ALBERT

Description: Background: We have previously shown that CMR predicts better outcomes in Ph+ ALL. The lack of achievement of CMR and particularly major molecular response (MMR) at 3 months may confer poor outcomes. We sought to investigate the outcomes of pts who did not achieve CMR at 3 months as best response in terms of progression free survival (PFS) and overall survival (OS), and the role of allogeneic stem cell transplant (ASCT) in this population. Methods: We reviewed 204 pts with newly diagnosed Ph+ ALL treated at our institution between January 2001 and June 2019 with the combination of Hyper-CVAD plus tyrosine kinase inhibitors (TKI); dasatinib (n=88, 43%), ponatinib (n=72, 35%) and imatinib (n= 44, 22%). PFS was defined from the start of therapy to relapse or death. OS was defined from diagnosis to death or last follow-up. Backward multivariate Cox regression was used to identify prognostic factors for PFS and OS after variable selection at a p-value cutoff of 0.200. Time to ASCT was handled as a time-dependent variable. Survival curves were estimated by Kaplan-Meier method. Landmark analysis at the median time to ASCT was analyzed to evaluate the impact of ASCT. Results: We identified 94 pts (46%) who did not achieve 3-month CMR. Of pts treated with imatinib, 29 (66%) did not achieve 3-month CMR and 16 pts (36%) achieved 3-month MMR. Of pts treated with dasatinib, 42 (48%) did not achieve 3-month CMR and 29 pts (33%) achieved 3-month MMR. Of pts treated with ponatinib, 23 (32%) did not achieve 3-month CMR and 17 pts (24%) achieved 3-month MMR. Patient characteristics are summarized in table 1. Median age was 54 years (range: 21-80). The TKI administered was dasatinib, imatinib and ponatinib in 42 (45%), 29 (31%) and 23 (24%) pts, respectively. Overall, ASCT was performed in 28 pts (30%); 21 out of 62 pts (34%) with 3-month MMR, and 7 out of 32 pts (22%) who did not achieve MMR, within a median time of 5 months (range, 2.3-12.3). After a median follow-up of 97 months, median PFS was 21 months and median OS was 46 months. There was no difference in survival by TKI choice. The 5-year PFS and OS rates were 52% and 23% (p=0.001) (Figure 1A), and 58% and 26% (p=0.001) (Figure 1B) for pts with and without 3-month MMR, respectively. In multivariate analysis (table 2), 3-month MMR predicted longer PFS (p

Description: BACKGROUND Combined fludarabine, cyclophosphamide, and rituximab (FCR) was the preferred regimen for young fit patients (pts) with CLL. The CLL10 trial established FCR as the preferred first-line chemoimmunotherapy (CIT). Recently, the E1912 trial compared first-line FCR vs. ibrutinib + rituximab for young fit pts with CLL. The ibrutinib arm showed an improved PFS and OS vs. the FCR arm; however, there was no difference in PFS for mutated IGHV (M-IGHV) group. With the FCR studies, it is already known that the long-term benefit is seen in pts with M-IGHV. In the MD Anderson Cancer Center (MDACC) FCR trial, long-term follow up demonstrated that the PFS at 10 yrs was approximately 55% for M-IGHV pts with a plateau after 8 yrs, suggesting that these pts may be cured of their CLL. Hence, CIT remains an appropriate first-line option for pts with M-IGHV with fixed duration treatment and expectation for long treatment-free interval. We hypothesized that 1) achieving higher U-MRD would improve PFS and OS and 2) reducing the amount of chemotherapy might lower the risk of t-MDS/AML. We thus developed a CIT regimen called iFCG which consists of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (GA101) for young fit CLL patients with mutated IGHV and without del(17p)/mutated TP53. To decrease chemotherapy exposure, we administered only 3 cycles of chemotherapy in the iFCG regimen. METHODS We designed a phase II study for previously untreated pts with CLL with M-IGHV and absence of del(17p)/mutated TP53 (NCT02629809). All pts had a 2008 IWCLL indication for treatment. Pts received ibrutinib, fludarabine, cyclophosphamide, obinutuzumab for the first 3 cycles. Pts who achieved CR/CRi with bone marrow (BM) undetectable minimal residual disease (U-MRD) after the first 3 cycles received 9 additional cycles of ibrutinib with 3 additional cycles of obinutuzumab; all other pts received 9 additional cycles of ibrutinib and obinutuzumab. Pts with U-MRD (CR/CRi or PR) at 12 cycles stop all therapy, including ibrutinib. Responses were assessed by 2008 IWCLL criteria with BM and CT scans every 3 cycles during the first yr. BM MRD was assessed by flow cytometry (sensitivity 10-4). Post-cycle 12, pts have MRD assessed in blood every 6 months. In pts with available BM samples, MRD was also assessed by an NGS assay (sensitivity up to 10-6). RESULTS 45 pts were treated. Pretreatment characteristics are in Table 1. The median follow-up is 30.2 months. After 3 cycles of iFCG, 39% achieved CR/CRi and 89% achieved BM U-MRD. Responses improved with continued therapy with ibrutinib and obinutuzumab (Figure 1); 73% achieved CR/CRi and 100% achieved BM U-MRD after cycle 12. 