Arsenic Trioxide (As₂O₃) in the Treatment of Patients with Newly Diagnosed Acute Promyelocytic Leukemia (APML) - Toxicity and Outcome.

There is limited data on outcome and toxicity in newly diagnosed patients with APML treated primarily with arsenic trioxide (As₂O₃). We have treated 58 patients with APML, who were unable to receive all-trans retinoic acid (ATRA) based therapy, with As₂O₃ between 1997–2004. As₂O₃ was administered as follows: 10 mg/day for adults and 0.15 mg/kg/day for children. For remission induction, it was given till hematological remission (CR) was achieved (or maximum of 60 days) followed by a consolidation course of 28 days, 1 month after achieving CR. Maintenance therapy was administered for 10 days every month for 6 months. Hydroxyurea was used to control rising white cell counts. Patients were monitored for blood counts, coagulation profile, liver and renal functions and for cardiac complications. Supportive treatment was provided as necessary. There were 58 patients (30 males, 28 females) with a mean age of 28 years (range: 6 – 60) and a median WBC count at diagnosis of 2.8 x 10⁹/L (range: 0.6 to 163.4). At diagnosis, 34 patients (58.6%) had severe thrombocytopenia < 20 x 10⁹/L, 5 (8.6%) had coagulopathy while 8 (13.7%) had abnormal liver functions. Leukocytosis was seen in 46 patients (79.3%) starting at an average of 5 days (range: 1–20) after starting treatment with As₂O₃. Only 4 of these went on to developn an ATRA-like syndrome which resolved with treatment in all. The mean WBC count at this time in these patients was 31.5 x 10⁹/L (range: 15.3 to 45.8). In 43 patients, leukocytosis was controlled with hydroxyurea while 3 patients required additional treatment with anthracyclines. Hydroxyurea was given for a mean of 11 days (range: 2 – 28) with temporary discontinuation of As₂O₃ in 6 patients. Asymptomatic elevation of liver enzymes and mild sensory neuropathy were seen in 9 patients each (15.5%) not requiring discontinuation of As₂O₃. One patient developed supraventricular tachycardia for which arsenic was temporarily discontinued, but was restarted later with cardiac medication without further complications. Hyperpigmentation and ichythosis of the skin were seen in 8 patients (13.7%). Twenty seven patients (46.5%) had coagulopathy and required corrective infusion of fresh frozen plasma for a median of 4 days (range: 2 – 15). Thirteen patients (22.4%) had >10% weight gain related to fluid retention. Gastrointestinal side effects of dyspepsia and vomiting were seen in 3 patients (5.1%). Minor side effects included myalgia and conjunctival suffusion in 1 patient each (1.7%). Nine patients expired less than 2 weeks into treatment due to intracranial hemorrhage. Response to As₂O₃ was therefore evaluable in 49 patients. Fortyseven patients (95%) achieved hematological remission. Of the two patients who did not achieve remission, one expired on day 21 due to intracranial bleed while the second died on day 22 due to bacterial sepsis. One patient in hematological remission died due to fungal pneumonia on day 60. Forty six patients have received subsequent courses of As₂O₃. At a median follow up of 23 months (range: 3 – 79), 4 (8.6%) have relapsed. Of these, 3 have achieved a second remission with As₂O₃ and ATRA. Presently, 45 patients (77.5%) are alive and in molecular remission with a leukemia free survival of 91.3%. Our data shows that As₂O₃ alone induces durable remission in a majority of patients with APML with no major toxicity. Long term follow up is required to assess the late effects of As₂O₃.