ALBERT

Description: Background: Treatment of chronic myeloid leukemia (CML) with a tyrosine kinase inhibitor (TKI) offers significant improvements over previous treatments in terms of survival and toxicity yet has been associated with reduced health-related quality of life and very high cost. Discontinuing TKIs with regular monitoring is safe, but little is known about the impact of discontinuation on patient-reported outcomes (PROs). In the largest U.S. study to date, we evaluated molecular recurrence of CML and PROs after TKI discontinuation. Methods: The Life After Stopping TKIs (LAST) study was a prospective single-group longitudinal study. Key inclusion criteria were age 〉 18 years, patient on TKI therapy (imatinib, dasatinib, nilotinib, or bosutinib) for 〉 3 years with documented BCR-ABL 〈 0.01% by PCR for 〉 2 years, and no previous TKI resistance. We monitored disease outcome (PCRs by central lab) and PROs (PROMIS computerized adaptive tests via REDCap) monthly for the first 6 months, every 2 months until 24 months, then every 3 months until 36 months. Molecular recurrence was defined as 〉 0.1% BCR-ABL IS by central lab (loss of major molecular response [MMR]). We considered 3 points to be clinically meaningful and hypothesized that by 6 months after TKI discontinuation, fatigue, depression, sleep disturbance, and diarrhea would improve by at least 3 points each, corresponding to a standardized effect size of 0.3. Given reports of a withdrawal syndrome of musculoskeletal pain in some patients after discontinuation, pain was an additional outcome of particular interest. For each PRO domain, we estimated a polynomial piecewise linear mixed effects model that specified one nonlinear trajectory after TKI discontinuation and, for those with molecular recurrence, another trajectory after TKI restart. The models included patient-level random effects for the intercepts and linear slopes. Results: From 12/2014 to 12/2016, 172 patients enrolled from 14 U.S. sites. Median age was 60 years (range 21-86) and 89 (52%) were female. The median time on TKI prior to enrollment was 81 months (IQR 54-123). With a minimum follow-up of 24 months, 107 (62%) patients remained in a treatment free remission (TFR). Reasons for restarting therapy were: loss of MMR by central (n=56) or local (n=2) lab, patient decision (n=4), and withdrawal syndrome (n=3). Missing PRO data was minimal (〈 5%) with 〉 2000 assessments completed. For patients in TFR at 6 months, the average estimated improvement in fatigue was 2.6 points (95% CI 2.5-2.7), depression was 1.9 points (95% CI 1.8-1.9), sleep disturbance was 0.9 points (95% CI 0.8-1.0), and diarrhea was 2.7 points (95% CI 2.6-2.7). The average estimated worsening in pain interference (i.e., the extent to which pain affects daily life) was 0.4 points (95% CI 0.3-0.5). The figure shows the distribution of estimated change for each domain at 6 months. All patients showed improvements in depression, diarrhea, and fatigue. About 1 in 6 patients (17%) experienced a clinically meaningful (i.e., at least 3 points) improvement in fatigue and/or diarrhea at 6 months. Conclusion: The LAST study is the largest US TKI discontinuation study to date, and the first to include comprehensive PRO measurement. For patients in TFR at 6 months, TKI discontinuation conferred modest benefits in fatigue and diarrhea on average, with a negligible increase in pain interference. Some patients experienced more notable improvements in fatigue and diarrhea. Planned secondary analyses will include change over time up to 3 years and evaluation of additional PRO domains, including anxiety, physical function, social function, and sexual function. Our results provide important new evidence to support shared patient-provider clinical decision making regarding TKI discontinuation for patients with CML. Figure. Disclosures Radich: Novartis: Other: RNA Sequencing; TwinStrand Biosciences: Research Funding. Mauro:Pfizer: Consultancy; Takeda: Consultancy; Novartis Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Pinilla Ibarz:Sanofi: Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Takeda: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy. Larson:Celgene: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Agios: Consultancy. Oehler:Blueprint Medicines: Consultancy; NCCN: Consultancy; Pfizer Inc.: Research Funding. Deininger:Humana: Honoraria; Incyte: Honoraria; Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Ascentage Pharma: Consultancy, Honoraria; TRM: Consultancy; Sangoma: Consultancy; Fusion Pharma: Consultancy; Adelphi: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Sangamo: Consultancy. Shah:Bristol-Myers Squibb: Research Funding. Ritchie:Tolero: Other: Advisory board; Celgene: Other: Advisory board; Celgene, Novartis: Other: travel support; Jazz Pharmaceuticals: Research Funding; Celgene, Incyte, Novartis, Pfizer: Consultancy; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Genentech: Other: Advisory board; Pfizer: Other: Advisory board, travel support; agios: Other: Advisory board. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cortes:Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Atallah:Jazz: Consultancy; Helsinn: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy; Helsinn: Consultancy; Novartis: Consultancy.

