Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents

Abstract

The prognosis for higher risk childhood B-cell non-Hodgkin lymphoma has improved over the past 20 years but the optimal intensity of treatment has yet to be determined. Children 21 years old or younger with newly diagnosed B-cell non-Hodgkin lymphoma/B-cell acute lymphoblastic leukemia (B-NHL/B-ALL) with higher risk factors (bone marrow [BM] with or without CNS involvement) were randomized to standard intensity French-American-British/Lymphoma Malignancy B (FAB/LMB) therapy or reduced intensity (reduced cytarabine plus etoposide and deletion of 3 maintenance courses M2, M3, M4). All patients with CNS disease had additional high-dose methotrexate (8 g/m2) plus extra intrathecal therapy. Fifty-one percent had BM involvement, 20% had CNS involvement, and 29% had BM and CNS involvement. One hundred ninety patients were randomized. The probabilities of 4-year event-free survival (EFS) and survival (S) were 79% +/- 2.7% and 82% +/- 2.6%, respectively. In patients in remission after 3 cycles who were randomized to standard versus reduced-intensity therapy, the 4-year EFS after randomization was 90% +/- 3.1% versus 80% +/- 4.2% (one-sided P = .064) and S was 93% +/- 2.7% versus 83% +/- 4.0% (one-sided P = .032). Patients with either combined BM/CNS disease at diagnosis or poor response to cyclophosphamide, Oncovin [vincristine], prednisone (COP) reduction therapy had a significantly inferior EFS and S (P < .001). Standard-intensity FAB/LMB therapy is recommended for children with high-risk B-NHL (B-ALL with or without CNS involvement).

Figure 1

Treatment and follow-up. Treatment and design schema (A) and patient follow-up diagram (B). Reduction phase COP: cyclophosphamide, Oncovin (vincristine), and prednisone. Induction phase COPADM1 and COPADM2: cyclophosphamide, Oncovin (vincristine), prednisone, Adriamycin (doxorubicin), and methotrexate. Intensification phase CYVE or mini CYVE: cytosine arabinosine 3 g/m² versus 2 g/m² and etoposide 200 mg/m² versus 100 mg/m². Maintenance phase: maintenance 1, 2, 3 and 4. Rectangles indicate approximate times of treatment failure events; SMN, secondary malignant neoplasm.

Figure 2

Probability of EFS and S of all patients and randomized patients. (A) Product-limit estimate of probability of EFS and S in all patients from study entry. EFS at 4 years, 79% ± 2.7%; S at 4 years, 82% ± 2.6%. (B) Product-limit estimate of probability of EFS from randomization of patients randomized to C1 versus C2 (mini CYVE and deletion M2, M3, M4 courses); EFS at 4 years 90% ± 3.1% versus 80% ± 4.2%, P = .064.

Figure 3

Stratified probabilities. Probability of EFS and S stratified by BM, CNS, or BM/CNS (A) and response to COP reduction (B). (A) Product-limit estimate of probability of EFS in patients with BM disease only (BM⁺/CNS⁻), CNS disease only (BM⁻/CNS⁺), and combined BM and CNS disease (BM⁺/CNS⁺) (88% ± 3.0% versus 82 ± 5.6% versus 61% ± 6.0%, P < .001). (B) Product-limit estimate of probability of EFS in patients with complete response (CR; 100%), incomplete response (IR; 20%-99%) and nonresponse (NR; < 20%) after COP reduction therapy (94% ± 3.8% versus 78 ± 3.1% versus 30% ± 16%, P < .001).

Figure 4

Survival probability after progression/recurrence. The probability of 4-year survival of patients with persistent, progressive, or recurrent disease, excluding those experiencing toxic deaths or secondary neoplasms, was 16% ± 6.1%.

Figure 5

Percentage of grade III/IV toxicities. Rates of grade III/IV stomatitis, infection, and other nonhematologic toxicities, within therapy courses. The left column shows the rates of these toxicities during COP, COPADM1, COPAMD2, and maintenance course that were common treatments received by all patients. The right column shows the comparative rates of these toxicities for the CYVE (standard) or mini CYVE (reduced) course received by patients with (CNS⁺) or without (CNS⁻) CNS disease at diagnosis. Reductions in stomatitis, infection, and other nonhematologic toxicities during these courses were statistically significant (P < .001, P < .01, and P < .005, respectively).