Halvorson, Alese E.

Abstract Background: Potent inhibitors of BCR-ABL1have improved remission results and altered post-remission therapy for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Dasatinib plus dexamethasone followed by hematopoietic cell transplantation (HCT) promises high response rates, reduced toxicity, and durable remissions. Methods: We conducted a Phase II trial at 17 U.S. centers with the primary objective being to estimate the 3-year overall survival and disease-free survival of patients with Ph+ ALL treated with dasatinib and dexamethasone for remission induction and intensification, central nervous system (CNS) prophylaxis, consolidation with reduced-intensity conditioning (RIC) allogeneic HCT, autologous HCT, or etoposide and cytarabine, and dasatinib-based maintenance. Eligible patients had untreated Ph+ ALL, were ≥18 years old, and had normal cardiac function. Induction (Course I) used dasatinib 140 mg oral daily and dexamethasone 10 mg/m2/day oral or intravenous (IV) days 1-7. For patients with ≤20% blasts in the Course I, Day 15 bone marrow biopsy, intensification (course II) continued daily dasatinib with another 7 days of dexamethasone. Those with >20% lymphoblasts also received vincristine (VCR) and daunorubicin (DNR). Patients (n=3) not in CR/CRi after Course II received a second induction (Course III) with dasatinib, cyclophosphamide, VCR, DNR, and dexamethasone. After Course II or III, CNS prophylaxis (Course IV) consisted of IV VCR and IV, oral, and intrathecal methotrexate (MTX). Dasatinib was restarted at serum [MTX] <0.05 microM. Course V consisted of HCT or chemotherapy. Patients aged 18-70 years with an HLA-matched donor underwent RIC allogeneic HCT; otherwise they underwent autologous HCT. Allogeneic HCT conditioning used fludarabine 30 mg/m2/day IV day -7 through -3, alemtuzumab 20 mg/day IV day -7 through -3, and melphalan 140 mg/m2 once on day -2. GVHD prophylaxis with tacrolimus began day -2. Patients undergoing autologous HCT received etoposide 10 mg/kg/day (age >65 years, 5 mg/kg/day) continuous IV for 4 days and cytarabine 2 g/m2 (age >65 years, 1 g/m2) IV every 12 hours for 8 doses (EA) then G-CSF for mobilization. Autologous HCT conditioning used melphalan 100 mg/m2/day on days -2 and -1. Patients >70 years or unable to undergo HCT received EA alone. Dasatinib maintenance (Course VI) began on day 30 of Course V and continued for 12 months and until 2 consecutively negative bone marrow BCR-ABL1RT-PCR assays 3 months apart or until relapse. Dasatinib levels were measured on day 15 of induction. Results: Sixty-six patients enrolled from 12/15/2010 to 11/14/2014; 65 received dasatinib and are evaluable. Median age was 60 years (22-87); 49% were male. Median presenting WBC count was 23.1 x 103/ul (0.3-453.6). No deaths occurred during induction or intensification. CR or CRi occurred 31 patients (48%) by Day 15 of induction and in 62 patients overall (95%; CR 86%). Median dasatinib levels in serum and CSF on Day 15 of induction were 30.3 ng/mL (<3-308) and 0.29 ng/mL (<0.2-1.37), respectively suggesting approximately 1% of plasma dasatinib penetrates into the CSF, less than the unbound fraction (6%). Fifty-four patients started Course IV, 38 Course V, and 37 Course VI. Fourteen patients continue on protocol therapy. Of 38 patients receiving Course V, 22 had allogeneic HCT, 6 had autologous HCT, and 10 had EA chemotherapy. Median age of allogeneic HCT recipients was 61 years (31-69). Robust autologous stem cell mobilization was observed [median CD34+ cell count, 90 x 106/kg (31-166, n=6)]. Dasatinib maintenance was feasible after allogeneic HCT, autologous HCT, and chemotherapy alone with no missed doses in 59%, 83%, and 63% of cycles, respectively. Ten patients have relapsed with one isolated CNS relapse. No relapses have occurred after allogeneic HCT with 3 relapses after autologous HCT and one after Course V EA alone. Median follow up for survivors is 22.8 months (longest, 51 months). There have been 23 deaths: 5 treatment-related (4 after allogeneic HCT, 1 after course V EA), 16 disease-related and 2 unrelated. Conclusions: Dasatinib with dexamethasone yields CR rates comparable to those reported with tyrosine kinase inhibitors combined with conventional chemotherapy. Post-remission therapy with reduced-intensity allogeneic HCT, autologous HCT, or chemotherapy followed by dasatinib maintenance is feasible. Survival follow up is maturing. Disclosures Stock: Sigma-Tau: Honoraria, Research Funding; Royalties for a chapter in Up to Date: Patents & Royalties; ADC Therapeutics: Honoraria; Amgen: Honoraria; Gilead Sciences: Honoraria. Beumer:Bristol-Myers Squibb: Research Funding. Stone:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Juno Therapeutics: Consultancy; Karyopharm: Consultancy; Sunesis Pharmaceuticals: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Jansen: Consultancy; Merck: Consultancy; ONO: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Xenetic Biosciences: Consultancy. Larson:Bristol-Myers Squibb: Consultancy; Astellas: Consultancy, Research Funding.

