MORBIDITY AND COSTS OF REMISSION INDUCTION THERAPY WITH ALL-TRANS-RETINOIC ACID COMPARED WITH STANDARD CHEMOTHERAPY IN ACUTE PROMYELOCYTIC LEUKEMIA

With the recent pressure to control health care expenditures, the cost s of patient participation in clinical trials, especially in their ear liest phases, have come under increasingly intense scrutiny. We theref ore reviewed our experience in patients with acute promyelocytic leuke mia (APL) who were treated during the first US trial of a new experime ntal drug, all-trans retinoic acid (RA). The purpose of the review was to evaluate parameters of patient morbidity and financial cost associ ated with the use of all-trans RA compared with standard chemotherapy for induction of complete remission in newly-diagnosed patients with A PL. We retrospectively compared outcomes of consecutive patients treat ed during the first 2 years of our studies that used all-trans RA for remission induction (1990-1992) with an identical number of patients c onsecutively treated with standard chemotherapy (cytosine arabinoside plus an anthracycline) during the immediately preceding period (1985-1 990). Responding patients in both groups received postremission chemot herapy. Evaluation parameters included transfusions of packed red bloo d cells and platelets, use of anti-bacterial and anti-fungal drugs, du ration of fever, time to remission, length of hospital stay, hospital charges, and both overall and relapse-free survival. Thirty patients w ere evaluated in each group. Complete remission was achieved in 26 pat ients (87%) treated with all-trans RA, and 24 patients (77%) treated w ith chemotherapy (p=0.5). In the chemotherapy group, there were five e arly deaths (four from hemorrhage, one from sepsis); one other patient was resistant to treatment and died at 6 months. Four patients in the all-trans RA group died prior to response from complications of the ' retinoic acid syndrome'. The median time to complete response by all c riteria was 41 days (range, 18-78) for the all-trans RA group and 50 d ays (range, 24-121) for patients who received conventional chemotherap y (p=0.2). Looking only at patients who achieved remission, chemothera py-treated patients required a significantly greater number of platele t transfusions (medians, 14 vs. 4; p < 0.001) and packed red blood cel l transfusions (15 vs. 4; p < 0.001). Patients who received chemothera py also experienced a significantly larger number of days with fever ( 13 vs. 6; p=0.01) that was reflected in a greater median number of day s on combination antibiotics (35 vs. 21; p=0.001) and Amphotericin B ( 20 vs. O; p < 0.001). For patients who achieved complete remission, th e median length of hospital stay during induction was 30 days for the all-trans RA group and 44 days for the chemotherapy group (p=0.002). F or all patients, the median cost of hospitalization during induction e xclusive of physician charges expressed in constant 1992 dollars was $ 61756 for the all-trans RA group compared with $97944 for the chemothe rapy group (p=0.012). Kaplan-Meier analysis of both relapse-free (p=0. 011) and overall survival (p=0.014) significantly favored patients who received all-trans RA for remission induction. Both standard chemothe rapy and all-trans RA induce complete remission in a high proportion o f patients with APL. Compared to the use of chemotherapy alone, early mortality has not yet been substantially altered by all-trans RA. Howe ver, this treatment program that employs all-trans RA alone for remiss ion induction, followed by cytotoxic chemotherapy for consolidation, h as improved survival with significantly less morbidity and lower cost. For patients with serious diseases such as cancer, participation in e arly-stage clinical trials may not only be cost-effective but may also represent state-of-the-art clinical care for these individuals.