ALBERT

Description: Abstract 3597 The c-kit (CD117) receptor is expressed on 〉 10% blasts in 64% of de novo AMLs and mediates proliferation and anti-apoptotic effects. High c-kit levels correlate with a shorter time to relapse and decreased overall survival (OS). Imatinib mesylate (IM), a c-kit inhibitor, has activity against relapsed/refractory AML. The primary objective of this study was to determine whether adding maintenance IM for 1 yr after completion of standard induction (IT) and post-remission therapy (PRT) in patients (pts) with newly diagnosed c-kit+ AML improves relapse-free survival (RFS) compared to historical controls. Secondary objectives included: (1) assessing the feasibility of this approach; (2) evaluating outcomes based on c-kit expression (c-kit mean fluorescent intensity [MFI]); (3) determining whether c-kit expression correlates with AF1q gene and/or multi-drug resistance (MDR) gene expression. Methods: Pts were treated at Cleveland Clinic, Duke, Roswell Park, and University Hospitals of Cleveland from 2008 to 2012. IM was supplied by Novartis. Eligibility criteria included: pts age ≥ 18 yrs, AML in first complete remission (CR1), ≥ 20% c-kit+ blasts at diagnosis (dx), ECOG performance status 0–2. Cytogenetics (CG) were classified by CALGB 8461. Pts must have received IT (7+3 [continuous infusion cytarabine (C) and an anthracycline] or ADE [C, daunorubicin, etoposide]) and PRT (≥ 1 course for pts 〉 60 yrs; ≥ 2 courses for pts 〈 60 yrs). CR status was confirmed by bone marrow analysis prior to study enrollment. MDR expression was analyzed by immunohistochemistry on diagnostic samples (n=19); AF1q gene expression was analyzed by RT-PCR on RNA from available diagnostic pt samples (n=9) as previously described (Tse et al. Blood 2004; 104: 3058–63). C-kit MFI was calculated as the mean channel number (MCN) of the blasts/MCN autofluorescence using a CD45/orthogonal light scatter gate to isolate blasts. All pts received IM 600 mg/day for 12 months (mos) unless they experienced toxicity or disease progression. Dose modifications were made for Grades 2–4 non-hematologic toxicity and Grades 3–4 neutropenia and thrombocytopenia. Pts remaining off IM for 〉 4 wks were removed from treatment. Cumulative dose intensity was defined as the proportion of the total optimum dose administered over time. Results: Thirty-three pts were enrolled, with 32 pts having complete data. The median age was 54 yrs (range 19–81), median WBC at dx 22.13 K/μL (1.55–98.44), median peripheral blood blasts at dx 23.6% (range 0–85), and 44% were male. CG risk included: 47% (15) good, 31% (10) intermediate, and 22% (7) poor. The median c-kit % was 79.9, and median c-kit MFI 39.8 (range 6.5–120.1). Median AF1q expression was 9.59 (range 1.83–161.8.5). Eighty-four percent of pts had moderate or high levels of MDR expression (GSTP1, MDR1, LRP1, and/or MRP1); almost half (47%) had high expression. The majority of pts (74%, n=20) received PRT with high dose C (3 g/m2/dose × 6 doses/cycle). Pts received IM for a median of 4.0 mos (range 0.1–12.2), and the median daily dose was 600 mg. Twelve pts (38%) were dose reduced to 400 mg. Forty-five percent (13/29) of pts experienced grade 3 reactions possibly related to treatment, with the majority (31%) being myelosuppression. The most commonly reported adverse events were Grade 1/2 nausea and vomiting (72%), edema (59%), and fatigue (41%). Twelve pts (38%) discontinued treatment for adverse events. The median RFS survival is 18.8 mos, with a median follow-up of 19.1 mos (range 6.4–37.2). Estimated 2-yr OS is 62% ± 10%. Predictors of RFS included: age, WBC at dx, % peripheral blasts at dx, and CG risk. Dose intensity of IM did not correlate with outcome. AF1q and MDR expression did not correlate with c-kit MFI; although the number of pts with AF1q data was small. Of note, neither c-kit MFI nor AF1q expression were prognostic in this subset of pts treated with IM. With the exception of LRP1 expression (p=0.03), there was no correlation of MDR expression with RFS. Conclusions: Previous studies have demonstrated that c-kit MFI 〉 20.3 is an independent adverse prognostic factor for RFS and OS (median RFS 10.7 months). Considering the high c-kit MFI of pts in this study, the outcomes using IM maintenance are encouraging, and suggest that further study of this approach is warranted. Given the toxicities observed, reducing the dose of IM to 400 mg in the maintenance setting may be better tolerated. Disclosures: Advani: Novartis: Research Funding. Rizzieri:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kalaycio:Novartis: Research Funding, Speakers Bureau. Maciejewski:Novartis: Research Funding.

