A Novel and Efficient Induction Approach for Accelerated Differentiation and Rapid Hematopoietic Recovery in Acute Promyelocytic Leukemia (APL) Patients by Combining All-Trans Retinoic Acid (ATRA) with Granulocyte-Colony Stimulating Factor (G-CSF).

Abstract

Background: Despite successful treatment with ATRA and chemotherapy (CT), nearly 10% of APL patients die during early part of treatment because of life threatening complications like bleeding, thrombosis, Retinoic Acid Syndrome (RAS) or infection. This number increases to >20% in most developing countries and presents significant challenge for clinicians. The goal is to develop therapy that rapidly corrects coagulopathy and also normalizes counts. Recent in-vitro data had suggested that G-CSF markedly and selectively stimulates the differentiating effect of ATRA in APL cells without increasing apoptosis. The objective of this pilot study was to evaluate the effect of G-CSF given along with ATRA during induction therapy in patients with APL. Patients and Methods: From 2003, 25 patients (ages 1 yr to 43 yrs; median 24 yrs) with APL ineligible for standard CT were treated on a pilot study with Oral CT: Prednisolone 40 mg/m2/d, Etoposide 50 mg/m2/d & 6TG 40 mg/m2/d (PET) for 21 days as induction therapy along with ATRA (45 mg/m2/d for 90 days) (Blood2005;106:900). On completion of oral CT, G-CSF (5 mg/kg/d) was added after day 25 to ATRA in 12 patients in view of persistent cytopenia (low ANC &/or platelets). Results: Patients received a median of 4 doses of G-CSF (range 2–12). The median ANC before starting G-CSF was 0.493 × 109/L (range 0.014–4.21) which increased to a median of 1.78 × 109/L (range 0.525–13.0) post G-CSF (> 1.0 × 109/L in 10/12 patients). Interestingly, platelet count which was < 50.0 × 109/L in 8/12 patients (median 44.15 × 109; range 12–178) prior to G-CSF, increased to > 100.0 × 109/L in all except one patient (median 177 × 109; range 64–357). Comparison of pre and post G-CSF cytogenetic status by FISH showed significant decrease in t (15; 17) positivity post ATRA-G-CSF exposure (78-0; 80-11; 54-10). In rest nine patients the bone marrow cytogenetic studies were done post G-CSF only. Complete morphological, cytogenetic and molecular remission was achieved in 9 patients (75%) at a median of 40 days. None of the patients developed RAS, bleeding or thrombotic complications. Presently all 12 patients continue to be in molecular remission at a median follow-up of 17 months (range 9–35 months). Conclusions: There is still a valuable role of single institutional trials in exploring innovative therapies in APL. Chemotherapy, ATRA and arsenic trioxide, all induce apoptosis which causes over expression of Annexin II, which in turn increases plasmin generation and thrombin generation. However, when G-CSF is used in combination with ATRA, neither proliferation arrest nor induction of apoptosis precedes the differentiation. Thus, use of G-CSF along with ATRA very early in therapy of APL may help to decrease or avoid the early life-threatening coagulation abnormalities. Also, rapid improvement in ANC and platelet count could decrease the other induction complications of infection & bleeding, further improving survival.