Description: Tumor lysis syndrome (TLS) is a potentially lethal metabolic complication of chemotherapy or cytolytic antibody therapy usually seen in patients with hematologic malignancies, especially those malignancies with a high proliferative rate, large cellular burden and/or sensitivity to chemotherapy. The prevention and management of TLS includes hydration and reduction of serum uric acid (SUA) levels. Although Allopurinol (ALLO) has had longstanding use for TLS prophylaxis, its efficacy in controlling SUA is limited, especially due of its lack of action on pre-existing hyperuricemia. Rasburicase (RAS), a recombinant urate oxidase, effectively reduces SUA due to conversion of UA into allantoin, a readily excretable and soluble substance. RAS has significant activity in the initial management of TLS-associated acute hyperuricemia in pediatric populations, and is currently indicated in the US for this condition in children and adolescents. A prospective, randomized, controlled phase III study was conducted in adult pts to compare the efficacy in SUA control of RAS (0.20 mg/kg/d, IV) days 1–5, versus RAS+ALLO (RAS 0.20 mg/kg/d, IV days 1–3 plus oral ALLO 300 mg/day days 3–5) versus ALLO alone (300 mg/d) days 1–5. 280 pts (275 evaluable) with hematological malignancies at high or potential risk for TLS were enrolled. 92 pts received RAS, 92 pts received RAS+ALLO, and 91 received ALLO. Treatment arms were well balanced in terms of demographics, baseline characteristics, TLS risk, and percentage of pts with baseline hyperuricemia. The SUA response rate - defined as normalization of SUA (≤ 7.5mg/dl) at days 3–7 was 87.0% in the RAS arm, 78.3% in the RAS+ALLO arm and 65.9% in the ALLO arm. RAS was superior over ALLO (p=0.0009) in the overall study population as well as in pts at high risk TLS (89.0% vs. 62.8%, p=0.0012), and in pts with baseline hyperuricemia (89.5% vs. 52.9%, p=0.0151). The time to control SUA in hyperuricemic pts was 4.1 h in the RAS arm and 27 h in the ALLO arm. The mean SUA area under the curve (AUC) results indicated that there was an 8.4-fold increase in UA exposure in the ALLO arm compared to the RAS arm. There were no significant differences in the incidence or severity of adverse events, serious adverse events or deaths. The majority of RAS and/or ALLO-related adverse events were grade 1 and 2, and most of these events were hypersensitivity-related reactions. No cases of anaphylaxis, methemoglobinemia or hemolysis were observed with RAS treatment. In conclusion, RAS is superior to ALLO in normalization of SUA, with a faster effect, in adult pts at risk for TLS. RAS alone or followed by ALLO are two valid options for this patient population.

