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Treatment of adult acute lymphoblastic leukemia Phase II trial of dose intensification of daunorubicin and cytarabine followed by high-dose methotrexate and intrathecal methotrexate in place of cranial irradiation



Treatment of adult acute lymphoblastic leukemia Phase II trial of dose intensification of daunorubicin and cytarabine followed by high-dose methotrexate and intrathecal methotrexate in place of cranial irradiation



Blood 98(11 Part 1): 590a, November 16



During the past decade, aggressive combination chemotherapy for adults with ALL has resulted in overall survival rates of 30-40%. Based on results of recent studies, we hypothesized that early dose intensification of daunorubicin and cytarabine may improve disease free survival (DFS) but may not result in increases in an already high remission rate. Other data suggest that aggressive systemic and intrathecal (IT) methotrexate (MTX) can replace cranial RT for central nervous system (CNS) prophylaxis. The CALGB undertook a Phase II study (19802) to examine these issues. Treatment consisted of 6 monthly courses of intensive therapy followed by 18 months (mos) of maintenance therapy. Module A (Courses 1 and 4) consisted of 5-drug induction (cyclophosphamide (Cy), daunorubicin (D), prednisone, vincristine, 1-asparaginase) with G-CSF support (Blood 1998; 92:1556). In patients (pts) <60 yrs, the D dose in module A was increased stepwise from 45 mg/m2 daily X3 (used in prior CALGB ALL studies) to 60 and then to 80 mg/m2 daily X3. In pts gtoreq60 years old, D was increased from 30 to 60 mg/m2 daily X3. Cy was omitted from module A in pts gtoreq60. Module B (courses 2 and 5) introduced high-dose cytarabine (Ara-C), 2 gm/m2 daily X3, plus Cy and G-CSF. Module C (courses 3 and 6) consisted of CNS prophylaxis with IT, intravenous (IV), and oral MTX. From 1/99-1/01, 163 adults with untreated ALL (FAB L1-L2) were entered onto CALGB 19802. Median age was 40 years (16-82); 100 (61%) were male. Central cytogenetic review has been completed in 86 pts and reveals a large proportion of high-risk pts; 27 (31%) had a t(9;22), and 4 (5%) had a t(4;11). 154 pts are evaluable for response. 122 (79%) (95% CI, 71-86%) achieved a complete remission (CR). By age, CR rate was 41/45 (91%) for pts <30 years, 63/78 (81%) in pts 30-59, and 18/31 (58%) in those gtoreq60. 17 (10%) pts died during induction, and there were 15 (9%) who had refractory ALL. The CR rate for pts with t(9;22) or t(4;11) was 71% vs 83% for pts without these abnormalities (p=0.4). Similarly, there was no significant difference in CR rate based on presenting WBC count. CR rates on this study are comparable to those achieved (81-85%) on the 3 preceding CALGB studies (9111, 9311, and 9511) where lower doses of D during induction therapy were administered. Module C therapy appears to be well tolerated and allows 24 hour exposure to high MTX concentrations as an outpatient. As of 6/01, there have been 5 relapses (4%) in the CNS during or following post-remission therapy. We conclude that intensified D during induction therapy is feasible in both younger and older pts with ALL; however, the impact of intensified D and Ara-C on DFS remains to be determined. With limited follow-up, CNS prophylaxis without cranial RT has been well tolerated and has not resulted in an increase in CNS relapses. These data demonstrate that the modular treatment schedule piloted in CALGB 19802 is feasible in a cooperative group and provides a platform for the introduction of novel therapeutic agents in subsequent trials. Longer follow-up is needed to determine whether early dose intensification of daunorubicin and cytarabine will result in better overall survival in adult ALL.

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