrome (MF/SS) and aggressive T cell lymphomas and compared to our experience with every 3 week dosing in 36 pts to evaluate tolerability and efficacy of the weekly schedule.. Methods We reviewed charts of 67 pts, 36 received dosing q 3 weeks and 37 received a dose weekly for 3 consecutive weeks on a 4-week schedule. Pts included MF/SS (n=35), gamma delta T cell lymphoma (n=2), anaplastic large cell lymphoma (n=12), Peripheral T cell Lymphoma (n=10), angioimmunoblastic T cell lymphoma (n=4), adult T cell leukemia (n=2), and NK-T cell lymphoma. Pts were treated with brentuximab vedotin at a dose of either 1.8 mg/kg every 3 weeks or 1.2 mg/kg weekly x 3 every 4 weeks. CD30 expression was scored by the pathologist in tumor biopsies as high (&lt;50%), low (5-10%), or intermediate (&gt;10%-49%). Toxicity data was recorded from the medical records and data analyzed descriptively. Results Of 67 pts in this study, the average age was 61. Doses were 1.8 mg/kg for the q 3 week schedule and 0.75 to 1.2 mg/kg for the weekly x 3 schedule. Cycles were 3-47 for q 3 weeks and 1-9.7 for weekly dosing. CD30 expression was high in 13% of pts, low in 43%, and absent in 6% with equal distribution between the weekly and q 3 week cohorts, as shown in Table 1. Dose adjustments were made in 67% of q 3 week and 61% of weekly pts for neurotoxicity (n=28), with a higher incidence in the q 3 week pts compared to those with weekly dosing (75% vs 53%, p=0.01) . Discontinuation for progression (25% vs 30%) was similar for both groups. In the weekly group, 8 pts had a stem cell transplant, including allogeneic transplantation in 3. Conclusion In the Phase II registration trial of brentuximab vedotin 1.8 mg/kg q3 weeks, 41% of pts had neuropathy (severe in 12%). 1 Forty two percent of discontinuations were for neuropathy. In our weekly schedule, incidence of neuropathy was lower and led to fewer treatment discontinuations. Our retrospective data shows that Brentuximab vedotin is well tolerated on a weekly dosing schedule and has activity in pts with MF/SS and aggressive T cell lymphomas. As in prior studies, responses were seen with low CD30 expression4, 5. Prospective clinical trials with a self-reported neurotoxicity scale and quality of life instruments should be performed address the impact of more frequent, lower doses of brentuximab vedotin on patient outcomes. 1 Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T et al.J Clin Oncol 2012; 30(18): 2190-2196. doi: 10.1200/JCO.2011.38.0402 2 Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P et al.Lancet 2017; 390(10094): 555-566. doi: 10.1016/S0140-6736(17)31266-7 3 Fanale MA, Forero-Torres A, Rosenblatt JD, Advani RH, Franklin AR, Kennedy DA et al.Clin Cancer Res 2012; 18(1): 248-255. doi: 10.1158/1078-0432.CCR-11-1425 4 Duvic M, Tetzlaff MT, Gangar P, Clos AL, Sui D, Talpur R. J Clin Oncol 2015; 33(32): 3759-3765. doi: 10.1200/JCO.2014.60.3787 5 Kim YH, Tavallaee M, Sundram U, Salva KA, Wood GS, Li S et al.J Clin Oncol 2015; 33(32): 3750-3758. doi: 10.1200/JCO.2014.60.3969 Figure Disclosures Huntington: Pharmacyclics: Honoraria; DTRM: Research Funding; Genentech: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Bayer: Consultancy, Honoraria; AbbVie: Consultancy; Astrazeneca: Honoraria. Xu:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals CD70 Expression in Mature T-Cell Lymphomas

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4493-4493
Author(s):  
Mario L. Marques-Piubelli ◽  
Luisa Solis Soto ◽  
Swaminathan Padmanabhan Iyer ◽  
Jason Sagert ◽  
Minh Thu Pham ◽  
...  