Description: Previously we have demonstrated that multiple myeloma cell lines and primary cells express CD52, the antigenic target of Campath-1H, and that they undergo apoptosis following treatment with alemtuzumab in-vitro (Gasparetto et al. ASH #3210,2002). Based on these observations, we initiated a clinical trial where patients with advanced, multiply relapsed MM were treated with subcutaneous (sc) alemtuzumab as a single agent. Nine patients (6 men/4 women, age range 45–69 yrs) were initially treated with the standard dose of 30mg sc three times per week for up to 12 weeks. All patients had at least 4 lines of prior therapy and 8/9 patients had undergone high dose chemotherapy followed by autologous peripheral blood stem cell transplant. Treatment related toxicities included pancytopenia in all patients with grade IV neutropenia in the first four patients, necessitating withdrawal from study. Subsequently, all patients were treated with G-CSF and aggressive transfusion support and no further patients were removed from study due to cytopenias. All patients were prophylaxed with Famvir, Fluconazole and Septra and no opportunistic infections were noted during treatment. Two patients developed acute renal insufficiency that reversed when alemtuzumab was discontinued. One patient completed the entire 12 weeks of treatment. One patient had a PR with a 40% reduction in M-protein after two months of treatment, which reversed once Campath-1H was discontinued. Pharmacokinetic studies of one patient demonstrated that it required 8–10 weeks of treatment using the sc protocol to achieve serum levels of alemtuzumab of 1ug/ml, the level considered to be tumoricidal in-vivo. Based on this observation, the treatment protocol was modified so that the initial week of escalating doses was given IV to achieve more rapid therapeutic levels. Following this, sc alemtuzumab was given as above. One patient with non-secretory multiple myeloma with relapsed disease following 5 prior lines of therapy has been treated with this modified protocol. Treatment with alemtuzumab and growth factor support in this patient has been well tolerated except for the development of RSV pneumonia. At 4 weeks, a PET scan demonstrated a significant overall decrease in metabolic activity in multiple bony areas consistent with a response to treatment. These initial results suggests that alemtuzumab is associated with significant toxicities in patients with advanced multiple myeloma including pancytopenia, infections and possibly renal insufficiency but all of these were reversible and have been minimized with aggressive prophylactic therapy. Alemtuzumab does appear to have modest activity against MM in this heavily pre-treated group suggesting that it should be explored in combination with other agents and at earlier stages of disease.

Description: Abstract 1462 Despite progress made in understanding the biology and risk-adapted treatment of AML, prognosis of older pts [age ≥60 years (y)] remains poor. We have shown that high expression of the BAALC gene bestows worse outcome in older CN-AML pts. Yet, the mechanism(s) by which BAALC affects response to therapy remain unknown. MicroRNAs (miRs) are small noncoding RNAs that hybridize to target mRNAs and inhibit their translation or promote degradation, resulting in downregulation of the corresponding proteins. Recently, miR-3151 was discovered embedded in intron 1 of BAALC. We thus hypothesized that miR-3151 might be co-expressed with BAALC and contributes alone or in concert with its host to poor prognostic impact in older CN-AML. MiR-3151 and BAALC expression were measured by quantitative real time (RT) PCR in pretreatment blood of 179 older CN-AML pts enrolled on Cancer and Leukemia Group B (CALGB) cytarabine/daunorubicin-based protocols. The expression values of miR-3151 and BAALC were normalized to the internal controls SNORD44 and RN18S1, respectively. MiR-3151 expression correlated only weakly with the expression of BAALC (Spearman correlation r= 0.3). For clinical and prognostic analyses pts were dichotomized into high and low miR-3151 and BAALC expressers at the median miR and gene transcript expression values and analyzed for other molecular prognosticators (FLT3 -ITD, FLT3 -TKD, CEBPA, IDH1, IDH2, NPM1, TET2, WT1 mutations and ERG expression). Gene (GEP) and microRNA (MEP) expression profiles associated with miR-3151 expression were derived, using Affymetrix U133 plus 2.0 & OSU CCC v4.0 arrays, respectively. At diagnosis, higher miR-3151 expression was associated with lower % blood blasts (P =.02), FAB types M4 and M5 (P =.05), and wild-type NPM1 (P

