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

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.

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Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE): First Detailed Report of Primary Treatment

Blood ◽

10.1182/blood.v120.21.1614.1614 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1614-1614 ◽

Cited By ~ 5

Author(s):

Francine M. Foss ◽

Kenneth R. Carson ◽

Lauren Pinter-Brown ◽

Steven M. Horwitz ◽

Steven T. Rosen ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Board Of Directors ◽

Initial Treatment ◽

Research Funding ◽

Cell Lymphoma ◽

Primary Treatment ◽

T Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Advisory Committees

Abstract 1614 Background: Registries can be invaluable for describing patterns of care for a population of patients. COMPLETE is a registry of peripheral T-cell lymphoma (PTCL) patients designed to identify the lymphoma-directed treatments and supportive care measures that PTCL patients receive. We report here the first detailed findings of initial therapy. Methods: This is a prospective, longitudinal, observational registry that is led by a global steering committee. Patients with newly diagnosed PTCL and providing written informed consent are eligible. Patients are entered into the registry from time of initial diagnosis and followed for up to 5 years. Only locked records are reported. Results: As of July 2012, 330 patients have been enrolled from the United States. The first patient was enrolled in February 2010. Locked baseline and treatment records are available for 124 and 81 patients, respectively. Of the 124 patients with locked baseline records, 67 patients (54%) were male, the mean age was 59 (range: 19–89), and race/ethnicity was recorded as: White (87 patients; 70%), Black (19; 15%), Asian (5; 4%) and other/unknown (13; 11%). Histology was reported as follows: PTCL-not otherwise specified (27%), anaplastic large cell lymphoma-primary systemic type (18%), angioimmunoblastic T-cell lymphoma (17%), transformed mycosis fungoides (7%), T/NK-cell lymphoma-nasal and nasal type (6%), adult T-cell leukemia/lymphoma, HTLV 1+ (6%) and other (19%). 25 patients (20%) had received another diagnosis, including B-cell lymphoma, Hodgkin's disease and other T-cell lymphomas, prior to their current diagnosis of PTCL. 49 patients (40%) had B symptoms, 102 patients (82%) had an Ann Arbor stage of III/IV, 116 patients (94%) had ECOG performance status of 0–1, and international prognostic index (IPI) score was distributed as follows: IPI 0 (7% of patients), 1 (15%), 2 (43%), 3 (26%), and 4 (9%). Of the 81 patients with locked treatment records, details on initial treatment can be found in table below. Conclusions: This first detailed analysis of primary treatment of PTCL indicates that this disease is still largely being treated with regimens derived primarily from studies of B-cell lymphomas and that a single standard of care does not exist. The fact that a meaningful proportion of patients were initially diagnosed with something other than their current diagnosis of PTCL points out the challenges of diagnosing the disease. While the intent of initial treatment for most patients is to affect a cure, more than 20% of patients were noted as deceased at the end of initial treatment, underscoring the need for more effective, disease-specific therapy. Disclosures: Foss: Merck: Study Grant, Study Grant Other; Celgene: Study Grant, Study Grant Other; Eisai: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Allos: Consultancy. Carson:Allos: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Pinter-Brown:Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees. Horwitz:Allos: Consultancy, Research Funding. Rosen:Allos: Consultancy, Honoraria. Pro:Celgene: Honoraria, Research Funding; Spectrum: Honoraria; Allos: Honoraria; Seattle Genetics: Research Funding. Gisselbrecht:Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hsi:Allos: Research Funding; Eli Lilly: Research Funding; Abbott: Research Funding; Cellerant Therapeutics: Research Funding; BD Biosciences: Research Funding; Millenium: Research Funding.

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Pralatrexate in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results From the Pivotal PROPEL Study

Journal of Clinical Oncology ◽

10.1200/jco.2010.29.9024 ◽

2011 ◽

Vol 29 (9) ◽

pp. 1182-1189 ◽

Cited By ~ 360

Author(s):

Owen A. O'Connor ◽

Barbara Pro ◽

Lauren Pinter-Brown ◽

Nancy Bartlett ◽

Leslie Popplewell ◽

...

