Treatment of Acute Promyelocytic Leukaemia in Jehovah’s Witness(JW) Population

Treatment Of Acute Promyelocytic Leukemia (APML) In The Jehovah’s Witness (JW) Population. Colm Keane, Peter Mollee, Paula Marlton, Devinder Gill. Background: Treatment of acute myeloid leukaemia in JW patients is challenging. The refusal to accept blood products is usually a contraindication to intensive chemotherapy and a potential cure. Methods: We review three cases of APML occurring in JW patients treated at our institution which demonstrate the benefit of newer targeted combination therapies that induce less marrow suppression. Suggested management principles are derived from these anecdotal rare cases. Case 1 was a 39 year old male who was initially treated with ATRA (25 mg/m2) and Darbopoietin 100μg twice weekly with arsenic added on day 10 (0.15mg/kg/day). He initially tolerated therapy well despite severe pancytopenia until (day 20) the hemoglobin fell to 52g/L when he developed chest pain. He was diagnosed to have had a myocardial infarct in the setting of fluid retention. His WCC was 10.4 × 109/L with platelet count of 20 × 109/L. He was managed conservatively with no anticoagulation. His hemoglobin nadir was 44 g/L before rising above 80 g/L by day 38 of therapy at which time he was in cytogenetic and molecular remission. He completed a further 28 weeks of consolidation with ATRA (45mg/m2 for 2 weeks every 4 weeks) and arsenic (0.15mg/kg/day Mon-Fri, d1-28 every 2 months for 4 cycles). He has completed 9 months of planned 2 yrs oral maintenance chemotherapy (ATRA, 6MP, MTX) without further incident. Case 2 was a 62 year old female who was treated with ATRA induction (initially at 25mg/m2 but increased to 45mg/m2 on day 18), plus Erythropoietin (Epo) 4,000U × 3 per week s/c. She was in complete cytogenetic remission on day 37 and complete molecular remission by day 87. She had a hemoglobin nadir of 60 g/L but remained asymptomatic. Consolidation therapy commenced on day 106 consisting 3 cycles of combination therapy with ATRA (45mg/m2/d po for 4 weeks) and arsenic (0.15mg/m2/d iv for 5d/week for 4 weeks). Between consolidation cycles there was a 3-week interval during which all therapy was ceased. This regimen was well tolerated. She remains in complete remission after 8 years. Case 3 was a 28-year-old male who was initially treated with ATRA, low dose cytarabine and Epo 4000U 3-times/week s/c. He developed symptoms of severe anemia when his hemoglobin dropped to 25g/L with syncopal episodes and hypotension. He was subsequently found to have t (11:17) mutation and the leukemia did not respond to ATRA. He died from severe anemia fourteen days after presentation. Case reports published subsequently have shown that ATRA resistance in t(11:17) APML may occasionally be overcome if combined with standard chemotherapy or GCSF. However to date Arsenic has not been useful in this variant form of APML. Recommendations: Therapy. Induction with ATRA 25mg/m2 followed on day 10 by arsenic 0.15mg/kg/day until morphologic remission. Consolidation with alternating cycles of ATRA and arsenic as per Case 1. Maintenance therapy with ATRA, 6MP and MTX for 2 years. Anemia. Our patients tolerated severe anemia reasonably well until hemoglobin dropped to approximately 50g/L (most deaths in the literature due to anemia in the JW population have occurred below this threshold). All JW patients receive maximal erythropoietin stimulation and sparing phlebotomy episodes using paediatric blood collection tubes. Thrombocytopenia and coagulopathy. Antifibrinolytics, DDAVP and newer agents such as FVIIa have been used successfully in JW patients undergoing high risk surgery and may be of benefit in the APML setting for patients with haemorrhagic complications. Differentiation syndrome (DS) Case 1 may have developed DS. The standard management of DS is to commence chemotherapy such as idarubicin, cytarabine or gemtuzumab ozogamicin but because of the potential prolonged myelosuppression such agents are not suitable options for JW patients. We would advocate corticosteroids for DS prophylaxis and if treatment of DS is required, hydroxyurea may be a safer option because of its limited and shorter duration of myelosuppression. Conclusion: Our series demonstrates the benefit of more targeted therapy in APML allowing patients who refuse transfusion of blood products a realistic chance of cure.