Keyword(s):  
T Cell ◽  
Mycosis Fungoides ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Advanced Age ◽  
Oncology Research ◽  
T Cell Lymphomas ◽  
Pathologic Classification

Abstract Introduction Mature T-cell lymphomas (TCLs) represent about 15% of the non-Hodgkin lymphomas in U.S. and are a heterogeneous group of neoplasms. TCLs usually have poor outcomes and are resistant to conventional chemotherapy regimens. Therefore, there is a need for identifying biomarkers that could translate into effective novel treatments. CD70 is the TNF superfamily ligand of CD27 and it is being explored as a potential target in CAR-T therapy against TCLs and other neoplasms. Although CD70 expression has been documented in TCL cell lines, thus providing a potential rationale for its use as a therapeutic target, the expression of CD70 among the most frequent TCL subtypes in patient samples has not been previously evaluated. Methods Patients with de novo and/or relapsed mature TCLs diagnosed between 01/2010 and 06/2020 and with available tissue sections were included in the study. The assessment of CD70 expression was performed by immunohistochemistry (IHC) using a novel proprietary antibody developed by CRISPR Therapeutics. CD70 expression was scored using % of expression, intensity (negative, +1, +2, and +3) and H-score {H-score = [(%positive cells intensity 1+) x 1] + [(%positive cells intensity 2+) x 2] + [(%positive cells intensity 3+) x 3]} in neoplastic cells (Figure 1). Clinicopathologic characteristics were collected retrospectively and included age, sex, staging, biopsy site, WHO pathologic classification, immunophenotype, presence of other malignancies, treatment status, disease progression/relapsed, and follow-up. These characteristics were compared with CD70 expression using ANOVA or non-parametric analysis. Overall-survival (OS) was estimated using Kaplan-Meier method and compared using log-rank. A p&lt; 0.05 was considered statistically significant. Results One hundred thirty-six patient samples representing the major subtypes of the 4 categories of mature TCLs were included [nodal TCLs (n=64; including PTCL Th1, and Th2 subtypes and angioimmunoblastic T cell lymphoma - AITL), extranodal (n=35; including primary intestinal lymphomas), cutaneous (n=24; including mycosis fungoides (MF) with large cell transformation), and leukemic (n=13; including adult T cell leukemia/lymphoma)]. Most patients were male (58.8%), in the 6 th or 7 th decade (47.1%), with advanced stage IV (55.7%), no previous malignancies (69.9%) and previously treated (57.2%); 59 of which (88%) received two or more lines of treatment. The median expression of CD70 was 40% (ranged from 0 to 100%) and the median H-score was 110 (ranged from 0 to 300) and was significantly higher (p= 0.006) in peripheral T-cell lymphoma, NOS, primary cutaneous TCLs (non-mycosis fungoides), and AITL (180, 150, and 150, respectively) (Figure 1). The expression of CD70 was more frequent in nodal and extranodal subtypes (including skin), compared to leukemic TCLs (p= 0.005). The expression of CD70 was associated with advanced age at the diagnosis (p= 0.003), CD2 expression (p= 0.01), CD3 expression (p= 0.001), CD16 negativity (p= 0.03), and absence of ALK-1 expression (p= 0.005). After a median follow-up of 19 months (range: 1 - 300 months), 42% of the patients died of disease. The median OS was 76 months (CI95, 38.5 - 113.4 months) and it was not associated with CD70 expression. Conclusions CD70 was highly expressed in most mature TCLs and it was negative in most ALK-positive ALCL. Its expression was associated with nodal and extranodal subtypes, advanced age, expression of CD2, CD3, and negativity for CD16. Therefore, CD70 can be used as a potential biomarker and a target in clinical trials of patients with mature TCLs. Figure 1 Figure 1. Disclosures Iyer: CRISPRX: Research Funding; Seattle Genetics: Research Funding; Rhizen: Research Funding; Merck: Research Funding; Legend: Research Funding; Innate: Research Funding; Spectrum: Research Funding; Trillium: Research Funding; Astra Zeneca: Research Funding; Yingli: Research Funding; Cyclacel: Research Funding. Sagert: CRISPR Therapeutics: Current Employment. Pham: CRISPR Therapeutics: Current Employment. Tipton: CRISPR Therapeutics: Current Employment. Vega: i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, and the Society of Hematology Oncology: Research Funding; CRISPR Therapeutics and Geron: Research Funding.