41/45 pts completed all planned 12 cycles (4 pts came off study, details below). Per trial design, all 41 pts completing 12 cycles of treatment discontinued ibrutinib since all achieved U-MRD. PFS and OS are shown in Figure 2. No pt had MRD recurrence, CLL progression or Richter transformation, with a median follow-up of 18.7 months (range, 0.2-28.8) post discontinuing ibrutinib. In pts with available BM samples, we also assessed MRD by NGS assay. After 3 cycles of iFCG, 68% (n=28) achieved U-MRD at 10-5 sensitivity and 50% (n=22) achieved U-MRD at 10-6 sensitivity. After cycle 6, the corresponding numbers were 83% (n=30) and 58% (n=24), respectively. After cycle 12, the corresponding numbers were 91% (n=22) and 63% (n=16), respectively. Reasons for study discontinuation included 1) death due to CHF (see below), 2) pulmonary MAC infection, 3) infusion reaction to obinutuzumab, and 4) pt decision. One pt died; 26-yr-old man who developed CHF in cycle 9 (receiving ibrutinib and obinutuzumab). He had no known cardiac comorbidities; he started a weight loss supplement (sympathomimetic agent) few days prior to symptom onset. The pt died from worsening heart failure. One pt developed t-MDS. Grade 3-4 neutropenia and thrombocytopenia occurred in 58% and 40% pts, respectively. Neutropenic fever occurred in 6 pts (culture negative 4 pts, PJP pneumonia 1 pt, staphylococcus skin infection 1 pt). Additional infectious complications without neutropenia leading to hospitalization included pneumonia (culture negative) (n=2), cellulitis (n=1), pulmonary MAC infection (n=1), fever (n=1), acute cholecystitis (n=1), and colitis (n=1). CONCLUSIONS The iFCG regimen with only 3 cycles of chemotherapy is an effective time-limited regimen for young pts with M-IGHV and without del(17p)/ mutated TP53. Disclosures Jain: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Thompson:Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Pfizer: Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Research Funding. Burger:Pharmacyclics, an AbbVie company: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria; BeiGene: Research Funding; Gilead Sciences: Research Funding; Aptose Biosciences, Inc: Research Funding; AstraZeneca: Honoraria. Takahashi:Symbio Pharmaceuticals: Consultancy. Borthakur:AstraZeneca: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Strategia Therapeutics: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Cyclacel: Research Funding; Tetralogic Pharmaceuticals: Research Funding; NKarta: Consultancy; Cantargia AB: Research Funding; Arvinas: Research Funding; PTC Therapeutics: Consultancy; Oncoceutics, Inc.: Research Funding; BMS: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly and Co.: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Polaris: Research Funding. Bose:Pfizer: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding; Constellation: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; NS Pharma: Research Funding; Astellas: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pemmaraju:mustangbio: Consultancy, Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Garg:Garglet LLC: Other: Owner; Enlitic inc.: Other: Advisor. Plunkett:Cyclacel Ltd: Research Funding. Kantarjian:Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Immunogen: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria. Wierda:Xencor: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; KITE pharma: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Pharmacyclics LLC: Research Funding; Acerta Pharma Inc: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Janssen: Research Funding; Loxo Oncology Inc.: Research Funding. OffLabel Disclosure: Combination of ibrutinib with chemotherapy is not FDA approved

Description: Anti-HLA donor-specific Abs (DSAs) have been reported to be associated with graft failure in mismatched hematopoietic stem cell transplantation; however, their role in the development of graft failure in matched unrelated donor (MUD) transplantation remains unclear. We hypothesize that DSAs against a mismatched HLA-DPB1 locus is associated with graft failure in this setting. The presence of anti-HLA Abs before transplantation was determined prospectively in 592 MUD transplantation recipients using mixed-screen beads in a solid-phase fluorescent assay. DSA identification was performed using single-Ag beads containing the corresponding donor's HLA-mismatched Ags. Anti-HLA Abs were detected in 116 patients (19.6%), including 20 patients (3.4%) with anti-DPB1 Abs. Overall, graft failure occurred in 19 of 592 patients (3.2%), including 16 of 584 (2.7%) patients without anti-HLA Abs compared with 3 of 8 (37.5%) patients with DSA (P = .0014). In multivariate analysis, DSAs were the only factor highly associated with graft failure (P = .0001; odds ratio = 21.3). Anti-HLA allosensitization was higher overall in women than in men (30.8% vs 12.1%; P 〈 .0001) and higher in women with 1 (P = .008) and 2 or more pregnancies (P = .0003) than in men. We conclude that the presence of anti-DPB1 DSAs is associated with graft failure in MUD hematopoietic stem cell transplantation.