Description: Abstract 2681 Background: Despite recent advances, the 5 year overall survival for patients with high risk diffuse large B cell lymphoma (DLBCL) is approximately 50% and there is still no known cure for patients with mantle cell lymphoma (MCL). This phase II study of multimodal dose dense therapy evaluated 2 courses of dose intense chemotherapy followed by radioimmunotherapy (RIT) consolidation in patients with previously untreated, mantle cell or high/high intermediate (int) risk aggressive B cell lymphoma. Aim: To evaluate the efficacy and safety of dose intense/dose dense, multimodal chemo-immunotherapy combined with RIT. Methods: Patients with untreated MCL or high int/high risk DLBCL were enrolled. Treatment regimen involved 3 phases of therapy: induction 1, induction 2 and consolidation with RIT (Table 1). Induction 2 occurred approximately 5 weeks after induction 1 and RIT was given 12–24 weeks after rituximab was completed. Patients were evaluated after each treatment phase and those with stable disease (SD) or better and blood count recovery could proceed to the next phase of therapy. Results: Thirty nine patients (pts) with high/high int risk DLBCL (n=25) or MCL (n=14) were enrolled. The median age was 60 years (range 21–80). Toxicity: Common, anticipated toxicities in the induction phases were thrombocytopenia, neutropenia, nausea, fatigue, and anemia. During Ind1 (n=39), grade (gr) III mucositis occurred in 13 pts (33%) and febrile neutropenia (FN) in 31 (79%). Three pts did not proceed to Ind2 due to death (1 candidemia, 1 septic knee prosthesis, 1 from complications of colectomy for prolonged diverticulitis after count recovery) and 2 withdrew to pursue less intense chemotherapy. During Ind2 (n=34) gr III mucositis occurred in 12pts (35%) and FN in 24 (67%). Two pts had gr III/IV cerebellar toxicity that was disabling in 1 pt. Of the 34 pts who received the Ind2, 9 did not receive RIT due to progressive disease (PD) (4), prolonged cytopenias (4), or diagnosis of pancreatic cancer (1). Twenty five pts received RIT and 3 (12%) had FN, 20 (80%) had gr III/IV neutropenia, 23 (92%) had gr III/IV thrombocytopenia, 1 pt died from bacteremia. Two pts developed myelodysplasia 21 and 48 months after starting therapy. Response: Pts were evaluated for response after Ind1, Ind2 and RIT. 38/39 pts were evaluable for response, with 1 pt withdrawing prior to assessment. The pts who died prior to response evaluation were counted as non-responders. The best overall response rate (ORR) was 95% (36/38) with a complete response rate (CR) of 84% (32/38). See tables 2 and 3 for more detailed response data by phase of treatment and disease type. After a median follow up of 17.2 months, 30 pts (77%) are alive (see figure). The median overall survival for MCL has not been reached and is 36.5 months for DLBCL. Deaths were from Hodgkin lymphoma (1), infection (3), DLBCL (2), complications of surgery (1), MCL (2). The median progression free survival is 36.5 months with 11/14 (79%) MCL and 14/25 (56%) DLBCL pts alive and in continued CR. Conclusion: The combination of dose dense, dose intense chemotherapy, monoclonal antibody, and RIT demonstrates considerable efficacy, despite expected toxicity, in high risk DLBCL and MCL pts. The response rates seen in this study are higher than expected from standard R-CHOP in this pt population. Further follow up to determine impact on OS and long term complications will be required to confirm these promising outcomes. Disclosures: Beaven: Glaxo Smith Kline: Family Member Employed by GSK. Off Label Use: Tositumomab is approved for use in relapsed/refractory low grade CD20 positive NHL. It is not FDA approved for first line use in diffuse large B cell lymphoma or mantle cell lymphoma. Neither cytarabine nor etoposide are approved for use in non-Hodgkin lymphoma. Rizzieri:Glaxo Smith Kline: Speakers Bureau. Moore:Glaxo Smith Kline: Speakers Bureau.