scholarly journals A Real World Experience of Combined Treatment with Romidepsin and Azacitidine in Patients with Peripheral T-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4550-4550
Author(s):  
Matko Kalac ◽  
Constantine S. Tam ◽  
Mendel Goldfinger ◽  
Zhengrui Xiao ◽  
Francesca Montanari ◽  
...  
Keyword(s):  
T Cell ◽  
Real World ◽  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Cell Transplant ◽  
Publicly Traded ◽  
Peripheral T Cell Lymphoma ◽  
Advisory Committees ◽  
Pet Ct

Abstract BACKGROUND Patients with peripheral T-cell lymphoma (PTCL) lack good treatment options, particularly in the relapsed and refractory setting (Mak V et al. J Clin Oncol 2013). The development of the targeted therapies in PTCL has been lagging behind those developed for B cell lymphomas. Our work suggested that combinations of epigenetic therapies can be a safe and effective approach for patients with PTCL, particularly those with T-cell lymphomas with a follicular helper phenotype (Marchi E et al. Br. J Haematol 2015; O'Connor O.A. et al; Blood 2019; Falchi L et al. Blood 2020). While the reason for this is not clear, it is thought recurrent mutations in epigenetic factors, including Ten-Eleven Translocation-2 (TET2), DNA methyl transferase-3A (DNMT3A) and isocitrate dehydrogenase-2 (IDH2) may contribute for their increased vulnerability (Couronné L. et al. N Eng J Med 2012; Lemonnier F et al. Blood 2012). Despite these presumptions, a direct explanation for the sensitivity to epigenetic based treatment remains to be established. OBJECTIVES To evaluate the merits of romidepsin plus subcutaneous azacitidine in patients with PTCL when administered in a 'real-world' scenario. METHODS We retrospectively identified PTCL patients that were treated with azacitidine and romidepsin outside of a clinical trial based upon queries regarding off study use. The study was reviewed and approved by each Medical Center Institutional Review Board. We have identified 13 patients world-wide whose pretreatment characteristics are shown in Table 1. These patients were treated using 3 different schedules: Schedule A: azacitidine 75mg/m2 s.c. on days 1-7, romidepsin 14 mg/m2 on day 1, 8 and 15 of a 28 day cycle (total of 6 patients); Schedule B: azacitidine 75mg/m2 s.c. on days 1-5, romidepsin 14 mg/m2 on day 8, 15 and 22 of a 35 day cycle; and Schedule C (total of 2 patients): azacitidine 75mg/m2 s.c. on days 1-7, romidepsin 12-14 mg/m2 on day 8, 15 and 22 of a 28 day cycle (total of 5 patients). RESULTS We retrospectively identified 13 patients that were treated with romidepsin and azacitidine off study. Ten patients had angioimmunoblastic lymphoma (AITL), 2 had adult T-cell leukemia/lymphoma (ATLL) and 1 had PTCL-NOS. Eight of the 13 patients had next generation sequencing performed. Most common mutations found were those of TET2 (5 pts), RHOA (4pts), IDH2 (3pts) and DNMT3A (1 pt). One ATLL patient had mutations in TRAF3, FAT1 and MED12. Among these 13 patients, overall response rate (ORR) was 84% and the complete response rate (CR) was 61%. Median number of cycles was 3 (range 1-12). Treatment was well tolerated but notable adverse effects included nausea, fatigue, rash, neutropenia and thrombocytopenia. One patient experienced febrile neutropenia while another had pulmonary infiltrates (differential diagnosis included drug toxicity versus infection). Thrombocytopenia was the most common reason for dose reduction of romidepsin (to 12mg/m2) or its omission on day 8, 15 or 22. In 3 patients, azacitidine and romidepsin were used to achieve remission prior to allogeneic transplant (range of cycles 1-3), with all 3 patients were in CR at their last disease assessment. One patient died of transplant related mortality 8 months after his allogeneic stem cell transplant. There was 1 patient with AITL (treatment naïve) noted to have progression of disease at first imaging following 2 cycles of romidepsin and azacitidine. On the day of her PET/CT, she was however diagnosed with symptomatic Covid19 infection and was hospitalized. A repeat PET/CT 6 weeks later (without any additional lymphoma treatment) revealed PR. CONCLUSIONS Subcutaneous azacitidine and romidepsin administered in a 'real-world' situation is highly effective in patients with relapsed PTCL with tolerable toxicity, and can be used to successfully bridge patients to stem cell transplant. Notably, the efficacy was similar to the one reported on a clinical study with oral azacitidine and romidepsin. Figure 1 Figure 1. Disclosures Kalac: Astra Zeneca: Consultancy; Kyowa Kirin: Consultancy; Gilead: Consultancy; Johnson and Johnson: Research Funding; Guidepoint: Consultancy; GLG: Consultancy. Tam: Beigene: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Loxo: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Montanari: Seattle Genetics: Research Funding. O'Connor: Servier: Research Funding; Mundipharma: Honoraria; Myeloid Therapeutics: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kymera: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; BMS: Research Funding; Merck: Research Funding; TG Therapeutics: Current Employment, Current equity holder in publicly-traded company. Marchi: BMS: Research Funding; Astex: Research Funding; Merck: Research Funding; Myeloid Therapeutics: Honoraria; Kyowa Kirin: Honoraria; Kymera Therapeutics: Other: Scientific Advisor.