Keyword(s):

T Cell ◽

Response Rate ◽

Cell Lymphoma ◽

International Workshop ◽

Progression Free Survival ◽

Median Number ◽

T Cell Lymphoma ◽

Cell Transplant ◽

Peripheral T Cell Lymphoma ◽

Prior Therapy

Purpose Peripheral T-cell lymphoma (PTCL) is a poor prognosis subtype of non-Hodgkin's lymphoma with no accepted standard of care. This study evaluated the efficacy and tolerability of pralatrexate, a novel antifolate with promising activity. Patients and Methods Patients with independently confirmed PTCL who progressed following ≥ 1 line of prior therapy received pralatrexate intravenously at 30 mg/m2/wk for 6 weeks in 7-week cycles. Primary assessment of response was made by independent central review using the International Workshop Criteria. The primary end point was overall response rate. Secondary end points included duration of response, progression-free survival (PFS), and overall survival (OS). Results Of 115 patients enrolled, 111 were treated with pralatrexate. The median number of prior systemic therapies was three (range, 1 to 12). The response rate in 109 evaluable patients was 29% (32 of 109), including 12 complete responses (11%) and 20 partial responses (18%), with a median DoR of 10.1 months. Median PFS and OS were 3.5 and 14.5 months, respectively. The most common grade 3/4 adverse events were thrombocytopenia (32%), mucositis (22%), neutropenia (22%), and anemia (18%). Conclusion To our knowledge, PROPEL (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma) is the largest prospective study conducted in patients with relapsed or refractory PTCL. Pralatrexate induced durable responses in relapsed or refractory PTCL irrespective of age, histologic subtypes, amount of prior therapy, prior methotrexate, and prior autologous stem-cell transplant. These data formed the basis for the US Food and Drug Administration approval of pralatrexate, the first drug approved for this disease.

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Frontline Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin and Prednisone in Patients with Peripheral T-Cell Lymphoma with Less Than 10% CD30 Expression (SGN35-032, Trial in Progress)

Blood ◽

10.1182/blood-2021-151645 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1401-1401

Author(s):

Deepa Jagadeesh ◽

Scott Knowles ◽

Steven M. Horwitz

Keyword(s):

T Cell ◽

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

Brentuximab Vedotin ◽

T Cell Lymphoma ◽

Efficacy And Safety ◽

Time To Event ◽

Peripheral T Cell Lymphoma ◽

Secondary Endpoints

Abstract Background Brentuximab vedotin (BV) was the first antibody-drug conjugate to be approved in multiple cancer types (Gauzy-Lazo 2020). The combination of a CD30-directed monoclonal antibody, a protease-cleavable linker, and the microtubule-disrupting agent monomethyl auristatin E drives the anticancer activity of BV by inducing CD30-targeted cell cycle arrest and apoptosis as well as the bystander effect on adjacent cells (Sutherland 2006, Hansen 2016, Schönberger 2018). In the ECHELON-2 phase 3 clinical trial, BV, cyclophosphamide, doxorubicin, and prednisone (A+CHP) showed efficacy in patients with peripheral T-cell lymphoma (PTCL) across a range of CD30 expression levels, including the lowest eligible level of 10% by immunohistochemistry when compared with patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (Advani 2019). It is hypothesized that A+CHP will demonstrate efficacy in PTCL with <10% CD30 expression because i) clinical responses to BV have occurred in patients with PTCL, cutaneous T-cell lymphoma, or B-cell lymphoma with low (<10%) and undetectable CD30 expression (Jagadeesh 2019) and ii) CD30 expression levels were not predictive of A+CHP responses in non-systemic anaplastic large cell lymphoma (sALCL) (Advani 2019). Study Design and Methods SGN35-032 is a dual-cohort, open-label, multicenter, phase 2 clinical trial (NCT04569032) designed to evaluate the efficacy and safety of A+CHP in patients with non-sALCL PTCL and CD30 expression of <10% on tumor cells. Up to approximately 40 patients will be enrolled in each of the CD30-negative (expression <1%) and the CD30-low (expression ≥1% to <10%) cohorts. Patients will be enrolled based on local results but only patients with CD30 expression <10% per central confirmation will be analyzed for the primary and secondary endpoints. Patients will receive 21-day cycles of A+CHP for 6-8 cycles. Key inclusion criteria include adults with newly diagnosed PTCL, excluding sALCL, per the World Health Organization 2016 classification; CD30 expression <10% by local assessment; and fluorodeoxyglucose-avid disease by positron emission tomography (PET) and measurable disease of at least 1.5 cm by computed tomography (CT), as assessed by the site radiologist. Patients with previous exposure to BV or doxorubicin will not be eligible. The primary endpoint of this trial is objective response rate (ORR) per blinded independent central review (BICR) using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Secondary endpoints include ORR by BICR using the modified Lugano criteria (Cheson 2014), complete response rate, progression-free survival (PFS), and duration of response per BICR using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007), overall survival, and safety and tolerability. A PET scan is required at baseline, after Cycle 4, and after the completion of study treatment. Follow-up restaging CT scans will be performed over the next 2 years. In both the CD30-negative and the CD30-low cohorts, efficacy and safety endpoints will be summarized using descriptive statistics to describe continuous variables by cohort. Time-to-event endpoints, such as PFS, will be estimated using Kaplan-Meier (KM) methodology and KM plots will be presented. Medians for time-to-event analyses (e.g., median PFS) will be presented and two-sided 95% confidence intervals will be calculated using the log-log transformation method. Enrollment is planned for 15 US sites and 32 sites across the Czech Republic, France, Italy, and the UK. Disclosures Knowles: Seagen Inc.: Current Employment. Horwitz: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Affimed: Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding.

