Pilot Study Using Induction Chemo-Immunotherapy Followed By Consolidation with Reduced Toxicity Conditioning and Allogeneic Stem Cell Transplant in Advanced Stage Mature Non-Anaplastic T- or NK-Cell Lymphoma/Leukemia in Children, Adolescent, and Young Adults

Background: Mature (non-anaplastic) T/NK-cell lymphomas (MTCL) are rare among children, adolescent and young adults (CAYA) population, and more importantly, associated with dismal outcomes (Flower, Xavier. BJH 2019). For instance, we reported the outcomes of US pediatric patients with rare T/NK-cell lymphomas and found that patients <21 years with peripheral T-cell lymphoma (PTCL), extranodal NK/T-cell lymphoma, nasal type (ENKL), or hepatosplenic T-cell lymphoma (HSTL) have very guarded prognosis [5-year overall survival (OS) 59%, 47%, and 9.6%, respectively, all stages combined] highlighting the urgent need for new therapies (Sorge, Cairo, Xavier. BJH 2019). In recent years, significant progress in the understanding of lymphoma cell biology and its microenvironment has led to the development of novel therapies that are more specific in targeting T/NK lymphoma cells in adults. However, no standard of care treatment or better understanding of lymphoma biology have been established for MTCL in CAYA patients.

Study Design and Methods: This is a multicenter pilot study aiming at patients with de novo stage III/IV ENKL/aggressive NK-cell leukemia (cohort 1) or other de novo stage III/IV MTCL (cohort 2, to include histologies such as PTCL NOS, HSTL, angioimmunoblastic T-cell lymphoma, etc). Patients in cohort 1 will receive a combination of daratumumab, dexamethasone, methotrexate, ifosfamide, calaspargase pegol-mknl, and etoposide chemo-immunotherapy (D-SMILE). Cohort 1 patients in complete remission (CR) after 2 induction cycles will undergo consolidation with reduced toxicity conditioning (RTC) and allogeneic stem cell transplant (alloSCT). Patients not in CR after induction will be eligible to receive pembrolizumab with the goal of achieving an optimal disease status before alloSCT. Patients in cohort 2 will receive a combination of brentuximab vedotin, cyclophosphamide, doxorubicin, prednisone (Bv-CHP). Cohort 2 patients in CR after 2 induction cycles will undergo consolidation with RTC and alloSCT. Patients not in CR after induction will be eligible to receive pralatrexate with the goal of achieving an optimal disease status before alloSCT.

Results: Forty patients age ≥ 12 months and < 31 years will be enrolled with a primary objective to assess safety (occurrence of 3+ nonhematological toxicity) and overall response rate (ORR) by central imaging review of the 2 induction regimens and safety and feasibility of consolidation with RTC and alloSCT. Secondary endpoints include event-free survival (EFS), OS, and probability of non-engraftment, donor chimerism, (grade 3/4) acute and chronic GVHD, hematopoietic and immune reconstitution post RTC and alloSCT. Correlative aims include performing targeted mutational profiling by next generation sequencing and RNASe1, and centrally reviewing the hematopathology, and genomic profiling of advanced stage MTCL in CAYA, Accrual is ongoing.

Conclusion: The addition of immunotherapy with daratumumab or brentuximab vedotin to induction chemotherapy and consolidation with RTC and alloSCT in CAYA patients with MTCL will be safe, feasible and result in improved outcomes. Clinical trial supported by Pediatric Cancer Research Foundation and Servier Pharmaceutics. (NCT03719105).

Lim:EUSA Pharma: Honoraria. Cairo:Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Nektar: Consultancy; AbbVie: Consultancy; Omeros: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; Sobi: Speakers Bureau.

Phase II trial using daratumumab in patients with advanced stage NK cell lymphoma/leukemia.