Description: The c-kit (CD117) receptor is expressed on 〉 10% blasts in 64% of de novo AMLs and mediates proliferation and anti-apoptotic effects. High c-kit levels [defined as mean fluorescent intensity (MFI) 〉 20] correlate with a shorter time to relapse and decreased overall survival (OS). Imatinib mesylate (IM), a c-kit inhibitor, has activity against relapsed/ refractory AML. The primary objective of this study was to determine whether adding maintenance IM for 1 yr after completion of standard induction (IT) and post-remission therapy (PRT) in pts with newly diagnosed c-kit + AML improves progression-free survival (PFS) compared to historical controls. We previously presented our toxicity and correlative data at ASH 2012 (Abstract 3597). Here, we present our long term follow-up results. Methods: Pts were treated at Cleveland Clinic, Duke, Roswell Park, and University Hospitals of Cleveland from 2008 to 2012. IM was supplied by Novartis. Eligibility criteria: pts age ≥ 18 yrs, AML in first complete remission (CR1), ≥ 20% c-kit+ blasts at diagnosis (dx), ECOG performance status 0-2. Cytogenetics (CG) were classified per CALGB 8461. Pts must have received IT (7+3 [continuous infusion cytarabine and an anthracycline] or ADE [cytarabine, daunorubicin, etoposide]) and PRT (≥ 1 course for pts ≥ 60 yrs; ≥ 2 courses for pts 〈 60 yrs). CR was confirmed by bone marrow analysis prior to study enrollment. MDR expression was analyzed by IHC on diagnostic samples (n=19); AF1q gene expression was analyzed by RT-PCR on RNA from available diagnostic pt samples (n=9). C-kit MFI was calculated as the mean channel number (MCN) of the blasts/ MCN auto fluorescence using a CD45/orthogonal light scatter gate to isolate blasts and lymphocytes. All pts received IM 600 mg/day for 12 months (mos) unless they experienced toxicity or disease progression. Dose modifications were made for Grade 2-4 non-hematologic toxicity and Grades 3-4 neutropenia and thrombocytopenia. PFS was measured from the CR date to the time of relapse or death. Primary endpoints: Based on historical data from the Cleveland Clinic and SWOG, the median PFS for all AML pts undergoing IT 〈 60 yrs of age is 13 mos and for pts ≥ 60 yrs of age is 8 mos. The goal of this study was to see a 30% improvement in PFS at these time points in the respective age groups (i.e. 65% PFS at 13 mos for pts 〈 60 yrs; 65% PFS at 8 mos for pts ≥ 60 yrs). Results: Of 32 pts enrolled, the median age was 54 yrs (range 19-81), median WBC at dx 22.13 K/ uL (1.55-98.44), median peripheral blood blasts at dx 23.6% (range 0-85), and 44% were male. CG risk included: 16% (5) good, 66% (21) intermediate, 16% (5) poor, 3% (1) miscellaneous. Of the pts with normal CG, 10 were NPM1+, FLT3 ITD negative; and 1 pt was FLT3 ITD+. The median c-kit+ blast % was 79.9, and median c-kit MFI 39.8 (range 6.5-120.1). Median AF1q expression was 9.59 (range 1.83-161.85) (〉 9 is considered high and is associated with a poor prognosis; high AF1q is also associated with high c-kit expression). Eight-four percent of pts had moderate or high levels of drug resistance factors (GST1, MDR1, LRP1, and/or MRP1); almost half (47%) had high expression. There was no correlation between MDR and c-kit MFI. Pts received IM for a median of 4.0 mos (range 0.1-12.2) and the median daily dose was 600 mg. Twelve pts (38%) were dose reduced to 400 mg. Forty-five percent of pts experienced Grade 3 reactions possibly related to treatment, with the majority (31%) being myelosuppression. With a median follow-up time of 56.3 mos, the estimated median OS was 51.3 mos and estimated median relapse-free survival (RFS) 18.9 mos. The estimated PFS at 13 mos for pts 〈 60 yrs of age was 71 ± 10% (p=0.017, compared to the null hypothesis); and the estimated PFS at 8 mos for pts ≥ 60 yrs of age was 64 ± 15% (p=0.166, compared to the null hypothesis). Predictors of worse RFS included: age, WBC at dx, % peripheral blasts at dx, CG risk, and MDR expression. C-kit MFI and Af1q were not associated with RFS or OS. Conclusions: Use of IM maintenance therapy appeared to be associated with improved PFS compared to historical controls in pts 〈 60 yrs of age. In addition to a high c-kit MFI, these pts had other adverse characteristics (moderate to high levels of MDR. high AF1q). Though previous studies have demonstrated that c-kit MFI 〉 20.3 was an independent adverse prognostic factor for RFS and OS (median RFS 10.7 months) in AML, use of IM maintenance therapy in this study appeared to mitigate this, supporting further investigation. Disclosures Off Label Use: imatinib in the treatment of AML. Rao:Boehringer-Ingelheim: Other: Advisory Board; amgen: Other: ad board; novartis: Other: ad board. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Wang:Immunogen: Research Funding. Griffiths:Alexion Pharmaceuticals: Honoraria; Astex: Research Funding; Celgene: Honoraria. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.