Abstract Background: Autologous stem cell transplantation is an integral part of myeloma therapy for patients who are able to undergo the treatment. While high dose melphalan has remained the typical conditioning regimen for ASCT in MM, recently there have been efforts to enhance the conditioning therapy by adding newer drugs to melphalan. Addition of bortezomib as well as carfilzomib have been attempted in phase 2 trials. Previous studies have shown that the combination of melphalan and total body irradiation (TBI) is an effective conditioning regimen. Pre-clinical studies have shown that bortezomib can sensitize MM cells to radiation, and based on this finding, we designed a clinical trial to examine the feasibility of combining low dose TBI with a combination of melphalan and bortezomib. Patients and Methods: The primary goal of the phase 1 study was to determine the maximally tolerated dose (MTD) of bortezomib that can be added to high dose melphalan and low dose TBI as part of conditioning chemotherapy in patients undergoing an ASCT for MM. The secondary goals were to examine the toxicities associated with addition of bortezomib to high dose melphalan and TBI in patients with MM and to determine the progression free rate at 1 and 2 years. Patients eligible to receive full dose melphalan conditioning regimen for ASCT were included as long as they had no more than 2 prior regimens and had not received a prior transplant. An accelerated design that was later converted to a standard 3+3 cohort design was used for dose escalation. Three patients were treated at a given dose level combination and observed for at least 36 days to assess toxicity. Melphalan 80 mg/m2 was given days -4, -3, with bortezomib at increasing doses given on day -5, -2 along with TBI of 200 cGY given on the same days of bortezomib, timed after bortezomib administration. Stem cells were infused day 0. Results: Eleven patients were enrolled; 6 were males, and the median age was 60 years. Median time from diagnosis was 5.4 months (range 3.4-7.0). Four dose levels were explored with increasing doses of bortezomib (0.7 mg/m2 to 1.6 mg/m2). No dose limiting toxicities were observed. The dose levels and the best response after ASCT are as shown in the Table. The overall response rate was 100%, including 7/11 with a CR or sCR. With a median follow-up of 12.5 months, two patients have progressed; median OS was not reached. Toxicity was mostly hematologic, with other AEs being grade 3 or less and attributable to the conditioning therapy. All patients engrafted their counts adequately. Conclusion: The combination of melphalan, bortezomib, and low dose TBI is a safe conditioning regimen in patients with MM with good efficacy. The regimen should be further examined in the phase 2 setting. Table Table. Disclosures Kapoor: Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Kumar:Noxxon: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Research Funding; Janssen: Research Funding; Skyline: Consultancy, Honoraria.