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

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-4
Author(s):  
Tycel J. Phillips ◽  
Kristina Yu-Isenberg ◽  
Nicholas Liu ◽  
Andy Surinach ◽  
Carlos Flores ◽  
...  
Keyword(s):  
Propensity Score ◽  
Propensity Score Matching ◽  
Real World ◽  
Research Funding ◽  
Index Date ◽  
Primary Prophylaxis ◽  
Brentuximab Vedotin ◽  
Stage Iii ◽  
Publicly Traded ◽  
Pet Ct

Introduction: In the phase 3 ECHELON-1 study (NCT01712490), treatment with brentuximab vedotin, doxorubicin, vinblastine and dacarbazine (A+AVD) significantly improved modified progression-free survival in patients with newly-diagnosed stage III or IV classical Hodgkin lymphoma (cHL) compared with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). The results of ECHELON-1 supported the March 2018 US FDA approval of A+AVD for adults with frontline (FL) stage III or IV cHL. To optimize outcomes for patients with stage III or IV cHL receiving ABVD, the current National Comprehensive Cancer Network guidelines recommend an interim PET/CT imaging (PET2) at the end of cycle 2 to inform escalation or de-escalation of therapy. In the current study we describe the real-world patient characteristics, supportive care use, and PET2 utilization in A+AVD and ABVD patients outside of the clinical trial setting in the US. Methods: Using medical and pharmacy claims data in the US Symphony Health Solutions database, a retrospective cohort analysis of patients with cHL receiving FL A+AVD or ABVD was conducted to compare treatment and utilization characteristics. Patients ≥18 years with one inpatient or two outpatient ICD-9 or 10 cHL diagnosis codes, newly prescribed A+AVD or ABVD (index date) between March 2018 and January 2020, and with ≥6 months continuous activity before and a minimum of 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 4259 patients met inclusion criteria (1002 A+AVD and 3257 ABVD) with a median follow-up duration of 14 and 15 months, respectively. In unmatched cohorts, median age at index date of A+AVD vs ABVD was 48 and 39 years, with 41% and 52% of patients between the ages of 18-39, and 34% vs 20% age ≥60, respectively. Patients on A+AVD had higher comorbidity burden across all conditions included in the Charlson Comorbidity Index, with 41% vs 33% of ABVD patients reporting 1+ comorbidities, with chronic pulmonary disease (18% vs 14%, p=0.006) being the most prevalent (Table 1). Following propensity score matching, A+AVD patients received significantly higher granulocyte-colony stimulating factor (G-CSF), 90% vs 44%, with 80% and 20% as primary prophylaxis (p&lt;0.001) vs ABVD, respectively. In the A+AVD and ABVD cohorts, only 31% and 38% of patients underwent interim PET2 restaging, respectively (Table 2). In ABVD patients, 44% who received an interim PET2 and 33% who did not receive an interim PET2 de-escalated to AVD. The rate of subsequent therapy was similar between A+AVD and ABVD (13% vs 11%; p=0.163); of the patients who received subsequent therapy, 43% of ABVD patients received a brentuximab vedotin-containing regimen and 19% of A+AVD were retreated with a brentuximab vedotin-containing regimen. Conclusions: In this first real-world evaluation, patients with cHL receiving FL A+AVD were older, had higher burden of comorbidities, utilized recommended G-CSF as primary prophylaxis, and had similar rate of subsequent therapy compared to ECHELON-1 patients. Only about one third of patients underwent interim PET2 restaging, and less than half of the patients who started on ABVD were de-escalated to AVD. Confounding by unmeasured characteristics, such as disease stage and PET/CT results, is a limitation of this and any retrospective study based on claims data. However, this hypothesis-generating analysis suggests the need to: 1) control for patient characteristics (e.g., age, comorbidities) in comparative real-world analyses; 2) understand reasons for the lack of PET/CT use; and 3) evaluate the actual use of the