Description: Background: Ibrutinib (IBR), a BTK inhibitor, and venetoclax (VEN), a BCL-2 inhibitor are approved for patients (pts) with CLL. We recently reported results of the first-line cohort (n=80) of an investigator-initiated phase II trial of combined IBR and VEN for pts with CLL (Jain N et al. NEJM 2019) (NCT02756897). Here we report updated data for these 80 pts with focus on MRD results. Methods: Pts with previously untreated CLL meeting 2008 IWCLL treatment criteria were enrolled. All pts had at least one of the following features: del(17p), mutated TP53, del(11q), unmutated IGHV, or an age of 65 years or older. Pts received IBR monotherapy (420 mg daily) for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily target dose). Combined therapy was administered for 24 cycles. Pts with bone marrow (BM) undetectable MRD (U-MRD) (assessed by multi-color flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy will stop both VEN and IBR; MRD+ pts could continue IBR. Response assessments were performed using blood, BM and CT imaging (2008 IWCLL criteria) at the following time-points (after cycle 3 of IBR monotherapy, and then after cycles 3, 6, 9, 12, 18, and 24 of the combination therapy). Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death. Overall survival (OS) was assessed as the time from the start of study drug to death. Results: A total of 80 pts were enrolled. The median age was 65 years (26-83). The baseline characteristics are shown in Table 1. A total of 30% of the pts were 70 years of age or older. Overall, 92% of the pts had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. The median follow-up for all pts is 22.8 months. Five pts came off study during IBR monotherapy (reasons listed below). 75 pts initiated VEN. Serial BM MRD responses are shown in Figure 1. After 3 cycles of IBR monotherapy, none of the 75 pts had achieved BM U-MRD. After addition of VEN, increasing proportions of pts achieved BM U-MRD remission. After 3 cycles of the combination, 12/74 (16%) achieved BM U-MRD remission. After 6 cycles of the combination, 30/72 (42%) achieved BM U-MRD remission. After 12 cycles of the combination, 45/69 (65%) achieved BM U-MRD remission. After 24 cycles of the combination, 23/29 (79%) achieved BM U-MRD remission. PFS and OS are shown in Figure 2. No pt has had CLL progression. Richter's transformation developed in one pt; this was a 63-year-old man with CLL with high-risk genomics (unmutated IGHV and mutated NOTCH1) in whom back pain developed during dose escalation of venetoclax and who was noted to have DLBCL transformation. Two pts died. One pt was a 60-year-old man who was having headache and numbness on the right side for 1 week before starting ibrutinib. The pt received 1 day of ibrutinib monotherapy, had progressive neurologic symptoms, and was found to have CNS cryptococcal infection. Ibrutinib was discontinued and the pt died 6 months later from complications of disseminated cryptococcal infection. This was deemed unrelated to ibrutinib as the pt had symptoms prior to starting ibrutinib. A second pt received only 2 weeks of ibrutinib and was taken off trial due to development of fungal pneumonia. The pt continued ibrutinib (off trial) and died 2 years later from infectious complications. A total of 12 (15%) pts have come off trial. Five pts came off trial during IBR monotherapy [skin rash, n=1; hypertension, n=1; prohibited medication, n=1; unrelated infection (cryptococcus), n=1; withdrew consent, n=1]. Seven pts came off study during the combination phase [recurrent neutropenia, n=2; DLBCL transformation, n=1; pneumonia, n=1; fallopian tube cancer, n=1; allogeneic SCT, n=1; hemolytic anemia/MDS, n=1]. 54% pts had dose reduction of IBR; 29% had dose reduction of VEN. Conclusions: Combined IBR and VEN is an effective chemotherapy-free oral regimen for pts with high-risk previously untreated CLL. Ongoing randomized studies will further help define the role of this combination approach in CLL. Disclosures Jain: BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding. Thompson:AbbVie: Research Funding; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pharmacyclics: Research Funding; Pfizer: Research Funding; Amgen: Consultancy, Research Funding. Burger:BeiGene: Research Funding; Pharmacyclics, an AbbVie company: Research Funding; Aptose Biosciences, Inc: Research Funding; AstraZeneca: Honoraria; Gilead Sciences: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria. Borthakur:Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; Xbiotech USA: Research Funding; Novartis: Research Funding; NKarta: Consultancy; Oncoceutics, Inc.: Research Funding; BMS: Research Funding; Oncoceutics: Research Funding; Agensys: Research Funding; PTC Therapeutics: Consultancy; Eli Lilly and Co.: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Fowler:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kadia:Bioline RX: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Konopleva:Agios: Research Funding; Astra Zeneca: Research Funding; Calithera: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding. Alvarado:Abbott: Honoraria; Jazz Pharmaceuticals: Research Funding. DiNardo:jazz: Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; medimmune: Honoraria. Bose:Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Garg:Garglet LLC: Other: Owner; Enlitic inc.: Other: Advisor. Plunkett:Cyclacel Ltd: Research Funding. Kantarjian:Agios: Honoraria, Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Novartis: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Astex: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Wierda:Janssen: Research Funding; Xencor: Research Funding; Loxo Oncology Inc.: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Pharmacyclics LLC: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding. OffLabel Disclosure: Combination of ibrutinib and venetoclax is not FDA approved

Description: Allogeneic stem cell transplantation offers curative therapy for many patients (pts) with high-risk hematologic malignancies. Donor availability remains a major limitation for many pts. The introduction of high-dose post-transplant cyclophosphamide (PTCy) has significantly improved the outcomes of pts undergoing haploidentical (HAPLO) stem cell transplants. The choice between a HAPLO or a one-antigen HLA mismatched unrelated donor (9/10 MUD) for pts lacking an HLA-matched donor remains unclear. Methods: We conducted a prospective non-randomized phase 2 clinical trial with two parallel arms, HAPLO (n=60) and 9/10 MUD (n=46) transplants, for pts with advanced hematologic malignancies or aplastic anemia who lacked an HLA-matched unrelated donor type at 10 loci (HLA-A, -B, -C, -DRB1, and -DQB1) using a MEL-based reduced-intensity conditioning regimen. The regimen included a single intravenous dose of MEL 140 mg/m2 (day -7), thiotepa 5 mg/kg (day -6), and four daily IV doses of fludarabine 40 mg/m2 (day -5 to day -2) (FM140). Thiotepa was intermittently available and was replaced by total body irradiation at a dose of 2 Gy on day -1. Pts 〉55 years (yr) old or with significant comorbidities received a lower MEL dose (100 mg/m2) (FM100). All pts with CD20-positive lymphoma received rituximab (375 mg/m2) on days -13, -6, +1 and +8. GVHD prophylaxis consisted of PTCy 50 mg/kg on day +3 and +4, and tacrolimus and mycophenolate for 6 and 3 months (mo), respectively. The stem cell source was unmodified bone marrow for both arms. Results: Patient characteristics are shown in Table 1. The median follow-up duration was 24 mo in the HAPLO arm and 29 mo in the 9/10 MUD arm. The cumulative incidence (CI) of neutrophil (ANC) recovery at day 45 was 95% and 98% in the HAPLO and 9/10 MUD arm, respectively. The median time to ANC recovery was 18 days in both arms; the median time to platelet recovery was 25 days in the HAPLO arm and 28 days in the 9/10 MUD arm. Primary graft failure developed in two pts in the HAPLO arm (one due to anti-donor HLA antibodies) and one patient in the 9/10 MUD arm. One pt in both arms developed mixed donor chimerism at day 100; otherwise, all pts in both arms achieved full (〉95%) donor chimerism. Bone marrow was the graft source in all pts except 2 in the HAPLO arm and 8 in the 9/10 MUD arm who received a peripheral blood graft. The 1-yr overall and progression free survival were 70% and 60%, respectively, in the HAPLO arm (Fig. 1A) and 60% and 47%, respectively, in the 9/10 MUD arm (Fig. 1B). Day 100 CI of grade II-IV aGVHD and III-IV aGVHD were 28% and 3%, respectively, in the HAPLO arm versus 33% and 13%, respectively, in the 9/10 MUD arm; the 2-yr CI of chronic extensive GVHD was 13% and 14% in the two groups, respectively. The 1-yr CI of non-relapse mortality was 21% in the HAPLO arm and 31% in the 