Background: Growing evidence indicates that aberrant DNA hypermethylation is associated with leukemogenesis, drug resistance, and relapse. It has been shown that pre-treating leukemia cells with AZA or decitabine could partially reverse the aberrant DNA methylation, restore the expression of tumor suppressor genes, and sensitize cells to chemotherapeutic agents.

Therapy of relapsed pediatric acute lymphoblastic leukemia (ALL) is hampered by low remission rates and high toxicity, especially in second and subsequent relapses. Our phase 1 study, T2005-003, showed that the combination of bortezomib with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin had acceptable toxicity. We report the phase 2 expansion of this combination in patients with relapsed ALL who failed 2-3 previous regimens. Twenty-two patients with relapsed ALL were treated with bortezomib combined with this regimen; their ages ranged from 1 to 22 years, and they had either B-precursor ALL (n = 20) or T-cell ALL (n = 2). Grade 3 peripheral neuropathy developed in 2 (9%) patients. After 3 patients died from bacterial infections, treatment with vancomycin, levofloxacin, and voriconazole prophylaxis resulted in no further infectious mortality in the last 6 patients. Fourteen patients achieved complete remission (CR), and 2 achieved CR without platelet recovery, for an overall 73% response rate, meeting predefined criteria allowing for early closure. B-precursor patients faired best, with 16 of 20 (80%) CR + CR without platelet recovery, whereas the 2 patients with T-cell ALL did not respond. Thus, this combination of bortezomib with chemotherapy is active in B-precursor ALL, and prophylactic antibiotics may be useful in reducing mortality. Bortezomib merits further evaluation in combination therapy in pediatric B-precursor ALL. This study is registered at http://www.clinicaltrials.gov as NCT00440726.

Abstract 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.ResponseAllBTn22202CR14 (64%)14 (70%)0CRp2 (9%)2 (10%)0Total Response16 (73%)16 (80%)0Deaths3 (14%)3 (15%)0SD/PD2 (9%)02 (100%)N/E1 (4.5%)1 (5%)0 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. Disclosures: Messinger: Genzyme: Consultancy. Off Label Use: Bortezomib (Velcade®) is approved for multiple myeloma and mantle cell lymphoma both B cell malignancies. We are describing use in relapsed B cell Acute Lymphoblastic Leukemia which is off label.”

Outcomes remain poor for children after relapse of acute lymphoblastic leukemia (ALL), especially after early marrow relapse. Bortezomib is a proteasome inhibitor with in vitro synergy with corticosteroids and clinical activity in human lymphoid malignancies.

The outcome of relapsed ALL remains very poor, and many re-induction regimens are highly toxic. We report here the Phase I component of a Phase I/II study of bortezomib added to 4-drug induction with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin in children with relapsed ALL. A total of 10 patients were enrolled, 5 in 1 st marrow relapse (2 early and 3 late relapses) and 5 in 2 nd or subsequent relapse. Four patients were enrolled at dose level 1 (1 mg/m 2 ) to obtain 3 evaluable patients. One patient was inevaluable for toxicity because of an error in dexamethasone doses and was removed after 8 days. No dose-limiting toxicity (DLT) was observed. Six patients were enrolled at dose level 2 (1.3 mg/m 2 ), the standard single agent dose. One patient had a DLT (hypophosphatemia and rhabdomyolysis) after1 dose of bortezomib, and that patient died from diffuse zygomyces infection by day 17. Five additional patients were enrolled with no further DLT’s. As planned, no further dose escalation was pursued. The regimen had predictable toxicity related to the chemotherapy drugs. Only 2 patients had mild peripheral neuropathy (grades 1 and 2). Seven of the10 patients (70%) achieved a CR, and 1/10 had bone marrow CR with persistent central nervous system (CNS) leukemia despite weekly intrathecal (IT) methotrexate, for a total of 80% bone marrow CR rate. In conclusion: the combination of bortezomib with 4 standard drugs is highly active with acceptable toxicity in heavily pretreated relapsed pediatric ALL patients. We are expanding the MTD cohort for a phase II estimate, and intend to report updated results at the ASH meeting.