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Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1192-1200
A Randomized Comparison of All Transretinoic Acid (ATRA) Followed by
Chemotherapy and ATRA Plus Chemotherapy and the Role of Maintenance
Therapy in Newly Diagnosed Acute Promyelocytic Leukemia
Pierre Fenaux,
Claude Chastang ,
Sylvie Chevret,
Miguel Sanz,
Hervé Dombret,
Eric Archimbaud,
Martin Fey,
Consuelo Rayon,
Françoise Huguet,
Jean-Jacques Sotto,
Claude Gardin,
Pascale Cony Makhoul,
Philippe Travade,
Eric Solary,
Nathalie Fegueux,
Dominique Bordessoule,
Jesus San Miguel,
Harmut Link,
Bernard Desablens,
Aspasia Stamatoullas,
E. Deconinck,
Fréderic Maloisel,
Sylvie Castaigne,
Claude Preudhomme, and
Laurent Degos for the European
APL Group
From the European APL Group (list of participants in appendix).
All transretinoic acid (ATRA) followed by daunorubicin (DNR)-AraC
chemotherapy (CT) has improved the outcome of acute promyelocytic leukemia (APL) by comparison to CT alone. In a randomized trial, (1) we
compared 2 induction schedules (ATRA followed by CT
[ATRA CT] and ATRA plus CT [ATRA+CT, with CT added on day
3 of ATRA treatment]) and (2) we assessed the role of maintenance
treatment. Four hundred thirteen patients  75 years of age and with
newly diagnosed APL were included. Induction treatment was stratified
on white blood cell (WBC) count and age: patients 65 years of age
and with an initial WBC count of 5,000/µL (n = 208)
were randomized between ATRACT and ATRA+CT
(initially randomized patients); patients with a WBC count greater than
(high WBC count group, n = 163) and patients 66 to 75 years of age
with a WBC count greater than 5,000/µL (elderly group, n = 42) were
not initially randomized and received ATRA+CT from day 1 and
ATRA CT, respectively. All patients achieving CR
received 2 additional DNR-AraC courses (only 1 in patients 66 to 75 years of age) and were then randomized for maintenance between no
treatment, intermittent ATRA (15 days every 3 months) for 2 years,
continuous low-dose CT (6 mercaptopurine + methotrexate) for 2 years,
or both, using a 2-by-2 factorial design. Overall, 381 (92%) of the
patients achieved complete remission (CR), 31 (7%) suffered an early
death, and only 1 patient had leukemic resistance. ATRA syndrome
occurred in 64 patients (15%) and was fatal in 5 cases. The CR rate
was similar in all induction treatment groups. Event-free survival
(EFS) was significantly lower in the high WBC group (P = .0002) and close to significance in the elderly group (P = .086) as compared with initially randomized patients. Relapse at 2 years was estimated at 6% in the ATRA+CT group, versus 16% in the
ATRACT group (P = .04, relative risk [RR]
= .41). EFS at 2 years was estimated at 84% in the ATRA+CT group, versus 77% in the ATRACT group (P = .1, RR
= .62). Two hundred eighty-nine patients were randomized for
maintenance. The 2-year relapse rate was 11% in patients randomized to
continuous maintenance CT and 27% in patients randomized to no CT
(P = .0002) and 13% in patients randomized to
intermittent ATRA and 25% in patients randomized to no ATRA (P
= .02). An additive effect of continuous maintenance CT and
intermittent ATRA was seen, and only 6 of the 74 patients who received
both maintenance treatments had relapsed. Overall survival was improved
in patients who received maintenance CT (P = .01), and there
was a trend for better survival in patients who received maintenance
ATRA (P = .22). Our findings strongly suggest that early
addition of chemotherapy to ATRA and maintenance therapy combining
continuous CT and intermittent ATRA can reduce the incidence of relapse
in APL. This effect already translates into significantly better
survival for maintenance treatment with continuous CT.
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