Risk-Adapted Therapy in Adults with Burkitt Lymphoma: Results of NCI 9177, a Multicenter Prospective Phase II Study of DA-EPOCH-R

Background: Burkitt lymphoma (BL) is a highly aggressive lymphoma curable with short-duration, high-intensity chemotherapy. Standard BL regimens are highly effective in pediatric pts, but treatment-related toxicity is a significant barrier in adults and HIV⁺ patients. In an NCI study, we demonstrated lowering treatment intensity with DA-EPOCH-R was highly curative and well-tolerated in 30 adults with sporadic or HIV-associated BL (N Engl J Med 2013; 369:1915-1925). We aimed to validate these results in a multicenter study of DA-EPOCH-R in adult patients with BL, including HIV⁺. We employed a risk-adapted approach based on baseline risk category and interim PET scans after 2 cycles to further reduce treatment-related toxicity.

Methods: Patients with newly diagnosed BL, age over 18 and any HIV status were enrolled at 22 participating sites. Patients with normal LDH, ECOG PS 0-1, </= stage II, and no tumor lesion > 7 cm were considered low-risk (LR). All other patients were considered high-risk (HR). LR patients received 2 cycles of DA-EPOCH-R without intrathecal therapy (IT) followed by PET. If interim PET was negative, LR patients received 1 more cycle. HR patients with negative brain MRI and CSF cytology/ flow cytometry received 2 cycles of DA-EPOCH-R without IT therapy followed by PET. Unless interim PET showed progression, HR patients received 4 additional cycles of DA-EPOCH-R including MTX 12mg IT on days 1 and 5 (8 total doses). HR patients with active CNS disease at baseline received concurrent MTX 12mg IT twice weekly for 2 weeks past negative (minimum of 4 weeks), followed by MTX 12mg IT once weekly x 6, and MTX 12mg IT monthly x 6. No cranial irradiation was permitted.

Results: The study is fully accrued with 113 pts; 110 pts completed therapy and 3 pts on treatment. Characteristics include median age 49 (18-86)y with 55 (49%) patients >/= age 50y and 29 (26%) patients >/= age 60y; male sex 89 (79%); stage III-IV disease 78 (69%); elevated LDH 75 (66%); CNS involvement 10 (10%); HIV⁺ 29 (26%). Fourteen (12%) and 99 (88%) pts were LR and HR, respectively. After a median potential follow-up of 35.7 mos, the progression-free survival (PFS) for all pts beyond 10.2 mos is 85.7% (95% CI: 77.3-91.1%); freedom-from-progression (FFP) is 91.8% (95% CI: 84.2-95.8%) and overall survival is 85.9% (95% CI: 77.3-91.4%). HIV status did not impact survival and therapy was equally effective across all age groups (Figure 1). Patients with BM and/or CNS involvement were at highest risk of treatment failure. The FFP probability after 6 mos for this group was 75.3% (95% CI: 53.0-88.1%) compared to 97.3% (95% CI: 89.4-99.3%), for those without BM/CNS involvement, p=0.0005 (Figure 2). The PFS probability after 6.0 mos was 62.8% (95% CI:42.9-77.4%) compared to 94.6% (95% CI:86.1-97.9%),P<0.0001, respectively (Figure 3). No progressions or deaths occurred on the LR arm. There were 14 deaths, all in the HR arm. Seven deaths were due to disease progression: 3 occurred during therapy, and 4 occurred after therapy complete. Three pts progressed with CNS parenchymal lesions. All 3 had BM involvement but not CNS at baseline, and received prophylactic MTX only. No pt treated for active CNS involvement with IT MTX starting during cycle 1 progressed in the CNS. 5 of 7 progressions included sites of previous involvement. No progression occurred after 10 mos from study entry. Seven deaths were attributable to factors other than disease progression: four toxic deaths occurred during first cycle (2 due to sepsis and 2 due to multi-system organ failure); 1 pt died of respiratory failure after 4 cycles, 1 died of cholangiocarcinoma after 2 cycles, and 1 died of MI in remission 4 months after therapy. Only 1 pt who progressed was successfully salvaged. Results of interim PET scans will be presented at the meeting.

Conclusions: This multicenter study confirms that DA-EPOCH-R cures most adult patients with BL irrespective of HIV status. Low-risk BL is cured with 3 cycles of systemic therapy and no IT therapy is required. The outcome of protocol-defined HR pts compares favorably with more intensive regimens and can be used across all age groups. Patients with BM and/or CNS involvement are at highest risk of treatment failure, and early IT MTX for pts with BM involvement should be considered. Future studies that incorporate rational targeted agents to the DA-EPOCH-R backbone may further improve outcomes by addressing CNS disease and overcoming intrinsic treatment resistance.

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