ABSTRACT
Angioimmunoblastic T-cell lymphoma (AITL) is an uncommon type of cluster of differentiation (CD)4 T-cell peripheral lymphoma. The varied clinical presentations of AITL present a challenge for accurate diagnosis. We present a case of a 57-year-old female with a history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in May 2020, who presented to the hospital in the summer of 2021 with shortness of breath for 3 months. She underwent an extensive workup for lymphadenopathy while in Canada involving multiple core lymph node biopsies, which were inconclusive. Here in our institution, several tests for infectious diseases were unremarkable. Imaging tests revealed bilateral pleural effusion, lymphadenopathies, and rectal thickening. Results from rectal biopsy and excisional cervical lymph node biopsy revealed findings typical of AITL. Due to worsening hypoxia with pleural fluid accumulation, bilateral chest tubes (PleurX catheter) were placed. Steroids and chemotherapy were started. She was discharged in stable condition to follow-up care. An integrated and persistent approach comprising clinical, morphologic, excisional biopsy, immunophenotyping, and molecular tests is essential in reaching a correct diagnosis of AITL. Through our consistent effort to obtain further imaging and tissue biopsies, we came to the diagnosis which allowed her to begin appropriate life-saving treatments.
ABSTRACT
Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphomas associated with poor outcomes following anthracycline-based chemotherapy, even when consolidative autologous stem cell transplantation (ASCT) is used. CD30 expression is universal in anaplastic large cell lymphoma (ALCL) and is frequently expressed in other PTCL subtypes. Brentuximab vedotin (BV) is a CD30-directed antibody drug conjugate that prolongs progression-free survival (PFS) and overall survival (OS) when combined with cyclophosphamide, doxorubicin, and prednisone (CHP) as compared to CHOP chemotherapy (Horwitz, 2020). Although a majority of pts treated with BV-CHP remained in durable remission (5y PFS 51%), there is room for improvement. Based on retrospective studies that demonstrated improved outcomes in younger pts, the addition of etoposide to CHOP (CHOEP) is commonly used as initial therapy for PTCL. We performed a multicenter phase 2 trial to evaluate the safety and efficacy of adding etoposide to BV-CHP (CHEP-BV) followed by BV consolidation in pts with newly diagnosed CD30-expressing PTCL. Methods: Adults with newly diagnosed CD30+ (≥ 1% of tumor cells by local pathology) PTCL were eligible, including pts with ALK+ ALCL and IPI score ≥ 2, ALK-negative ALCL, PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), adult Tcell leukemia/lymphoma (ATLL), among others. After accrual of 28 pts, the protocol was amended to allow enrollment of 20 additional pts with CD30+ non-ALCL PTCL (with ALCL allowed in Canada). Pts could receive prephase steroids and/or 1 cycle of CHOPequivalent chemotherapy prior to study entry. 6 pts were treated in a safety lead-in cohort and all pts received CHEP-BV at the recommended phase 2 dose: 6 x 21-day cycles of CHP+BV (1.8mg/kg) on d1 and etoposide 100mg/m2 on d1-3. G-CSF prophylaxis was mandatory. Pts in response after CHEP-BV could receive BV consolidation (1.8mg/kg q3w) for up to 10 additional cycles (16 total BV cycles) either after ASCT or CHEP-BV if no ASCT was performed. The co-primary endpoints were safety and the CR rate (Deauville score 1-3) by PET-CT after CHEP-BV assessed by investigators according to the 2014 Lugano classification. Secondary endpoints were PFS and OS. Results: Accrual has completed and 48 pts were enrolled;all were evaluable for toxicity, 46 were evaluable for efficacy. 16 pts had ALCL (13 ALK+, 3 ALK-) and 32 had non-ALCL PTCL subtypes, including 18 with AITL, 11 with PTCL NOS, 2 with T-follicular helper PTCL, and 1 with ATLL. Baseline characteristics are shown in Table. 43 pts completed CHEP-BV, 2 had progressive disease (PD) prior to completion, 1 pt discontinued CHEP-BV early (MD discretion), 1 pt died due to COVID-19, and 1 remains on CHEP-BV. Of 43 pts who completed CHEP-BV, 24 proceeded to ASCT and 19 did not. 33 (74%) pts received BV consolidation (20 after ASCT, 13 directly after CHEP-BV) and completed a median 8 of the planned 10 cycles (range, 1-10). 13 pts completed all cycles of consolidation;19 pts discontinued early-12 due to adverse events (AE), 5 due to PD, and 2 due to patient/physician choice. The most frequent CHEP-BV related AEs (all grades, G) include fatigue (73%), peripheral sensory neuropathy (67%), anemia (62.5%), nausea (56%), neutropenia (50%), lymphopenia (44%), leukopenia (42%), thrombocytopenia (40%), elevated transaminases (33%). The most common G3+ AEs were neutropenia (37.5%), febrile neutropenia (23%), lymphopenia (21%), anemia (19%), thrombocytopenia (19%). There were 5 deaths, 4 due to PD and 1 due to COVID-19 infection during C3 of CHEP-BV. The interim (n=46) ORR and CR rates (after 3 CHEP-BV cycles, except 1 pt after 2) were 96% and 59% (27 CR, 17 PR), respectively. At completion of CHEP-BV (n=46), the ORR was 91% with 80% CR (37 CR, 5 PR, 4 PD). The ORR/CR rates in ALCL (n=16) vs non-ALCL (n=30) pts were 94%/94% vs 90%/73%, respectively. The ORR/CR rates in pts with CD30 expression 1-9% (n=15) vs 10+% (n=31) were 93%/67% and 90%/87%, respectively. The median follow-up in surviving pts is 1 .1 months (range, 0.9-32.5). The overall 18mo PFS and OS were 61% and 89%;18mo PFS by subgroup: ALCL 81%, non-ALCL 49%, CD30 1-9% 48%, CD30 10+% 67%. Landmark 1y PFS from end of CHEP-BV in responding pts (n=41) was 82% in pts who underwent ASCT vs 48% in pts who did not Conclusions: In a cohort of pts with mostly non-ALCL CD30-expressing PTCL, CHEP-BV (+/-ASCT) followed by BV consolidation was tolerable and effective.
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. [Formula presented] 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.