Bortezomib salvage therapy in refractory acute adult T-cell leukemia/lymphoma

Outcomes for acute/leukemic adult T-cell leukemia/lymphoma (ATL) remain extremely suboptimal^1,2. Median survival of only nine months and five year overall survival rates of less than 30% have been recently been reported in acute ATL patients receiving best available therapy³. Treatment for refractory and relapsed disease is particularly challenging due to chemotherapy resistance^4,5. In in vitro and in vivo ATL models, bortezomib⁶ can induce suppression of nuclear factor-κB (NF-κB) activation and reduce BIRC5 expression⁷, leading to caspase-dependent apoptosis, an effect that may be augmented by concurrent chemotherapy⁸.

A 48 year old male was hospitalized with a three week history of drenching night sweats, weight loss and left upper quadrant pain. Examination and imaging demonstrated submandibular, cervical, axillary, pelvic and inguinal lymphadenopathy with massive splenomegaly. Laboratories revealed a leukocytosis of 39,000/mm³ with 66% lymphocytes, hypercalcemia at 13.6 mg/dl and LDH elevated greater than ten times the upper limit of normal. Bone marrow biopsy showed a hypercellular marrow with numerous atypical lymphoid aggregates; flow cytometry demonstrated a 51% population of abnormal CD4+, CD25+ and CD7− T lymphocytes consistent with ATL⁹. The patient tested HIV negative and HTLV-1 positive. Treatment with EPOCH chemotherapy¹⁰, oral zidovudine 300mg twice daily and intrathecal cytarabine prophylaxis was initiated. After the first cycle there was RECIST progression with enlarging lymphadenopathy and increasing LDH. Bortezomib (IV) 1mg/m² on days 1, 4, 8 and 11 of each cycle was added as salvage therapy. After a single cycle of “V-EPOCH” his lymphadenopathy resolved and his LDH normalized. After four cycles of V-EPOCH peripheral blood flow cytometry and a bone marrow examination revealed no evidence of residual leukemia. After five cycles of V-EPOCH, a consolidative non-myeloablative haploidentical bone marrow transplant was undertaken but complicated by non-engraftment in the setting of CMV viremia. However, he experienced full autologous count recovery and remains in complete remission¹ 36 months since treatment completion.

This is the first report of the successful clinical use of bortezomib to treat ATL; we await with interest prospective results from the phase I/II trial (NCT01000285) “Dose-adjusted EPOCH chemotherapy with bortezomib combined with integrase inhibitor therapy for HTLV-1 Associated T-Cell Leukemia Lymphoma” currently recruiting patients at multiple centers in the United States. Itonaga and colleagues⁵ recently reported that effective immune mediated anti-leukemic salvage therapy for ATL relapse after allogeneic stem cell transplantation (SCT) was associated with chronic graft versus host disease (GVHD)¹¹. Given the diverse immunomodulatory effects associated with bortezomib, including increased susceptibility to NK cell lysis¹², altered MHC class I epitope presentation^12,13, enhanced early immune recovery and importantly reduction in acute and chronic GVHD following mismatched unrelated donor transplantation¹⁴, clinical trials of this class of agent in ATL relapse prevention and treatment may also be warranted, particularly in the setting of SCT.