interim PET2 to escalate or de-escalate treatment in patients with cHL. The need to optimize treatment outcomes while maximizing short- and long-term treatment efficacy and safety is paramount. Characteristics and management of this real-world population with cHL differed from those in the ECHELON-1 trial, demonstrating the importance of retrospective studies in assessing the impact of new regimens on clinical practice and in identifying areas for further education of practitioners. Disclosures Phillips: Beigene: Consultancy; Karyopharm: Consultancy; AstraZeneca: Consultancy; Incyte: Consultancy, Research Funding; Seattle Genetics: Consultancy; BMS: Consultancy; Bayer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Cardinal Health: Consultancy. Yu-Isenberg:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Liu: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. Fanale:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Burke:Verastem: Consultancy; Astra Zeneca: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Roche: Consultancy; Bristol Myers Squibb: Consultancy; Gilead: Consultancy; Seattle Genetics: Speakers Bureau; Celgene: Consultancy; Kura: Consultancy; Epizyme: Consultancy; Adaptive: Consultancy; Morphosys: Consultancy; Adaptive Biotechnologies: Consultancy.

Three-Year Survival Results From An Ongoing Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory Systemic Anaplastic Large Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1809-1809 ◽  
Author(s):  
Barbara Pro ◽  
Ranjana H. Advani ◽  
Pauline Brice ◽  
Nancy L. Bartlett ◽  
Joseph D. Rosenblatt ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Objective Response ◽  
Brentuximab Vedotin ◽  
Observation Time ◽  
Board Membership ◽  
Equity Ownership

Abstract Background Systemic anaplastic large cell lymphoma (sALCL) is a CD30-positive aggressive subtype of mature T-cell lymphoma. Approximately 40–65% of patients (pts) with sALCL develop recurrent disease after frontline treatment. Outcomes are poor for pts with relapsed T cell lymphomas, including sALCL, with a median overall survival (OS) of 7.0 mos (Mak et al, 2013). Few effective therapies are available to address this unmet need. Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate comprising a CD30-directed antibody attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. A phase 2 study evaluated the efficacy and safety of brentuximab vedotin in 58 pts with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047). Long-term follow-up data from this ongoing trial are presented. Methods Pts received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results In this heavily pre-treated pt population with poor prognosis, 62% had primary refractory disease (defined as no complete remission [CR] or relapse within 3 mos of frontline therapy), 26% had failed a prior autologous stem cell transplant (SCT), and 72% had ALK-negative disease. As previously reported, the ORR with brentuximab vedotin was 86% (50 of 58 pts) and the CR rate was 59% (34 of 58 pts). At the time of this analysis (datacut June 2013), all pts had discontinued treatment and the median observation time from first dose was 33.4 mos (range, 0.8-45.6). The median duration of objective response for all pts was 13.2 mos (95% CI: 5.7, 26.3) and the median duration of response for pts who obtained a CR was 26.3 mos (95% CI: 13.2, -). Of the 34 pts who achieved a CR, 16 (47%) remained in remission at the time of this analysis. Thirty-seven of 58 pts (64%) were alive at the time of last follow up. The median progression-free survival (PFS) for all pts was 14.6 mos and the median OS has not yet been reached. The estimated 3-year survival rate was 63% (95% CI: 51%, 76%). Median OS for pts who obtained a CR has not yet been reached while median OS for pts who did not obtain a CR was 7.7 mos (95% CI: 4.5, 13.7). Median OS for pts with PET-negative disease at Cycle 4 has not yet been reached while median OS for pts with PET-positive disease at Cycle 4 was 14.6 mos. After