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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.

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Trial-in-Progress: Frontline Brentuximab Vedotin and CHP (A+CHP) in Patients with Peripheral T-Cell Lymphoma with Less Than 10% CD30 Expression

Blood ◽

10.1182/blood-2020-136402 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-30

Author(s):

Deepa Jagadeesh ◽

Robert B. Sims ◽

Steven M. Horwitz

Keyword(s):

T Cell ◽

Research Funding ◽

Cell Lymphoma ◽

Large Cell ◽

Brentuximab Vedotin ◽

T Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Advisory Committees ◽

Kaplan Meier ◽

Secondary Endpoints

Background In the ECHELON-2 phase 3 clinical trial, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) showed clinically meaningful and statistically significant efficacy in patients with peripheral T-cell lymphoma (PTCL) across a range of CD30 expression levels, including the lowest eligible level of 10% by IHC. In addition to the ECHELON-2 study, response data are available from an additional 344 subjects with CD30-expressing PTCL and other large-cell lymphomas (including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma-NOS) who had been treated in studies with brentuximab vedotin as a single agent or in combination with chemotherapy, in both frontline and relapsed/refractory settings. Among these 344 subjects, 184 had tumors with CD30 expression <10% by local assessment, including 83/184 with undetectable CD30 by immunohistochemistry (CD30=0). Responses to brentuximab vedotin have been observed at all levels of CD30 expression, including in tumors with undetectable CD30 levels (Advani 2019; Horwitz 2019). It is hypothesized that A+CHP will demonstrate efficacy in subjects with PTCL and CD30 expression <10% because: i) brentuximab vedotin has shown activity in lymphomas with low CD30 expression; and ii) the activity of CHP chemotherapy in PTCL is unrelated to CD30 expression. This study will include subjects with PTCL subtypes other than systemic anaplastic large cell lymphoma (sALCL). Study Design and Methods This is a dual-cohort, open-label, multicenter, phase 2 clinical trial designed to evaluate the efficacy and safety of A+CHP in subjects with non-sALCL PTCL and CD30 expression <10% on tumor cells. Enrollment will be based on CD30 expression per local lab assessment. Subjects will be assigned to 1 of 2 cohorts based on CD30 expression; up to approximately 40 subjects will be enrolled in the CD30 negative (expression <1%) cohort and approximately 40 subjects will be enrolled in the CD30 positive (expression ≥1% to <10%) cohort. An archived tumor biopsy specimen will be submitted to a central pathology lab for confirmation of CD30 expression. Only subjects with CD30 expression <10% per central confirmation will be analyzed for the primary and secondary endpoints. Subjects will receive 21-day cycles of A+CHP for a target of 6-8 cycles. The primary endpoint of this trial is objective response rate (ORR) per blinded independent central review (BICR). Key secondary endpoints include CR and PFS per BICR and overall survival. Key inclusion criteria include the following: subjects aged 18 years and older with newly diagnosed PTCL, excluding sALCL, per the WHO 2016 classification; CD30 expression <10% by local assessment; and fluorodeoxyglucose-avid disease by PET and measurable disease of at least 1.5 cm by CT, as assessed by the site radiologist. Lymphoma response and progression will be assessed by BICR using Revised Response Criteria for Malignant Lymphoma and modified Lugano criteria. A CT scan will be performed at the time of suspected clinical progression. Subsequent restage assessments (CT scans only) will be performed according to the calendar, relative to the first dose of study treatment, to ensure that tumor progression is uniformly assessed between the treatment arms. Efficacy and safety endpoints will be summarized with descriptive statistics by cohort, with the CD30 negative cohort and the CD30 positive cohort. The summary of overall (CD30 negative and positive cohort combined) may be presented as appropriate. Descriptive statistics (mean, median, standard deviation, minimum, and maximum) will be used to describe continuous variables. Time-to-event endpoints, such as PFS, will be estimated using Kaplan-Meier methodology and Kaplan-Meier plots will be presented. Medians for time-to-event analyses (eg, median PFS), will be presented and two-sided 95% confidence intervals will be calculated using the log-log transformation method. The trial will have sites open in the US and multiple countries in Europe, with enrollment planning to begin in September 2020. Disclosures Jagadeesh: Verastem: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Research Funding; Debiopharm Group: Research Funding; Regeneron: Research Funding. Sims:Seattle Genetics, Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Travel expenses. Horwitz:ASTEX: Consultancy; Millenium/Takeda: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Kyowa Hakka Kirin: Consultancy, Research Funding; Beigene: Consultancy; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Portola: Consultancy, Research Funding.