Description: BACKGROUND: With the poor prognosis and outcome described in mantle cell lymphoma (MCL), there is a continuing need to explore treatment options that might overcome suspected underlying drug resistance and improve the current median survival of about 24 months. One strategy to overcome drug resistance has been the use of high dose therapy followed by autologous transplant. Newer agents such as the monoclonal antibodies (MoAb) rituximab and alemtuzumab which target CD20 and CD52 respectively have recently become available. We have therefore incorporated both a dose dense approach in combination with these antibodies to treat newly diagnosed and relapsed MCL patients. PATIENTS AND METHODS: A total of 16 patients have been enrolled since February 2003. Induction therapy consisted of 1 cycle of cytarabine 3gm/m2 IV Q12H for 8 doses, mitoxantrone 10mg/m2 daily for 3 days, and Alemtuzumab 30mg IV 3 times a week for 6 weeks with growth factor support. All responding patients were mobilized with cyclophosphamide 4gm/m2 and G-CSF 10 mcg/kg/day and/or bone marrow harvest. The transplant preparative regimen was carmustine 15mg/kg on day -6, etoposide 60mg/kg on day -4, and cyclophosphamide 100mg/kg on day -2 followed by autologous re-infusion. Consolidation was given with rituximab 375mg/m2 weekly for 4 doses at 6 weeks and 6 months post transplant. RESULT: Of the 16 patients, 12 had stage IV, 1 stage III, 3 stage IIA, and 1 stage I disease. The median age was 60 (48 66 years). Eight were newly diagnosed and 8 had relapsed disease with at least 2 prior chemotherapy treatments. In the induction phase, overall response rate was 94% (15/16 patients) with 73% complete response (CR) and 27% partial response (PR). Response rate were 100% and 88% in the newly diagnosed and relapsed patients respectively but CR was similar (75%) in both groups. Nine patients have been transplanted and one patient is awaiting transplant. Six patients were not transplanted due to death in 2 patients with relapsed disease at study entry, and one each due to progression of disease, prolonged cytopenias of 〉 60days, mental status changes and inability to collect peripheral or bone marrow stem cell respectively. Among the transplanted patient, 78% (7/9) remain in CR with 2-year lymphoma progression free survival of 67% after a median follow-up of 487 days (range 175–787 days). Induction therapy toxicities included average neutropenia duration of 11.6 days and CMV reactivation of 50% that was equally distributed in the transplanted and non-transplanted patients. Peripheral stem cell collection was inadequate in 5 of the transplanted patients requiring bone marrow harvest. CONCLUSION: Our preliminary data continue to show a high induction response rate with majority of patients who are able to proceed to the transplant phase remaining free of lymphoma at 24 months. Toxicity was manageable although bone marrow harvest was needed to obtain adequate stem cells in majority of transplanted patients. While CMV reactivation was observed in half of the patients, its effect on the ability of subjects to complete the study and on survival appear to be minimal. Although a small study, multimodal dose dense strategy with maintenance MoAb for patients with mantle cell lymphoma is a promising strategy that needs to be confirmed in larger number of patients with prolonged follow-up.