discontinuing treatment in the study, 17 pts (29%) received a hematopoietic SCT (9 allogeneic, 8 autologous). The median PFS has not yet been met for the group of pts who achieved a CR and received a subsequent SCT (95% CI: 14.6, -), while the median PFS for the group who achieved a CR and did not receive post-treatment SCT was 18.4 mos (95% CI: 8.4, 33.7). As previously reported, adverse events (AEs) in ≥20% of pts were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). The majority of AEs were Grade 1 or 2 in severity. Conclusions After a median observation time of 33.4 mos from first dose of brentuximab vedotin, 64% of pts with relapsed or refractory sALCL were alive at the time of last follow up and the median OS has not yet been reached. Pts who achieved a CR with brentuximab vedotin experienced longer OS than pts who did not achieve a CR and early PET-negative status appeared to be important for long-term survival. These long-term follow-up results further underscore the durability of clinical benefit obtained with brentuximab vedotin. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-positive mature T-cell lymphomas, including sALCL (ClinicalTrials.gov #NCT01777152). Disclosures: Pro: Seattle Genetics, Inc.: Advisory/Scientific board membership and travel expenses Other, Consultancy, Research Funding. Advani:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Research Funding. Brice:Seattle Genetics, Inc.: Honoraria, Research Funding. Bartlett:Seattle Genetics, Inc.: Advisory/Scientific Board Membership and Travel Expenses Other, Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Fanale:Seattle Genetics, Inc.: Advisory/Scientific Board Membership and Travel Expenses Other, Consultancy, Honoraria, Research Funding. Connors:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Huebner:Takeda: Equity Ownership; Takeda Cambridge US: Employment. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Honoraria, Research Funding, Speakers Bureau.

Four-Year Survival Data from an Ongoing Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3095-3095 ◽  
Author(s):  
Barbara Pro ◽  
Ranjana Advani ◽  
Pauline Brice ◽  
Nancy L. Bartlett ◽  
Joseph D. Rosenblatt ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Sensory Neuropathy ◽  
Large Cell ◽  
Brentuximab Vedotin ◽  
Observation Time ◽  
Employment Equity ◽  
Equity Ownership

Abstract Background: Systemic anaplastic large cell lymphoma (sALCL) is a CD30-positive aggressive subtype of mature T-cell lymphoma. Approximately 50% of patients (pts) with sALCL develop recurrent disease after frontline treatment (Savage, 2008). Outcomes have historically been poor for pts with relapsed T-cell lymphomas, including sALCL, with a median overall survival (OS) and progression-free survival (PFS) of 5.5 months (mos) and 3.1 mos, respectively (Mak, 2013). A phase 2 study evaluated the efficacy and safety of brentuximab vedotin, a CD30-directed antibody-drug conjugate, in pts with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047). Four-year follow-up data from this ongoing trial are presented. Methods: Pts received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. Response was assessed according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Assessments of response and durability of response per an independent review facility (IRF) have been previously reported. Following a protocol amendment that removed the requirement for routine CT scanning during the follow-up period, response is now being assessed per the investigator. Survival and disease status are being assessed every 3 mos for 2 years, every 6 mos during years 3 to 5, and annually thereafter. CT scans are required if progression is suspected clinically. Results: The enrolled population of 58 pts was heavily pretreated with poor prognosis. As previously reported, 72% of patients had ALK-negative disease, 62% had primary refractory disease (defined as no complete remission [CR] or relapse within 3 months of frontline therapy), and 26% had