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Pralatrexate Is Effective In Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL) with Prior Ifosfamide, Carboplatin, and Etoposide (ICE)-Based Regimens

Blood ◽

10.1182/blood.v116.21.1753.1753 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1753-1753 ◽

Cited By ~ 2

Author(s):

Andre Goy ◽

Barbara Pro ◽

Kerry Joanne Savage ◽

Nancy L. Bartlett ◽

Mary Jo Lechowicz ◽

...

Keyword(s):

T Cell ◽

Combination Chemotherapy ◽

Research Funding ◽

Cell Lymphoma ◽

The United States ◽

T Cell Lymphoma ◽

Cell Transplant ◽

Second Line ◽

Peripheral T Cell Lymphoma ◽

Line Therapy

Abstract Abstract 1753 Background: Peripheral T-cell lymphoma (PTCL) is a group of aggressive T- and NK-cell lymphomas with a poor prognosis, with most patients progressing within 6 to 12 months after first-line therapy. Despite a paucity of data in PTCL, combination chemotherapy such as ifosfamide/carboplatin/etoposide (ICE)-based regimens (eg, ICE, rituximab-ICE [RICE] and dexamethasome-ICE [DICE]), are often used in the salvage setting. These regimens can induce responses allowing some patients to proceed to a stem cell transplant (SCT), yet most patients relapse quickly (Horwitz et al, Blood. 2005;(106:a2679; Zelenetz et al Annals Oncol. 2003;14:i5-i10.). Pralatrexate (FOLOTYN®), a rationally-designed folate analog, was granted accelerated approval in the United States for the treatment of relapsed or refractory PTCL, based on results of the pivotal study, PROPEL (Pralatrexate in Patients with Relapsed Or Refractory Peripheral T-cell Lymphoma). The present exploratory analysis of PROPEL data was conducted to assess the efficacy of pralatrexate postfailure of ICE-based regimens. Methods: Of the 109 patients enrolled in PROPEL and evaluable for efficacy, a subset of 20 patients had received an ICE-based regimen as their second-line therapy and progressed at some point prior to treatment with pralatrexate (30 mg/m2 weekly for 6 of 7 week cycles). Results: The median age of the 20 patients with a prior ICE-based regimen was 45 years. A summary of pralatrexate efficacy data is presented in the table below. Pralatrexate demonstrated ORR of 40% in ICE-pretreated patients (n=20). Nine of the 20 patients received ICE-based regimens as their most recent therapy prior to pralatrexate. Of these, 2 patients did not respond to these aggressive combination chemotherapies, but did respond to pralatrexate (1 CR and 1 PR). Two of the 20 patients achieved a CR on pralatrexate and proceeded to SCT; DoR to pralatrexate in these patients was censored (at 1.3 and 4.9 months). However, these 2 patients remain in CR and the current disease-free period (DoR: pralatrexate + transplant) is 10.9 and 30.8 months. The most common grade 3 adverse events (AEs) were anemia (8 patients) and mucositis (5 patients), and grade 4 AEs was thrombocytopenia (6 patients). Five patients discontinued treatment with pralatrexate due to AEs. From a safety perspective, this compares favorably with ICE-based regimens, recognized for their intensity and their need for hospitalization for administration (Hertzberg et al, Ann Oncol. 2003;14[suppl 1] i11-i16). The PROPEL study also collected information on response to therapies administered prior to study entry. In the 20 patients included in the analysis, the ORR to prior ICE-based regimens was 25% with 3 patients achieving CR (15%) and 2 PR (10%). An additional 3 patients had SD (15%), 7 had PD (35%), and 5 patients had nonassessable response. The median duration on treatment for responders to ICE-based regimens was <1 month, in contrast with pralatrexate's long DoR (median 16.2 months according to investigators’ assessment). Conclusions Pralatrexate was highly active in patients with PTCL who received prior ICE-based chemotherapy, with an ORR of 40% including CRs leading to SCT in some patients. Of note, is the long duration of pralatrexate responses in marked contrast to the short response duration of the combination chemotherapy regimens. Taken together, the efficacy of single-agent pralatrexate compared favorably with ICE-based regimens, a finding that is consistent with other exploratory analyses, showing that pralatrexate can reverse the characteristic progressive resistance of PTCL patients to second-line chemotherapy, and that pralatrexate is an effective second-line treatment for patients with PTCL. Disclosures: Goy: Allos Therapeutics, Inc.: Consultancy, Honoraria. Pro:Allos Therapeutics, Inc. : Research Funding. Savage:Allos Therapeutics, Inc.: Consultancy, Honoraria. Lechowicz:Allos Therapeutics, Inc.: Consultancy; Celgene Corporation: Consultancy. Jacobsen:Allos Therapeutics, Inc.: Consultancy. Fruchtman:Allos Therapeutics, Inc.: Employment. O'Connor:Allos Therapeutics, Inc.: Research Funding.

