Combination Chemotherapy with CHOP-Daclizumab in HTLV-I Associated Adult T-Cell Leukaemia/Lymphoma. (2006)

Abstract Adult T-cell leukaemia/lymphoma (ATLL) is a lymphoproliferative disorder linked aetiologically to the retrovirus HTLV-I. Despite new insights into the pathogenesis of ATLL, there has been little improvement in the treatment or survival of these patients. Since ATLL express abundant surface IL2-R (CD25), and following from the results with unmodified anti-CD25, we combined daclizumab (Zenapax - Roche) with standard CHOP to assess the feasibility of this combination. Eligibility criteria included: histologically confirmed ATLL requiring treatment, no previous therapy with anthracycline based chemotherapy, age 18–75 and informed consent. CHOP-daclizumab drug schedule: day 1 cyclophosphamide 750mg/m2 iv, doxorubicin 50mg/m2 iv, vincristine 1.4mg/m2 (max 2mg) iv, day 1–5 prednisolone 100mg po, and daclizumab 1mg/kg iv on day 7 and 14 during first cycle, and on day 1 from cycle 2 to 6. Daclizumab was administered on day 7 due to expected high levels of soluble IL2-R which would saturate the antibody activity. Cycles were repeated every 21 days. Infection prophylaxis included co-trimoxazole, itraconazole and acyclovir. Patients had weekly CMV PCR monitoring. Ten patients were enrolled into the study between February 2004 and October 2005 (9 females,1 male, median age 44 years (range 27–61 years). 9 patients were of Caribbean origin and 1 African. Five patients presented with acute leukaemia, four with lymphoma type and one with chronic ATLL. The main disease features were: lymphadenopathy (80%), hypercalcaemia (50%, median serum calcium 3.23 mmol/L), organomegaly (40%), skin lesions (20%), CNS symptoms (10%). Six patients had peripheral blood lymphocytosis (range 10–96x109/l), serum LDH was elevated in 9 patients (380–6065 IU/L, NR &lt;240 IU/L), six patients had LDH level more than 3 times above normal. All patients had serum antibodies to HTLV-I detected by ELISA and Western blot analysis. Median HTLV-I viral load 75.8 HTLV-I DNA copies/100 PBMCs (Leukaemia 100.4 copies/100 PBMCs; Lymphoma 27.8 copies/100 PBMCs). None of our patients received previous treatment for ATLL. Eight patients completed 6 cycles of treatment, one patient 4 cycles and one patient 3 cycles. Treatment was well tolerated and no unexpected toxicities, in particular viral complications, were observed. 50% of patients achieved CR with 2 patients remaining in CR after &gt;24 months of follow up. The other 3 patients suffered early relapse (after 1–3 months) and died from progressive disease. Two patients achieved PR, and 3 had progressive disease while on treatment. Seven out of 10 patients died 4–19 months from the diagnosis. Three patients are alive (2 in CR and 1 in PR - maintained on interferon/tenofovir) with median follow up of 23 months (range 11–30 months). Our data confirm that daclizumab in combination with CHOP chemotherapy is feasible with a response rate of 70%. There is minimal added toxicity, and specifically no added viral infections. However, the short duration of response remains the main problem in ATLL treatment and future studies with increased doses of daclizumab in addition to long term maintenance are warranted.