Bortezomib Combined with VXLD Chemotherapy Is Highly Effective In Advanced B-Lineage Acute Lymphoblastic Leukemia Allowing Early Study Termination Due to Efficacy. A Therapeutic Advances in Childhood Leukemia (TACL) Consortium Phase II Study

Abstract 251

Literature review and TACL experience support an expected less than 40% complete remission rate with variety of regimens in patients with ALL in second and subsequent relapse (Ko, J Clin Oncol 2010; 28: 648–654). We had shown that bortezomib might be safely combined with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin (VXLD) in the phase I portion of our study (Messinger, Pediatr Blood Cancer 2010;55:254–9). We now report the phase II expansion of that study.

ALL patients who relapsed or were refractory after 2 or 3 regimens were treated with bortezomib 1.3 mg/m²/dose on days 1, 4, 8 and 11, combined with VXLD. Patients between ages 1 to 21 years old, with more than 25% bone marrow blasts, were eligible. One patient from the phase I cohort with these criteria was included in the phase II extension.

In the phase II extension 22 patients were treated with this combination and all are included in analyses. All patients had relapsed or failed at least 2 prior regimens. Overall 14 achieved complete remission (CR; M1 marrow with ANC and platelet recovery and no extramedullary disease or circulating blasts) and 2 achieved CRp (CR with no platelet recovery) for total 73% remission rate (Table). This level of response exceeded the predefined criteria, allowing for early termination of the study. Three patients (14%) died from bacterial infections and two patients (9%) had no response (Table). One patient (4.5%) was not evaluable for response due to protocol violation, when additional therapy was administered before CR was confirmed with peripheral blood count recovery. B-Lineage ALL patients fared best, with 16/20 achieving CR + CRp (overall response rate 80%), whereas the two patients with T-cell ALL did not respond. Similarly, B-Lineage ALL had superior bone marrow response (M1 marrow): B-Lineage = 17/20 (85%) vs. T-cell = 0/2 (0%). Severe grade 3 or more peripheral neuropathy (PN) was seen in 2 (9%) patients, (one had prior vincristine PN). One patient has developed mucor invasive sinus and orbital infection, requiring halting therapy after day 14 but achieved CRp. After the 3 (14%) septic deaths, the use of vancomycin, levofloxacin and voriconazole or posaconazole prophylaxis in the last 6 patients has prevented further infectious mortality.

In conclusion, the regimen of bortezomib + VXLD is exceptionally effective in multiple relapsed B-Lineage ALL with the highest response rate for any multiply relapsed ALL trial reported thus far. The use of prophylactic antibiotics may be effective in reducing mortality. Bortezomib with VXLD should be further evaluated in randomized fashion on frontline relapse and high-risk pediatric B-Lineage ALL clinical studies.