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Biomarker Quality Assurance (QA) Findings From the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) Registry

Blood ◽

10.1182/blood.v120.21.4263.4263 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4263-4263 ◽

Cited By ~ 3

Author(s):

Eric D. Hsi ◽

Aaron M. Gruver ◽

Francine M. Foss ◽

Kenneth R. Carson ◽

Lauren Pinter-Brown ◽

...

Keyword(s):

T Cell ◽

Research Funding ◽

Gene Rearrangement ◽

Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Advisory Committees ◽

The Mean ◽

Pathology Reports ◽

A Site ◽

Biomarker Data

Abstract Abstract 4263 Background: COMPLETE is a registry of peripheral T-cell lymphoma (PTCL) patients from academic and community settings in the US. For the registry, selected biomarkers are recorded to determine which markers may have informed the diagnosis of PTCL. Research staff at participating sites enter data from pathology reports into an electronic data capture (EDC) system; however, pathology reports can be difficult to interpret, particularly for those who have not received specialized training. To ensure that biomarker data in COMPLETE accurately reflects pathology reports, a biomarker QA initiative was undertaken. A similar initiative was pursued by the International T-Cell Project and is the subject of a separate, parallel abstract. Methods: The COMPLETE biomarker QA initiative includes review of on-site data entered for 26 biomarkers commonly assessed in the diagnostic work-up of PTCL. External review by a board-certified pathologist is triggered once a site has entered the biomarker data into the EDC system for enrolled patients and uploaded the de-identified pathology reports. All patients enrolled at a site within 30 days of the first patient were reviewed. A single mismatch between the site-entered data and the reviewer's findings counts as an error. Findings of the review are entered into the EDC system to facilitate analysis and queries are sent to the site in cases where corrections are needed. Results: Data for 119 patients from 43 centers comprising a sum of 3570 biomarker entries were reviewed by an external hematopathologist. The mean number of phenotypic markers assessed per patient was 12 (range: 4–20), and the mean number of gene rearrangement tests performed was 0.2 (range: 0–3). Of the 119 patients, 13 (11%) had no EDC entry errors, 33 (28%) had 1–2 errors, 34 (29%) had 3–5 errors, 31 (26%) had 6–10 errors and the remaining 8 cases (7%) had 11–15 errors. The reviewer agreed with 74% of entries where the site noted a finding was positive; of the remaining entries where the site indicated the findings were positive, the reviewer noted they were negative (12%), not assessed (10%) or indeterminate (5%). For entries where the site indicated the finding was negative, the reviewer was in agreement 79% of the time; for the remaining 21% of negative-reported entries by the site, the reviewer indicated the marker was not assessed (12%), indeterminate (6%) or positive (3%). The reviewer was in agreement with the site in 92% of the entries where the site indicated the marker was not assessed; otherwise, the reviewer found the marker was negative (4%), positive (3%) or indeterminate (1%). The markers accounting for the most errors (each marker accounting for 5% or more of errors) were CD8, CD20, CD30, Epstein-Bar Virus (EBV) and T-cell receptor gamma gene rearrangement (TCR-g). The types of errors for these markers are noted in the table below. Sum may exceed 100% due to rounding. Recording the type of EBV test performed [in situ hybridization (ISH) and immunohistochemistry (IHC)] presented further challenges, accounting for 8% of errors. Common errors included: 1) the site indicated the test was not performed when it was performed per report and 2) the site indicated a particular test (ISH, IHC) was performed but the method used was unclear in the report. Conclusions: Results of the COMPLETE biomarker QA analysis indicate that errors in interpretation or recording of biomarker data from pathology reports are common. For registries and other observational studies, periodic reviews by an external pathologist may guide site training and improve the accuracy of data collection. For interventional clinical trials in PTCL, central review of all biomarker data by expert hematopathologists should be considered. Disclosures: Hsi: Allos: Research Funding; Eli Lilly: Research Funding; Abbott: Research Funding; Cellerant Therapeutics: Research Funding; BD Biosciences: Research Funding; Millenium: Research Funding. Gruver:MedNet Solutions: Honoraria. Foss:Allos: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Eisai: Consultancy; Celgene: Study Grant, Study Grant Other; Merck: Study Grant, Study Grant Other. Carson:Allos: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Pinter-Brown:Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees. Horwitz:Allos: Consultancy, Research Funding. Rosen:Allos: Consultancy, Honoraria. Pro:Celgene: Honoraria, Research Funding; Spectrum : Honoraria; Allos: Honoraria; Seattle Genetics : Research Funding. Gisselbrecht:Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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A Phase Ib/IIa Trial of the Combination of Romidepsin, Lenalidomide and Carfilzomib in Patients with Relapsed/Refractory Lymphoma Shows Complete Responses in Relapsed and Refractory T-Cell Lymphomas