9/10 MUD arm, while the 1-yr relapse rate was 19% and 25% in the two groups, respectively. Conclusions: This study establishes PTCy, tacrolimus, and mycophenolate as an effective regimen for GVHD prevention in mismatched transplantation using both haploidentical and mismatched unrelated donor sources. Melphalan-based reduced-intensity conditioning is an effective regimen for a broad range of hematologic malignancies. Prospective randomized studies comparing haploidentical and unrelated donor sources are needed. Table 1. HAPLO (n=60) 9/10 MUD (n=46) Median Age, years (Range) 45 (20-63) 51 (20-64) Sex (M/F) 29/31 23/23 KPS ³90 53 (88%) 40 (87%) 3 10 (17%) 8 (17%) Disease Risk Index* Very high 5 (8%) 3 (7%) High 18 (30%) 15 (33%) Intermediate 29 (48%) 12 (26%) Low 8 (13%) 12 (26%) NA 0 4 (9%)** Conditioning Regimen FM100 20 (33) 18 (39%) FM140 40 (67%) 28 (61%) Diagnosis AML/MDS 33 (55%) 18 (39%) ALL 7 (11%) 5 (11%) Lymphoma 10 (17%) 13 (28%) Others 10 (17%) 10 (22%) Disease Stage Acute Leukemia CR1/CR2 24 (66%) 9 (56%) CR3 or higher/ CRpx 6 (17%) 5 (31%) Active disease 6 (17%) 2 (13%) Lymphoma CR 3 (30%) 8 (62%) PR 5 (50%) 3 (23%) Chemoresistant 2 (20%) 2 (15%) *Disease Risk Index by Armand et al; xCRp: Complete Remission with incomplete count recovery; **Patients had aplastic anemia. Figure 1. Figure 1. Disclosures Brammer: Celgene: Research Funding. Lee:Ziopharm: Equity Ownership; Cyto-Sen: Equity Ownership; Intrexon: Equity Ownership. Rezvani:Pharmacyclics: Research Funding. Alousi:Therakos, Inc: Research Funding.

Description: Allogeneic hematopoietic cell transplantation (HCT) is considered definitive consolidation therapy for many patients with acute myeloid leukemia (AML) once complete remission (CR) is achieved. Nevertheless, relapse remains a major cause of treatment failure post-HCT.Increasing evidence suggests that the presence of minimal residual disease (MRD) at the time of HCT identifies a subset of patients that is at high risk of relapse. In the present analyses, we sought to determine the impact of MRD detected by 8-color flow cytometry (FC) at HCT on 1-year relapse incidence (RI) in patients transplanted in first CR (CR1). Between 2010 and 2012, 159 AML CR1 patients with a median age of 53 years were transplanted with matched sibling donor (MSD, n=42), matched unrelated donor (MUD, n=78) or mismatched donor (MMD (n=39). Of 159 patients, 50 had MRD by 10-color FC at HCT (MRDpos). Compared with patients without MRD (MRDneg), MRDpos were older (median age 60 vs. 53, p=0.0003), required more than 1 line of induction chemotherapy to achieve CR1 (40% vs. 17%, p=0.001), had more incomplete recovery of counts (CRi/p) at HCT (58% vs. 9%, p

Description: Abstract 2145 The hyper-CVAD regimen is an effective frontline program for de novo adult ALL [Kantarjian, JCO 18:547, 2000; Kantarjian, Cancer 101:2788, 2004]. Intensive cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternate with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone) interrupted with early and late intensifications. The regimen was modified in 1999 in order to improve on the results. Induction chemotherapy was administered in a laminar air flow room for pts aged 60 years or older owing to high induction mortality rate (17%). Rituximab 375 mg/m2 (days 1 & 11 of hyper-CVAD, days 1 & 8 of MTX-cytarabine for 8 total doses) was given if CD20 expression was 〉 20% owing to association with increased propensity for relapse [Thomas D, Blood 113:6330, 2009]. CNS prophylaxis alternated intrathecal MTX day 2 with cytarabine day 7 of the first 3 courses for low CNS risk and first 4 courses for high CNS risk (in the absence of CNS disease). The maintenance phase was extended from 24 to 30 mos with modifications of the early and late intensifications (hyper-CVAD followed by MTX-L-asparaginase mos 6 & 7 and 18 & 19) in order to reduce incidence of late relapses. Newly diagnosed or primary refractory (1 course only) pts with Philadelphia chromosome negative B-lymphoblastic leukemia (n=126) were treated with this modified hyper-CVAD regimen without anthracycline intensification (pts age 30 years or less have been allocated to treatment with the pediatric-inspired augmented Berlin-Frankfurt-Muenster regimen since 2006). Median age was 43 yrs (range, 15–83). CD20 expression was noted in 49%. Overall CR rate of the group was 93%; the rate of MRD negativity by 4- or 