7503 Background: Prior to use of novel targeted agents for CLL, debate existed regarding the best chemoimmunotherapy regimen to build upon in patients (pts) with non-del(11q) disease. The role of lenalidomide (L) was also not defined. CALGB 10404 was a randomized phase 2 study addressing these questions. Methods: Pts with untreated CLL requiring therapy were randomized to treatment with fludarabine + rituximab (FR), FR + 6 monthly consolidative treatments of L (5 mg days 1-21/28 x 1 then 10 mg days 1-21/28 x 5) (FR+L), or FR + cyclophosphamide (FCR). Based on pretreatment central interphase cytogenetic screening, pts with del(11q22.3) in at least 20% of cells were excluded from the primary analysis, testing whether 2-year progression-free survival (PFS) rate was improved in non-del(11q) pts within each arm. A target accrual of 103 non-del(11q) pts per arm provided at least 84% power to detect an increase in 2-year PFS rate from 60% to 73%; the critical value was 69% using a single stage design and type I error rate of 4%. Results: A total of 342 non-del(11q) CLL pts were randomized to treatment with FR (n = 123), FR+L (n = 109), or FCR (n = 110). Baseline characteristics were similar across arms. Two-year PFS rates with exact 90% CIs were 64% (57-71%) (FR), 71% (63-78%) (FR+L), and 74% (66-80%) (FCR). Median PFS was significantly shorter with FR compared to FR+L (p = 0.03) and FCR (p < 0.01): 43 (95% CI: 33-50), 66 (95% CI: 45-not reached), and 78 (95% CI: 58-not reached) months respectively. Median overall survival (OS) has not been reached for any arm. OS at 1, 2, and 3 years was similar across arms, although there was a plateau in OS with no events beyond 41 months in the FR+L arm, different from FR/FCR where events continued to occur. The most common adverse events were cytopenias and infections. Conclusions: FR+L and FCR met the protocol defined primary endpoint. FR+L extended PFS relative to FR and a plateau in survival differentiated this arm from the FR/FCR arms. Future studies comparing FR+L to FCR or incorporating L into other novel treatment regimens are justified. Support: U10CA180821, U10CA180882, Celgene. Clinical trial information: NCT00602459.

Key PointsBrief lenalidomide consolidation after chemoimmunotherapy is acceptably tolerated and extends PFS and OS in CLL. FCR has superior efficacy compared with FR chemoimmunotherapy for CLL.

AbstractWaldenström macroglobulinemia (WM) is an immunoglobulin M‐associated lymphoma, with majority of cases demonstrating MYD88 locus alteration, most commonly, MYD88L265P. Owing to low prevalence of the wild‐type (WT) MYD88 genotype in WM, clinically relevant data in this patient population are sparse, with one study showing nearly a 10‐fold increased risk of mortality in this subgroup compared to patients with MYD88L265P mutation. We studied a large cohort of patients with MYD88L265P and MYD88WT WM, evaluated at Mayo Clinic, Rochester, between 1995 and 2016, to specifically assess the impact of these genotypes on clinical course. Of 557 patients, MYD88L265P mutation status, as determined by allele‐specific polymerase chain reaction, was known in 219, and 174 (79%) of those exhibited MYD88L265P, 157 of 174 patients had active disease. Of 45 (21%) patients with MYD88WT genotype, 44 had active disease. The estimated median follow‐up was 7.0 years; median overall survival was 10.2 years (95% CI: 8.4‐16.5) for MYD88L265P versus 13.9 years (95% CI: 6.4‐29.3) for the MYD88WT (P = 0.86). The time‐to‐next therapy from frontline treatment and the presenting features were similar in the two patient populations. For patients with smoldering WM at diagnosis, the median time‐to‐progression to active disease was 2.8 years (95% CI: 2.2‐3.8) in the MYD88L265P cohort and 1.9 years (95% CI: 0.7‐3.1) in the MYD88WT cohort (P = 0.21). The frequency of transformation to high‐grade lymphoma, or the development of therapy‐elated myelodysplastic syndrome was higher in the MYD88WT cohort (16% versus 4% in the MYD88L265P, P = 0.009). In conclusion, MYD88L265P mutation does not appear to be a determinant of outcome, and its presence may not be a disease‐defining feature in WM. Our findings warrant external validation, preferably through prospective studies.

Key Points PVD is an active combination in relapsed lenalidomide-refractory MM patients. PVD with weekly bortezomib offers a simpler, more convenient, and well-tolerated regimen option.

Key Points The combination of ixazomib and dexamethasone has clinical activity in patients with relapsed and or refractory multiple myeloma. Higher dose of ixazomib leads to improved response rates but with higher rates of treatment related adverse events.