Romidepsin in Relapsed/Refractory HTLV-1 Associated Adult T-Cell Lymphoma/Leukemia: A Case Series

Introduction: Adult T-cell lymphoma/leukemia (ATLL) is a mature T-cell neoplasm associated with human T-cell lymphotropic virus -1 (HTLV-1) infection. The aggressive subtypes(acute/lymphomatous) have a median survival of 6-13 months. Presently, there is no established therapy for patients with relapsed/refractory disease. Romidepsin is bicyclic class 1 selective histone deacetylase inhibitor approved by the US Food and Drug Administration for the treatment of patients with peripheral T-cell lymphoma who have received ≥ 1 prior systemic therapy, after demonstrating objective response rate of 25% (33 of 130), including 15% (19 of 130) complete remissions. Approaches for relapsed/refractory Peripheral T cell lymphoma(PTCL) are often applied to ATLL, although there is little data for this subtype. Neither of the two Phase II trials leading to its approval had ATLL cases. Reactivation of latent DNA viruses has been described as a consequence of immune suppression associated with this drug although its impact on HTLV-1 associated neoplasm is not known. Here we present 3 cases of relapsed refractory ATLL treated with romidepsin.

Methods: We reviewed all patients with relapsed/refractory ATLL treated with romidepsin at King's County Hospital between 2012 and 2015.

Results:

Case 1: 43 year old male presented with multiple hyperpigmented nodules on the trunk and a 4 cm draining ulcerated left shoulder lesion. Complete blood count (CBC) was normal. Peripheral smear showed atypical lymphocytes with clover leaf pattern. CT scan Chest/abd/pelvis showed no enlarged lymphadenopathy. Punch biopsy of the skin confirmed involvement with peripheral T cell neoplasm HTLV-1 positive. Treated was initiated with EPOCH (etoposide/prednisone/vincristine/cisplatin/adriamycin) with partial response. He progressed on therapy after 4 cycles with new axillary/inguinal and retroperitoneal lymphadenopathy. Romidepsin was started at 14 mg/m2 IV Day 1, 8, 15 Q28 days. He tolerated cycle 1 well but continued to have progressive disease as evidenced by worsening hypercalcemia, atypical lymphocytosis and lymphadenopathy. Patient died 40 days after initiation of therapy from wound infection.

Case 2: 37 year old male presented with diffuse lymphadenopathy and massive hepatosplenomegaly. CBC revealed white cell count (WBC) of 103.9k/mm3 with 94% lymphocytes. Bone marrow biopsy and lymph node biopsy confirmed involvement with peripheral T cell neoplasm HTLV-1 positive. He was treated with EPOCH x 2, ICE (Iphosphamide, carboplatin, etoposide) x 1 and high dose methotrexate x 1 with disease progression. He was started on Romidepsin 10 mg/m2 IV Day 1, 8, 15 Q28 days (dose reduced due to T. bili 3.5gm/dl). After first dose, patient developed severe thrombocytopenia to 20k/mm3 necessitating treatment delay and dose reduction to 6mg/m2. He had temporary response as evidenced by reduction in WBC count from 103kmm3 to 5k/mm3 and improvement in liver function. Patient received 1 cycle of therapy and died on Day 50 from disease progression.

Case 3: 47 year old male presented with a 6x4 cm exophytic left forearm lesion, diffuse lymphadenopathy and normal CBC and metabolic profile. Skin biopsy confirmed CD30 positive peripheral T cell neoplasm HTLV-1 positive. Patient received 6 cycles of CHOP with complete resolution of lymphadenopathy and skin lesions. Patients stayed in remission for 12 months however relapsed with lymphocytosis to 57k/mm3, recurrence of skin lesions and diffuse lymphadenopathy. He received brentuximab x 2 cycles and ICE x 2 cycles with progressive disease. He was started on romidepsin 14mg/m2 IV Day 1, 8, 15 Q28 days. He received 1 dose and had prolonged Grade IV anemia/thrombocytopenia. He finally developed urosepsis and expired on Day 20.

Conclusion: ATLL is a rare and difficult disease to manage. In our small experience of romidepsin in relapsed/refractory ATLL, patients appear to have modest response rates and higher rate of cytopenias when compared to other PTCL subtypes in clinical trials. A dedicated phase II study of romidepsin in relapsed/refractory ATLL is needed to assess its efficacy and toxicity profile in this population. Given the concerns for viral reactivation and lack of data for use of romidepsin in ATLL, it should be used cautiously.