6-color MFC (sensitivity of 0.01%) at the time of CR in 95 evaluable pts was 72%. Overall, MRD positivity by MFC at the time of CR was associated with a higher relapse rate (52% versus 21%, p=.01) and lower 3-yr CR duration rates (45% versus 78%, p=.01). The CD20 positive pts (n=57) who were treated with rituximab had a higher rate of MRD negativity by MFC at CR than their CD20 negative counterparts (81% versus 58%, p=.02). MRD positivity by MFC after hyper-CVAD and rituximab was associated with a significantly lower 3-yr CR duration rate (24% versus 82%, p=.002), but survival rates were not statistically different (27% versus 70%) likely due in part to deaths in CR in the older subset of the MRD-negative group. In contrast, for the CD20 negative subset, presence of detectable MRD by MFC at the time of CR was not associated a with lower 3-yr CR duration rate (58% versus 63%). Dectectable MRD by MFC at the time of CR, despite subsequent eradication with consolidation chemotherapy in the majority of patients, predicts for increased risk of disease recurrence. Strategies to improve the MRD negativity rate at the time of CR (e.g., addition of monoclonal antibodies directed at other lymphoblast antigens such as CD22 for the CD20 negative subset and use of the newer anti-CD20 monoclonal antibodies for the CD20 positive subset) may further improve outcome after frontline therapy with the modified hyper-CVAD regimens. Disclosures: Thomas: Novartis: Honoraria; Bristol-Meyer-Squibb: Honoraria; Pfizer:; Amgen: Research Funding. Off Label Use: Imatinib for de novo Philadelphia positive ALL. Dasatinib for de novo Philadelphia positive ALL. Rituximab for CD20 positive ALL and Burkitt leukemia/lymphoma. Nelarabine for de novo T-lymphoblastic leukemia/lymphoma.

Description: INTRODUCTION: Pure erythroid leukemia (PEL) is a rare form of acute leukemia characterized by a neoplastic proliferation of immature erythroblasts with an extremely aggressive clinical course. Although there are previous reports describing its association with a complex karyotype and chromosome 5 and 7 abnormalities, there is no knowledge on the mutational landscape of this disease. Also, further evaluation of the optimal treatment strategy for this subset of patients is still required. METHODS: We retrospectively evaluated all patients with pure erythroid leukemia treated at The University of Texas MD Anderson Cancer Center from 1980 to 2016. Cytogenetic analysis was reported following the ISCN 2013 nomenclature. Sequencing data was obtained by use of a 28-gene targeted PCR-based next generation sequencing (NGS) platform. Clinical and demographic data was obtained from clinical records. Response was defined following 2003 IWG criteria. Generalized linear models were used to study the association of overall response (OR), complete response (CR) and risk factors. Kaplan-Meier produce limit method was used to estimate the median overall survival (OS) and leukemia-free survival (LFS). RESULTS: A total of 27 patients had PEL. Patient characteristics are shown in Table 1. Median age at diagnosis was 67 years (range 33-65). Eleven (41%) patients had therapy related disease, 10 (37%) evolved from a prior myelodysplastic syndrome and 1 (4%) from chronic myeloid leukemia. Presence of a complex karyotype was observed in 96% (25/26) patients. A total of 13 (48%) patients with PEL had mutation analysis available. Twelve (92%) had at least one detectable mutation. Median number of mutations was 1 (range 0-3). TP53 mutations were found in 11/12 (92%) patients, and ASXL1, PTPN11 and DNMT3A each found in 1 (8%) patient. Type and frequency of TP53 mutations is shown in Figure 1A. Fifteen (58%) patients with PEL had chromosome 17 abnormalities including monosomy 17, del(17p) and add(17)(p11.2). Five (50%) patients with cytogenetic and mutation data available had both TP53 mutation and chromosome 17 abnormalities. Nine (27%) patients were treated with hypomethylating agent based therapy, 11 (41%) with intensive chemotherapy, 1 (4%) with targeted therapy and 6 (22%) died before receiving any form of therapy. We compared clinical characteristics and outcomes of patients with PEL with that of 162 patients with acute erythroid/myeloid leukemia (AEL) treated at MDACC during the same time period. Patients with PEL tended to be older (p=0.006), have lower platelet count (p=0.009) and lower peripheral blast percentage (p=0.022), higher LDH levels (p