Description: Galiximab is a PRIMATIZED®, anti-CD80, monoclonal antibody with human IgG1 constant regions and macaque variable regions. CD80 is an immune costimulatory molecule that is constitutively expressed on the surface of follicular lymphomas. Modest single-agent clinical activity was demonstrated in a Phase I study in relapsed or refractory, follicular NHL (ORR=11%). Preclinical data show that galiximab + rituximab may be more effective than either antibody alone. Here we report updated results from the Phase II part of a multicenter study (Study 114–21) evaluating galiximab + rituximab for relapsed or refractory, follicular NHL. Patients (pts) were administered galiximab (500 mg/m2 qwk x 4) concurrently with a standard course of rituximab (375 mg/m2 qwk x 4). Rituximab-refractory pts (no response or a response with TTP

Description: High-dose therapy plus autologous stem cell transplant (ASCT) is the standard of care for patients with multiple myeloma (MM) aged ≤65 years. Melphalan–prednisone (MP)-based therapy is the standard for non-ASCT candidates but is not typically used for transplant-eligible patients as prolonged therapy with melphalan can adversely affect stem cell collection. The phase 3 VISTA study demonstrated the superior efficacy of bortezomib plus MP (VMP) versus MP in previously untreated MM patients ineligible for ASCT. In this phase 2 study, we evaluated the efficacy of a shorter course of VMP on a different treatment schedule as induction therapy prior to ASCT or as frontline therapy in non- ASCT candidates. Patients aged ≥18 years with previously untreated MM received up to six 28-day cycles of bortezomib 1.3 mg/m2 IV, days 1, 4, 8, and 11, plus oral melphalan 6 mg/m2 and oral prednisone 60 mg/m2, days 1–7. After 2–6 cycles, ASCT-eligible patients could proceed to stem cell mobilization (G-CSF 10 mg/kg/day ± GM-CSF 250 mg/m2/ day or cyclophosphamide 4 g/m2 + GM-CSF) and conditioning with melphalan 200 mg/ m2 (140 mg/m2 if aged 〉65 years). Response was assessed every two cycles and post- ASCT by International Uniform Response Criteria. The primary end point was complete response (CR) rate to VMP. A total of 45 patients were enrolled; 27 were male. Median age was 63 years (range 33–75). MM subtype was 67% IgG, 16% IgA, and 9% each κ- and λ- light-chain; 37% of patients had ISS Stage III MM, 22% had ECOG performance status 〉1, and 70% had ≥40% plasma cells in bone marrow. In total, 20 patients proceeded to ASCT. Median duration of VMP was 4 cycles in both non-ASCT (range 1–6) and ASCT (range 2–6) patients. Response rate (best response) to VMP was 95% (42 of 44 evaluable patients), including 9% stringent CR (sCR), 9% CR (18% ≥CR [95% CI: 7%, 30%]), 27% very good partial response (VGPR), and 50% partial response (PR). Best response was achieved after cycle 2 in 10 patients, cycle 4 in 25 patients, and cycle 6 in 7 patients. All 20 ASCT patients had successful stem cell mobilization; median yield of CD34+ cells/ kg was 5.6 x 106 (range 2.3–12.2 x 106), in a median of 2 collection days. Post-transplant responses were 10% sCR, 20% CR, 55% VGPR, and 5% PR; the remaining 2 patients need further follow-up for response assessment. Response improved post-VMP to post-ASCT in 10 patients (6 PR to VGPR, 2 PR to CR, 2 VGPR to CR). After median follow-up of 14.0 months (range 7.4–47.7) and 14.6 months (range 8.2–42.9) in non-ASCT and ASCT patients, respectively, both median time to progression and progression-free survival were 19.8 months (95% CI: 14.3 months, not estimable [NE]) in non-ASCT patients and 27.9 months (95% CI: 14.6 months, NE) in ASCT patients. A total of 7 patients (5 non- ASCT, 2 ASCT) have died; 1-year survival rate was 82% (95% CI: 59%, 93%) in non- ASCT patients and 95% (95% CI: 69%, 99%) in ASCT patients. Most common grade 3/4 adverse events in all 45 patients during VMP therapy included peripheral neuropathy (24%), thrombocytopenia (20%), neutropenia (18%), and infection (9%). Only 1 patient had deep-vein thrombosis. In conclusion, VMP represents a highly effective therapy for previously untreated MM, with 45% of patients achieving VGPR or better, including 18% sCR/CR. Toxicities were predictable and generally manageable. Short-course VMP therapy did not negatively impact stem cell mobilization, supporting its use as induction therapy prior to ASCT. Very high post-transplant response rates were seen, with 85% of patients achieving ≥VGPR, including 30% sCR/CR. Since achievement of CR/VGPR is associated with improved long-term outcomes in MM, the preliminary outcome data presented here appear promising; however, longer follow-up is required.