failed a prior autologous stem cell transplant (SCT). Pts had received a median of 2 prior systemic chemotherapy regimens (range, 1 to 6). Per investigator, the objective response rate (ORR) with brentuximab vedotin was 83% (48 pts) and the CR rate was 62% (36 pts), which were similar to the previously reported ORR (86%) and CR (59%) rates per IRF. At the time of this analysis (data cut June 2014), all pts had discontinued treatment and the median observation time from first dose was 46.3 mos (range, 0.8 to 57.7). Sixty-two percent (36 of 58) of pts were alive at last follow-up and the estimated 4-year survival rate by Kaplan-Meier analysis was 64% (95% CI: 51%, 76%). Median OS by best clinical response was CR (n=36): median not reached; partial remission (n=12): 11.6 mos; stable disease (n=4): 6.9 mos; and progressive disease (n=2): 4.2 mos. Median PFS was 20.0 mos (95% CI: 9.4, – [range, 0.8 to 54.9+]) for all pts and was not reached in pts with CR. Median PFS for pts with ALK-positive (25.5 mos) and ALK-negative (20.0 mos) disease were similar. Median PFS for pts with PET-negative disease at Cycle 4 (n=28) was not reached, whereas median PFS for pts with PET-positive disease at Cycle 4 (n=20) was 6.7 mos. After discontinuing treatment, 18 pts received a hematopoietic SCT (9 allogeneic, 9 autologous). The median PFS for the pts who achieved a CR and did not receive a post-treatment SCT (n=21) was 37.7 mos (95% CI: 14.1, - [range, 2.8 to 51.1+]) and the median PFS was not reached for the pts who achieved a CR and received a subsequent SCT (n=15) (95% CI: 9.5, - [range, 8.0 to 54.4+]). Of the 36 pts who achieved CR per the investigator, 17 (47%) remain in follow-up free of progression: 10 pts received a consolidative SCT following treatment with brentuximab vedotin and 7 pts received no further therapy after completing brentuximab vedotin treatment. As previously reported, adverse events (AEs) in ≥20% of pts were peripheral sensory neuropathy, nausea, fatigue, pyrexia, diarrhea, rash, constipation, and neutropenia. AEs ≥ Grade 3 that occurred in ≥5% of pts were neutropenia, thrombocytopenia, peripheral sensory neuropathy, anemia, recurrent ALCL, and fatigue. Conclusions: After a median observation time of approximately 4 years from first dose of brentuximab vedotin, the 4-year survival rate was 64%. Forty-seven percent of patients with CR remain in follow-up with no evidence of progression, suggesting that brentuximab vedotin treatment may be curative for some patients. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-positive mature T-cell lymphomas, including sALCL (ClinicalTrials.gov #NCT01777152). Figure 1 Figure 1. Disclosures Pro: Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other. Advani:Takeda Pharmaceuticals International Co.: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Janssen Pharmaceuticals: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Other, Research Funding. Brice:Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Roche: Honoraria. Bartlett:Genentech: Research Funding; ImaginAb: Research Funding; Celgene: Research Funding; MedImmune: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Other, Research Funding; Janssen: Research Funding; AstraZeneca: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding; University of Miami: Employment. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Consultancy, Honoraria. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Onyx: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau. Ramchandern:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Other, Research Funding. Connors:Seattle Genetics, Inc.: Research Funding; Roche: Research Funding. Wang:Seattle Genetics, Inc.: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Research Funding.

scholarly journals Five-Year Survival Data from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4144-4144 ◽  
Author(s):  
Barbara Pro ◽  
Ranjana H Advani ◽  
Pauline Brice ◽  
Nancy L Bartlett ◽  
Joseph D Rosenblatt ◽  
...  