Description: Abstract 1700 To better understand molecular bases of MDS pathogenesis, we performed a genome-wide CHIP-Seq analysis of H3K4me3, a histone mark associated with gene activation. In MDS CD34+ cells (N=4), 36 genes showed higher levels of promoter-H3K4me3 compared to controls. 10 of 11 randomly selected genes from these 36 showed increased mRNA expression in MDS CD34+ cells (N=100), supporting the positive correlation between expression and increased promoter H3K4me3. Pathway Analysis indicated that a majority of these genes are involved in innate immunity signal and NF-kB activation. This was validated by increased phospho-p65 in MDS bone marrow CD34+ specimens (N=15). Knock-down of 4 of these genes (C5AR1, FPR2, PTAFR and TYROBP) in OCI-AML3 cells resulted in reduction of p-p65. The observation of innate immunity signal activation and epigenetic deregulation led us screen key innate immunity activators, the Toll-like Receptor (TLR) family genes, and histone methylation regulators in MDS CD34+ cells. Among 8 TLRs and 24 histone methylation regulators, TLR1, 2 and 6, and Jmjc-domain histone demethylase JMJD3 were found to be significantly overexpressed in MDS CD34+ cells compared to control counterparts. This is of biological significance because TLR1 and 6 form functional hetero-dimmers with TLR2. Also, JMJD3 expression can be activated by TLR-NFkB in macrophages. To study TLR2 activation in HSC, we treated CD34+ cells with TLR2 agonists. This led to increased expression of JMJD3, supporting the biological function of TLR2 signal in HSC. We observed that JMJD3 knockdown in OCI-AML3 cells led to reduced expression of innate immunity genes (N=7), accompanied with changes of promoter H3K27me3 and H3K4me3, suggesting that JMJD3 forms a positive feedback to perpetuate innate immunity pathway. To further study the role of TLR-JMJD3 in MDS, we performed capture deep sequencing in 40 MDS bone marrow mononuclear cells (TLR1, 2, 4 and 6, JMJD3, UTX, UTY and JMJD1A). Seven different rare SNP in the coding regions of JMJD3, UTY, JMJD1A, and TLR2 were identified in 5 patients. Among them, one SNP of TLR2 causes a missense mutation, changing a conserved hydrophobic Phe217 to a hydrophilic Ser. We then analyzed the presence of TLR2 F217S in 150 MDS samples by Sanger sequencing. TLR2 F217S was observed in 17 (11%) patients. To evaluate the somatic nature of this alteration, CD3+ cells from 15 corresponding patients were sequenced and only two (13%) CD3+ cell samples carried TLR2 F217S. In the available 9 CD34+ cDNA samples, TLR2 F217S was observed in 8 (90%). We then expressed wild-type or F217S TLR2 in 293T cells, a cell line without endogenous TLR2 expression. Reporter assays indicated that in the absence of TLR2 agonist wildtype and F217S mutant TLR2 led to similar levels of NF-kB activation, whereas F217S led to an increased NF-kB activation compared to wildtype at the presence of TLR2 agonists. F217S also led to increased activation (phospho- and polyubiquitin-) of IRAK1, a key signal mediator for TLR signaling. These results suggest that TLR2 F217S led to more robust innate immunity signal activation when stimulated by agonists. We further studied the impact of TLR2 activation on hematopoietic differentiation. Colony formation of CD34+ cells indicated that TLR2 agonists led to decreased number of erythroid colonies, which was confirmed by flowcytometry that demonstrated TLR2 agonist treatments could reduce the number of CD71 high/HLADR low featured erythroid precursors. To examine the effect of targeting TLR2-JMJD3 in primary MDS cells, we transduced MDS CD34+ cells with shRNAs. In 4 CD34+ cases isolated from lower risk MDS, 3 transduced with JMJD3 shRNA and 4 transduced with TLR2 shRNA had increased ratio of erythroid colonies. In average, JMJD3 and TLR2 shRNA transduction led to a 50% increase in erythroid colonies. This was accompanied by increased expression of genes positively involved in differentiation of erythroid lineage (GYPA, GATA1 and EPOR). Finally, CD34+ cell mRNA expression levels of four genes in this study (NCF2, AQP9, MEFV and TLR1) were associated with overall survival of patients. Taken together, these studies highlight the implication of the deregulation of TLR2-JMJD3 mediated innate immunity signals in MDS pathogenesis and suggest that intervention of this pathway may have therapeutic potential in MDS. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Acute undifferentiated leukemia (AUL) is a rare type of acute leukemia that shows no evidence of differentiation along any lineage. Clinical, immunophenotypic and genetic data is limited: the largest study to date reported 16 AUL cases but did not use the current WHO classification and included limited genetic data on 5 cases (Ann Hematol 2013 92:747-758). Moreover, it is uncertain if AUL is biologically distinct from acute myeloid leukemia with minimal differentiation (AML MD), which also shows limited myeloid marker expression and has been reported to have a poor prognosis. Methods: A total of 95 cases (36 AUL cases 59 AML MD) were identified from pathology databases of eight academic institutions with available diagnostic flow cytometric data, cytogenetic findings, and clinical data by searching for diagnoses of "AUL" or "AML MD". Diagnosis of AUL required absence of any lineage-defining markers including MPO, CD19 and CD3. Using the WHO classification, diagnosis of AML with MD required expression of at least 2 myeloid markers (CD117, CD13 or CD33), absence of myeloid maturation (CD15) or monocytic markers (CD64, CD11b, lysozyme or non-specific esterase). Next generation sequencing with extensive mutational panel data was available in 78 cases. Outcome analysis for overall survival (OS) and relapse-free survival (RFS) and were performed using Kaplan Meier and log rank test for patients who received induction chemotherapy. Results: Based on cytogenetic abnormalities (N=27) or history of MDS (N=2), according to the 2016 WHO Classification, 28 cases (6 AUL and 22 AML MD) were re-classified as AML with myelodysplasia related changes (AML MRC). The remaining 30 AUL patients presented with similar age, blood counts, bone marrow cellularity, and blast percentage as the 37 AML MD patients (all p 〉 0.05). Comparison of immunophenotype in the two groups showed that AUL blasts had more frequent expression of TdT (p=0.0003) and lacked myeloid markers (CD117, CD13 or CD33 p0.05) were seen between these two groups. The frequency of abnormal karyotype was similar between AUL and AML MD (16/30 [53%] vs 15/37 [41%], respectively). The most common mutations identified in AUL were PHF6 (7/18), SRSF2 (7/18), RUNX1 (7/23), ASXL1 (6/23) and BCOR (5/16). Compared to AML MD, AUL cases were characterized by frequent mutations in PHF6 (7/18 vs 1/23, p=0.013) and SRSF2 (7/18 vs 2/22 p=0.028). Limiting AUL cases to only those with 1 myeloid marker or less also showed similar findings with more frequent mutations in PHF6 (7/16 vs 1/25, p=0.0031), SRSF2 (6/15 vs 3/26 p= 0.018) and trend towards higher BCOR frequency (5/15 vs 2/26, p=0.078) in AUL patients as compared to AML MD. RUNX1 mutation was seen in 7/23 AUL and 8/29 AML MD (p〉0.05). 19/30 AUL patients received induction chemotherapy (AML-type regimen in 18 cases and an ALL-type regimen in 1 case) and 15/30 achieved complete remission. In 10 AUL patients who relapsed, 9 showed identical immunophenotype and one case showed expression of CD13 and CD33. Outcome data in the subset of patients who received induction showed no difference in OS, RFS, or rates of complete remission between AUL and AML MD groups (p〉0.05). The 28 AML MRC cases that were originally classified as AUL or AML MD presented with lower WBC (p=0.026), more frequent abnormal karyotype (27/28) specifically complex karyotype (20/28 p=0.002), frequent TP53 mutations (p=0.0002) when compared to the AUL group. AML MRC patients showed worse overall OS (p=0.029) as compared with AUL patients and a trend toward worse outcome as compared with AML MD (p=0.068). Conclusions: In this largest series to date, AUL group shows distinct characteristics from AML MD, including more frequent PHF6 and SRSF2 mutations and expression of TdT. However, clinical outcome is similar between the two groups in patients treated with induction chemotherapy. Cases reclassified as AML-MRC had shorter survival compared to de novo AUL and trend towards worse outcome when compared to AML MD patients. These results suggest a genetic rationale for the separation of AUL as a distinct entity from AML MD and also support the WHO classification of cases with history of prior MDS and/or MDS-type karyotype findings as AML-MRC. Disclosures Garcia: Celgene: Consultancy.