Blood ◽

10.1182/blood.v128.22.2991.2991 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2991-2991 ◽

Cited By ~ 13

Author(s):

Neha Mehta-Shah ◽

Alison J Moskowitz ◽

Matthew Lunning ◽

Peggy Lynch ◽

Mark Scheuerman ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

T Cell Lymphoma ◽

Hematologic Toxicity ◽

Advisory Committees ◽

Grade 3

Abstract Background:Epigenetic manipulation and immunomodulation are therapeutic strategies in hematologic malignancies. In our previous study, the combination of romidepsin and lenalidomide demonstrated a 58% overall response rate, complete response rate of 11% and median event free survival was 16 weeks in patients (pts) with relapsed or refractory T-cell lymphoma. Given the potential synergy of proteasome inhibitors with histone deacetylase inhibitors and lenalidomide, we conducted a phase Ib/IIa study to evaluate the safety and toxicity of romidepsin and lenalidomide in combination with carfilzomib in pts with relapsed or refractory lymphoma. Here we report the safety, toxicity, and maximum tolerated dose (MTD) from the completed phase I portion of the study as well as the efficacy data from the completed T-cell lymphoma phase IIa cohort. Methods: The phase I portion evaluated toxicity and defined MTD. The clinicalactivity of the combination of romidepsin, lenalidomide, and carfilzomib was assessed in the phase I and lineage specific phase IIa cohorts. Romidepsin and carfilzomib were given IV on days 1, 8 and lenalidomide was given orally on days 1-14 of a 21-day cycle. A standard 3+3 dose escalation schema was followed: The starting dose was romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 36mg/m2. Dose-limiting toxicity (DLT) was defined in cycle 1 as ≥ grade 3 non-hematologic toxicity, grade 4 hematologic toxicity, grade ≥ 3 thrombocytopenia with bleeding, grade 3 hematologic toxicity resulting in a significant delay of treatment or inability to receive day 1 of cycle 2 due to continued drug related toxicity. Tumor response was based on disease-specific criteria.Pts could be treated until progression, intolerance, or response adequate to allow allogeneic transplantation. Results:20 pts were enrolled with 19 evaluable for toxicity (1 patient with T-cell lymphoma progressed prior to receipt of any study drug). 17 pts were treated for T-cell lymphoma (11 in the phase 1 portion and 6 in the phase IIa cohort): peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS)-9, angioimmunoblastic T-cell lymphoma (AITL)-4 (one with concurrent diffuse large B-cell lymphoma-DLBCL), mycosis fungoides (MF)-2, transformed MF-1, extra-nodal NK/T-cell lymphoma (ENKTCL)-1. 3 pts in the phase 1 portion were treated for B-cell lymphoma: DLBCL-3. The T-cell lymphoma cohort is complete and efficacy data is reported here. Dose level 2 (romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 45mg/m2) exceeded the MTD with 2/6 DLTs: 1 pt with grade 3 thrombocytopenia resulting in treatment delay and 1 pt with grade 4 thrombocytopenia. There were no DLTs among 6 pts treated in dose level 1 (romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 36mg/m2) and dose level 1 was deemed the MTD. Grade 3-4 toxicities in >10% pts included neutropenia and thrombocytopenia. SAEs included: infection-3, progression of disease resulting in hospitalization-3, fever-2, febrile neutropenia-1, DVT-1, edema-1, dyspnea-1, atrial flutter-1, generalized weakness-1, and vomiting with diarrhea-1. Of the 16 pts with T-cell lymphoma evaluable for response, the overall response rate was 50% (8/16, 95% CI: 25 to 75%). The complete responses rate was 31% (5/16, 95% CI: 11 to 59%) and the partial response rate was 19% (3/16, 95% CI: 4 to 46%). Complete responses were seen in AITL (4/5) and PTCL-NOS (1/8) with 3 pts in CR proceeding to allogeneic stem cell transplantation. Partial responses were seen in PTCL-NOS-1, AITL-1, and transformed MF-1. In T-cell lymphoma, the median event free survival for all pts was 9.7 weeks (95% CI: 6.0 to NR) and for responders was not reached (95% CI: 15.0 to NR). The median time to response was 5.8 weeks. The median duration of response was 9.6 weeks (95% CI: 8.0 to NR). 3 pts underwent allogeneic transplantation following this therapy and another 2 pts with CR remain in continuous remission. Median duration of follow up was 20.4 weeks (range 3.4-40.9 weeks). Conclusions: The MTD dose for phase 2 study was identified as romidepsin 8mg/m2, lenalidomide 15mg and carfilzomib 36mg/m2. No unexpected toxicities have emerged. The preliminary overall and complete response rates of this regimen are promising in T-cell lymphoma, particularly in AITL, and warrants further study. An expansion cohort in B-cell lymphoma cohort is ongoing. Disclosures Moskowitz: Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy. Lunning:Gilead: Consultancy; Bristol-Myer-Squibb: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Juno: Consultancy; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Spectrum: Consultancy; Celgene: Consultancy. Kumar:Celgene: Research Funding; Adaptive Biotechnologies: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria, Other: Scientific Advisory Board. Zelenetz:Gilead Sciences: Research Funding. Hamlin:Novartis: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Xencor: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Seattle Genetics: Research Funding; Molecular Templates: Research Funding. Noy:Pharmacyclics, LLC, an AbbVie Company: Other: travel, accommodations, expenses, Research Funding. Palomba:Pharmacyclics: Consultancy. Dogan:Seattle Genetics: Consultancy; Consulting Cancer Panel: Membership on an entity's Board of Directors or advisory committees; Cancer Genetics: Membership on an entity's Board of Directors or advisory committees; Peerview Institute: Consultancy. Horwitz:Bristol-Myers Squibb: Consultancy; Infinity: Consultancy, Research Funding; Celgene: Consultancy; Takeda: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Huya: Consultancy; Kyowa Hakka Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding.

