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Bezafibrate and medroxyprogesterone acetate in resistant and relapsed endemic Burkitt lymphoma in Malawi; an open-label, single-arm, phase 2 study (ISRCTN34303497)

2013; Wiley; Volume: 164; Issue: 6 Linguagem: Inglês

10.1111/bjh.12681

1365-2141

Elizabeth Molyneux, Blair Merrick, Farhat L. Khanim, Kondwani Joseph Banda, Janet Dunn, Gulnaz Iqbal, Christopher M. Bunce, Mark T. Drayson,

Acute Myeloid Leukemia Research

Endemic Burkitt lymphoma (eBL) accounts for half of childhood cancers where malaria is holoendemic (Molyneux et al, 2012). Limited healthcare resources preclude intensive chemotherapy, restricting cure rates to 90% for children in high income countries (Patte et al, 2001). Intensification of chemotherapy in Africa has produced 20% infection-related mortality rates (Harif et al, 2008; Hesseling et al, 2013). Malnutrition, late stage presentation and co-infections are compounding problems for managing eBL even with non-intensive regimens (Israels et al, 2009; Hesseling et al, 2013). Our laboratory studies showed BaP [Bezafibrate (Bez) and Medroxyprogesterone acetate (MPA)] had potent anti-eBL activity and thus might provide affordable, non-toxic therapy (Fenton et al, 2003). Concurrently we have shown BaP has activity against other blood cancers in the laboratory and in clinical trials (Desmond et al, 2003; Khanim et al, 2009; Murray et al, 2010 and ISRCTN99131400). Over 5 years, from February 2007, 95 children with relapsed or resistant eBL were recruited to assess three doses of BaP for toxicty and anti-eBL activity. At first diagnosis these children had received cyclophosphamide (CPM) 40 mg/kg i.v. on day 1 and CPM 60 mg/kg orally on days 8, 18 and 28, with intrathecal methotrexate and hydrocortisone (i.t. MTX/HC) both at 12·5 mg on days 1, 8, 18 and 28. Twenty-five patients had also received vincristine 1·5 mg/m2 iv on days 1, 8, 18 and 28. BaP was administered daily from study entry to end of all therapy. Low dose BaP comprised 4 mg/kg MPA twice daily with Bez 200 mg once daily for patients 20 kg. Both intermediate and high dose BaP comprised MPA at 20 mg/kg once daily. For intermediate dose BaP, Bez was one 400 mg tablet/10 kg daily and twice that for high dose BaP. In 61 patients, BaP was given alone for a week before starting CPM 60 mg/kg orally plus vincristine 1·5 mg/m2 on days 8, 18 and 28; in 34 patients BaP and chemotherapy were started concurrently. There was no significant difference in patient characteristics between the low, intermediate and high BaP dose cohorts (Table 1). Overall median age was 8 years (range 1–14); male:female ratio 58:37; resistant:relapsed disease ratio 24:71; weight <3rd centilein 68% patients. No toxicity occurred during BaP therapy alone (61 patients, 16 of whom received high dose BaP. A further 34 children received BaP therapy concurrently with chemotherapy from day 1 when the tumour burden was high, and no evidence of tumour lysis was seen. During all periods of concomitant administration of BaP and chemotherapy (95 patients) diarrhoea, vomiting, infection requiring antibiotics and blood transfusions occurred at the expected rates for chemotherapy alone with the only difference being a trend to more vomiting when taking high dose BaP. No patients stopped BaP therapy because of adverse events. Overall, 58% took BaP for 3–4 weeks and 24% for 2–3 weeks. It is important to note that laboratory assessment of toxicity was limited. However, only one death occurred during therapy in 95 children, which was less than expected with chemotherapy alone (Hesseling et al, 2013) and considerably less than the 25% treatment-related mortality encountered when applying more intensive chemotherapy in the Blantyre unit (Hesseling et al, 2013). The diagnosis of eBL can be difficult to make quickly and confidently in new patients in Africa (Naresh et al, 2011) but in this study this had been achieved at least some weeks prior to study entry with resistant or relapsed disease. The response of eBL to BaP was assessed directly in 61 patients receiving BaP alone for the first 7 d before adding standard rescue chemotherapy on day 8. Early assessment of lymphoma response can be difficult and was limited by lack of radiology. However progressive disease (PD) was defined as any clinical enlargement of the tumour or worsening of signs or symptoms. When PD was suspected during the first week of BaP therapy alone, standard rescue therapy was commenced immediately. PD was seen in only 7/24 evaluable children on low dose BaP and in none of the patients on intermediate or high dose BaP (Table 2). No Clinical Change (NCC) was considered to be significant evidence of BaP anti-eBL activity because eBL normally increases in size substantially in a week without anti-BL therapy. NCC was seen in 11/24 (46%) of the evaluable low dose BaP cohort patients. In the intermediate and high dose groups this percentage increased to 22/31 (71%) alongside a reduction in PD from 29% to 0% (Table 2). Comparing the four response groups between the three cohorts, there was a significant difference driven by the difference in PD in the patients receiving low dose (Fishers exact test, P = 0·04). In the low and intermediate BaP dose cohorts, complete clinical response (CCR) at the end of BaP plus rescue chemotherapy was seen in 39% of patients [95% confidence interval (CI) = 24–58%] and 44% patients (95% CI = 29–61%), respectively (Table 2). In the high BaP dose cohort, the CCR rate was significantly higher at 68% (95% CI = 51–81%; Mantel-Haenszel chi-square test for trend P = 0·03). One year plus follow-up in the low and intermediate BaP dose cohorts demonstrated a CCR of 24% (8/33; 95% CI = 13–41%) and 18% (5/28; 95% CI = 8–36%) respectively. Of the 34 high BaP dose patients, 21 are known to be dead and 8 alive beyond a year giving a CCR of 28% (95% CI = 15–46%); 6 were lost to follow-up. The only historical data from the Queen Elizabeth Central Hospital, Malawi for comparison is a cohort of 28 eBL patients who relapsed or were resistant after receiving less intense chemotherapy at first diagnosis than the current study patients received (Hesseling et al, 2013). In that cohort, the CCR 95% CI was similar (21–54%). The more successful the protocol of induction therapy is, the worse the prognosis is for patients resistant to or relapsing from that protocol (Molyneux et al, 2012). Accordingly, survival would be expected to be worse in this study than the historical comparators; the high dose BaP group also received vincristine at induction and would have been expected to have the worst CCR rates if BaP had no efficacy against eBL. Although this study has shown safety and efficacy of BaP against eBL, a randomized controlled trial is required to detect whether the addition of BaP to current non-intensive chemotherapy protocols produces a survival benefit for eBL patients. We would like to thank all the staff of SOBO paediatric oncology ward at QECH, and the children and their guardians who took part in the study. Leukaemia & Lymphoma Research and British Society of Haematology gave grants to BM and a programme grant to MD and CB which supported FK. Funding QECH; University of Birmingham, UK. MD, CB, FK conceived the study translation from laboratory studies. MD, EM, JD, GI designed the study and protocol. EM, KB managed the study. EM, KB and BM collected the data. MD, BM, EM, FK, JD, GI and CB analysed data and wrote the manuscript. All authors read and approved the final manuscript. None.