Keyword(s):  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Brentuximab Vedotin ◽  
Employment Equity ◽  
Genetics Research ◽  
Study Results ◽  
Equity Ownership ◽  
Alk Positive

Abstract Background Systemic anaplastic large cell lymphoma (ALCL) is a CD30-expressing subtype of peripheral T-cell lymphoma (PTCL). Approximately 40 to 65% of ALCL patients (pts) will develop recurrent disease after frontline treatment, with median overall survival (OS) and progression-free survival (PFS) after relapse of 5.5 and 3.1 months (mos) (Savage 2008, Mak 2013). We have previously reported results of a pivotal phase 2 study of brentuximab vedotin in pts with relapsed or refractory (R/R) systemic ALCL (NCT00866047). Efficacy was demonstrated with an objective response rate (ORR) per investigator of 86% and a complete response (CR) rate of 66%. Peripheral sensory neuropathy was the most common adverse event (AE), experienced in 41% of pts. Herein, we present the end-of-study results with updated data on response durability and peripheral neuropathy (PN) resolution. Methods Fifty-eight pts with R/R systemic ALCL, ALK-positive or ALK-negative, received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the ORR per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Long-term follow-up to evaluate disease status was assessed per the investigator every 3 mos for 2 years, every 6 mos through Year 5, and annually thereafter. CT scans were required if progression was suspected clinically. Pts who experienced PN were followed for symptom improvement/resolution until approximately 3 years into long-term follow-up. Results The estimated 5-year OS and PFS for all enrolled patients was 60% (95% CI: 47%, 73%) and 39% (95% CI: 25%, 52%), respectively. At study closure, which occurred 5 years after the last patient's end-of-treatment (EOT) visit, the median OS was not reached (95% CI: 21.3, -), and the median PFS was 20 mos (95% CI: 9.4, -). Pts were observed for a median of 71.4 mos (range, 0.8 to 82.4) from first dose. Of the pts who achieved a CR per investigator (38 of 58, 66%), the median OS (endpoints of 95% CI not estimable) and PFS (95% CI: 21.3, -) were not reached. Median OS for pts who achieved partial response per investigator (PR, 12 of 58, 21%) was 11.6 mos (95% CI: 3.1, -). Median duration of objective response was 25.6 mos (95% CI: 11.8, - [range, 0.9 to 79.7+]) and was not reached for CR pts (95% CI: 20.0, - [range, 0.9 to 79.7+]). Of the 58 enrolled pts, 42 (72%) had ALK-negative disease. Median PFS for ALK-negative and ALK-positive ALCL was 20 mos (95% CI: 6.7, -) and 25.5 mos (95% CI: 8.0, -) respectively, with the median OS not reached for each. The estimated 5-year OS was 61% (95% CI: 47%, 76%) for ALK-negative and 56% (95% CI: 32%, 81%) for ALK-positive pts. Of the 38 CR pts, 16 received a consolidative stem cell transplant (SCT, 8 allogeneic, 8 autologous). Median PFS was not reached in these pts who underwent transplant. Median PFS for the CR pts that did not undergo transplant was 39.4 mos (95% CI: 14.3, -). Sixteen pts, with a median observation time of 75.4 mos (range 69 to 82.4), remained in remission at the end of the study without the start of new therapy other than consolidative SCT. Among these pts, 8 received a consolidative SCT, and the remaining 8 pts (14% of all enrolled pts) remained on study and in remission without any additional therapy after single-agent brentuximab vedotin. Thirty-three pts (57% of enrolled pts) experienced PN. Thirty pts (30 of 33, 91%) experienced resolution or improvement, of whom, 22 (67%) reported complete resolution, and 8 (24%) reported some resolution or improvement at last assessment. Of the 11 pts with ongoing neuropathy at last follow-up, 8 pts had Grade 1 severity and 3 pts had Grade 2. Conclusions These end-of-study results demonstrate that among pts with R/R systemic ALCL, the majority of pts have achieved clinically significant durable remissions, and a subset may have been cured with single-agent brentuximab vedotin. Furthermore, associated toxicities are manageable, with high rates of resolution for PN, the most common toxicity associated with brentuximab vedotin. A randomized phase 3 trial is ongoing to evaluate the combination of brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-expressing peripheral T-cell lymphomas, including systemic ALCL (NCT01777152). Overall Survival and Progression-Free Survival Figure. Figure. Disclosures Pro: Takeda: Honoraria; Seattle Genetics: Honoraria; Celegene: Honoraria. Brice:Gilead: Honoraria; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Seattle Genetics: Research Funding; Bristol Myers-Squibb: Honoraria; Roche: Honoraria. Bartlett:Gilead: Consultancy. Rosenblatt:University of Miami: Employment; Seattle Genetics: Research Funding. Illidge:Takeda Pharmaceuticals International Co.: Consultancy, Honoraria; Seattle Genetics: Consultancy, Research Funding. Matous:Seattle Genetics: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau. Connors:Bristol Myers Squib: Research Funding; F Hoffmann-La Roche: Research Funding; Millennium Takeda: Research Funding; Seattle Genetics: Research Funding; NanoString Technologies: Research Funding. Fenton:Seattle Genetics: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Pinelli:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics: Research Funding; Celgene: Consultancy, Honoraria; Novartis: Research Funding; SPECTRUM: Consultancy, Research Funding; BMS: Consultancy, Honoraria.

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