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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.

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Final Analysis of the Front-Line Phase III Randomized ACT-1 Trial in Younger Patients with Systemic Peripheral T-Cell Lymphoma Treated with CHOP Chemotherapy with or without Alemtuzumab and Consolidated By Autologous Hematopoietic Stem Cell Transplant

Blood ◽

10.1182/blood-2018-99-110429 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 998-998 ◽

Cited By ~ 4

Author(s):

Francesco d'Amore ◽

Sirpa Leppä ◽

Maria Gomes da Silva ◽

Thomas Relander ◽

Grete Fossum Lauritzsen ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Stem Cell Transplant ◽

Cell Lymphoma ◽

Fungal Infections ◽

Final Analysis ◽

Cell Transplant ◽

Peripheral T Cell Lymphoma ◽

Advisory Committees ◽

Grade 3

Abstract [§ share last authorship] Background: In 2000-2010, the first large prospective trials in peripheral T-cell lymphoma (PTCL) showed outcomes burdened by high failure rates during induction. Concurrently, trials with the anti-CD52 monoclonal antibody alemtuzumab (ALZ) yielded promising responses in PTCL while demonstrating the feasibility of combining ALZ with CHOP. Hence, the Nordic Lymphoma Group initiated the randomized ACT-1 trial to test, in younger patients (pts) (18-65yrs), the addition of ALZ to CHOP + autologous stem cell transplant (ASCT). Primary endpoint was the 3 years event-free survival (EFS). Here, we present the final analysis of the ACT-1 trial (ClinicalTrials.gov: NCT00646854). Patients and Methods: Overall, 136 pts were randomized (43% of planned sample size due to slow accrual), five did not receive study treatment, and 131 were analyzed (ALZ-CHOP: 65; CHOP: 66). Due to lack of tumoral CD52 expression, anaplastic large cell lymphomas (ALCL) were not included in the ACT-1 trial. An amendment tapering ALZ dose from 360 mg (30 mg on days 1+2 of each CHOP course) to 120 mg (30 mg on day 1 of CHOP courses 1-4) was introduced early on due to systemic fungal infections in 2 pts. Of the 65 pts treated with ALZ-CHOP, 4 received the pre- and 61 (94%) the post-amendment dose. Monitoring for CMV- and EBV-DNA and antimicrobial prophylaxis were mandatory. Results: The median observation time for the Full Analysis Set was 66 months and the median age 51 yrs. The ALZ-CHOP and CHOP cohorts were well balanced with regard to classical prognostic factors and histological subtypes (PTCL-NOS 58% vs 54%, AILT 21% vs 25%, other 21% vs 21%). Feasibility: Neither CHOP nor ALZ-CHOP pts experienced substantial treatment delay. ALZ exposure did not affect stem cell harvest nor hematopoietic recovery. Grade 4 leucopenia was more frequent in ALZ-CHOP pts (73% vs 35%; p=0.001), whereas the occurrence of grade 3-4 anemia and thrombocytopenia did not differ significantly. After ALZ dose amendment, the frequency of bacterial and fungal infections of grade ≥3 was similar in both treatment arms. ALZ treated pts had more viral events (22/57=42% vs 4/23=17%), mainly due to asymptomatic CMV reactivations. The ratio of serious adverse events per ALZ-CHOP treated patient dropped markedly (from 3.25 to 0.86, comparable with 0.46 for CHOP) after dose amendment. Additional toxicity was mild and similar in both arms. Treatment related mortality was 4% (5% vs 3%). Efficacy: Complete remission (CR) was 52% in ALZ-CHOP vs 42% in CHOP. Primary refractory disease occurred for ALZ-CHOP and CHOP in 23% and 38% of pts, respectively. Overall, females had a significantly better outcome than males (p=0.004), also after adjustment for classical prognostic factors. Analyzing time-related endpoints without knowledge of CD52 expression, 3-years EFS, progression-free, and overall survival (PFS, OS) did not differ significantly between ALZ-CHOP and CHOP (EFS 35% vs 26%, PFS 37% vs 26%, OS 52% vs 50%). Fig.1A shows EFS by treatment arm, by gender, and by gender and treatment arm. Although not significantly different, EFS, PFS and OS values of ALZ-CHOP treated females in the ACT-1 trial were consistently higher than those of non-ALZ treated females or of males regardless of treatment group. RNA sequencing from evaluable pre-therapeutic tumor biopsies defined a signature of differentially expressed genes to be predictive of clinical outcome in ALZ-CHOP but not CHOP treated pts (n=33). Tumor microenvironment genes were prominent in determining response to ALZ. Tumors rich in B-cell milieu showed good responses, while the opposite was observed in tumors with signatures enriched with high endothelial cell genes (p<0.001) (Fig.1B). The good risk signature was associated with a higher frequency of X-linked and the bad risk with a higher frequency of Y-linked transcripts (Fig.1B). Conclusion: In previously untreated younger non-anaplastic PTCL pts, the addition of ALZ to CHOP + ASCT was feasible. Overall, we did not find a significant outcome benefit. However, a gene expression signature predictive of ALZ response was identified and found predominantly in female patients. Carriers of this signature had an outcome benefit only if exposed to ALZ. A validation of this predictor of ALZ response is ongoing. Due to the limited sample size of the ACT-1 study cohort, both the negative and the positive findings of the trial should be interpreted with caution. Disclosures Leppä: Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Bayer: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Silva:Gilead Sciences: Research Funding; Abbvie, Gilead Sciences, Janssen, BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche, Janssen, Celgene: Other: Travel Support; Roche, Janssen: Other: Institution's payment for consultancy. Hagberg:Roche: Honoraria. Lugtenburg:takeda: Consultancy, Research Funding; servier: Consultancy, Research Funding; roche: Consultancy; BMS: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; GenMab: Research Funding. Walewski:Roche, GSK/Novartis, Takeda, and Janssen-Cilag: Research Funding; Roche, Celgene, Takeda, Janssen-Cilag, and Servier: Honoraria; Roche, Celegene, Takeda, Janssen-Cilag, and Servier: Membership on an entity's Board of Directors or advisory committees. Hopfinger:Janssen: Honoraria; Gilead: Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Jantunen:Amgen: Honoraria; Genzyme/Sanofi: Honoraria; Takeda: Honoraria. Steidl:Seattle Genetics: Consultancy; Juno Therapeutics: Consultancy; Tioma: Research Funding; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: patent holding; Roche: Consultancy. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Celgene: Consultancy, Honoraria; Janssen: Research Funding; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding.

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