Risk-Adapted, Ofatumumab-Based Chemoimmunotherapy and Maintenance in Treatment-Naïve CLL: A Phase II Study

Introduction: Anti-CD20 monoclonal antibodies (mAb) are an essential component of CLL therapy. Addition of anti-CD20 mAb to induction chemotherapy improves progression-free survival (PFS) and overall survival (OS) in treatment-naïve CLL. Patients who achieve minimal residual disease negativity (MRD-) after induction chemoimmunotherapy (CIT) have prolonged PFS and OS. It is unclear, whether an extended therapy with an anti-CD20 mAb after induction CIT can improve the depth of response and long-term outcomes in patients with detectable residual disease (MRD+). Here we report results from a phase II study using risk-adapted, ofatumumab-based CIT induction followed by ofatumumab maintenance in treatment-naïve CLL patients. (NCT01145209) Methods: Treatment-naïve CLL patients were stratified twice: first, based on pre-treatment FISH, and second, based on post-induction peripheral blood (PB) MRD status. Patients with high-risk FISH (17p or 11q deletion) received up to 6 cycles of fludarabine, cyclophosphamide and ofatumumab (FCO). Patients without high-risk FISH received fludarabine, and ofatumumab (FO). Ofatumumab was dosed at 300mg for the first cycle, and 1000mg for subsequent cycles. After induction, patients were re-stratified based on PB MRD status using flow cytometry. MRD- was defined <10-4 CLL cells. MRD+ patients after CIT received 4 doses of ofatumumab as maintenance therapy while those with MRD- were observed without intervention. The primary endpoint was PFS at 2 years since starting the induction. We quantified the surface expression of CD20 and CD22 by using antibody binding capacity (ABC) of PB CLL cells in flow cytometry (QuantiBRITETM, BD Biosciences, San Jose, CA) and CD20 and CD79 expression in bone marrow (BM) CLL cells by using immunohistochemistry. We measured ofatumumab concentrations at pre-treatment; 2, 6, and 24 hours after the first dose of ofatumumab; after each ofatumumab dose during cycle 2 to 4; and after completion of induction CIT. Results: We enrolled 32 patients. Twenty-eight patients received 3 or more cycles of induction CIT and were evaluable for outcomes. The overall response rate was 100%, including 8 (28.6%) patients achieving a complete response. The median PFS was 42.8 months and was significantly longer for patients who achieved MRD- after induction CIT compared to those with MRD+ (Not reached vs 36.2 months, p<0.009). There was no statistically significant difference in PFS between the group with high-risk FISH treated with FCO vs. the non-high-risk group treated with FO (57.8 vs 39.2months, p=0.4). Additional doses of ofatumumab did not improve the depth of response as none of the MRD+ patients became MRD- after ofatumumab maintenance. However, ofatumumab kept CLL in control and none of the patients progressed during maintenance. After completion of maintenance ofatumumab, PB MRD levels increased with a mean doubling time of 5.37 months. At a median follow up of 43 months, 11 (61%) patients in the MRD+ group progressed. Antigen loss through Fc-gamma receptor-mediated uptake of antibody-antigen complexes into effector cells, referred to as trogocytosis, allows tumor cells to escape antibody-dependent cytotoxicity. At the same time, trogocytosis contributes to rapid clearance of circulating mAb. Investigating whether residual cells still expressed CD20, we measured expression of CD20 on CLL cells at the end of CIT. Most residual CLL in PB showed virtually complete loss of CD20 expression. We also stained BM biopsies obtained after 3 and 6 cycles of CIT for CD20 confirming absent or markedly reduced CD20 expressions on residual CD79+ CLL cells. In addition, the median trough level of ofatumumab on day 28 of each cycle increased with each advancing cycle (0, 13, and 51 mcg/mL after cycle 1, 2, and 3, respectively). Similarly, clearance of ofatumumab below the limit of detection (< 0.5mcg/mL) was observed in 60% of patients after the initial dose, and only 20% after cycle 3. Conclusions: Scaling intensity of CIT to genetic risk profiles achieved comparable outcomes for high-risk and standard-risk patients. MRD- remissions were associated with superior PFS, irrespective of the induction CIT regimen used. Maintenance therapy with ofatumumab did not improve the depth of response in MRD+ patients. Antibody induced antigen loss on tumor cells limits the efficacy of anti-CD20 mAbs even in settings with low tumor burden. Disclosures Farooqui: Merck: Employment. Lindorfer:Genmab: Research Funding. Wiestner:Pharmayclics: Research Funding; Acerta: Research Funding; Merck: Research Funding; Nurix: Research Funding.

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Real-World Experience with Minimal Residual Disease Testing with Next Generation Flow Cytometry and Functional Imaging in Multiple Myeloma

Blood ◽

10.1182/blood-2020-140772 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 17-18

Author(s):

David Böckle ◽

Paula Tabares Gaviria ◽

Xiang Zhou ◽

Janin Messerschmidt ◽

Lukas Scheller ◽

...

Keyword(s):

Multiple Myeloma ◽

Flow Cytometry ◽

High Risk ◽

Functional Imaging ◽

Real World ◽

Research Funding ◽

Residual Disease ◽

Focal Lesions ◽

High Risk Disease ◽

Minimal Residual

Background: Minimal residual disease (MRD) diagnostics in multiple myeloma (MM) are gaining increasing importance to determine response depth beyond complete remission (CR) since novel agents have shown to induce high rates of deep clinical responses. Moreover, recent reports indicated combining functional imaging with next generation flow cytometry (NGF) could be beneficial in predicting clinical outcome. This applies in particular to the subset of patients suffering from relapsed/refractory multiple myeloma (RRMM) who tend to show a higher incidence of residual focal lesions despite serological response. Here, we report our institutions experience with implementing both functional imaging and NGF-guided MRD diagnostics in clinical practice. Methods: Our study included patients with newly diagnosed multiple myeloma (NDMM) and RRMM achieving VGPR, CR or sCR. Bone marrow aspirates were obtained for MRD-testing according to IMWG 2016 criteria. Samples were collected between July 2019 and July 2020 and analyzed with NGF (according to EuroFlowTM guidelines) at a sensitivity level of 10-5. Results were compared to functional imaging obtained with positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI). High-risk disease was defined as presence of deletion 17p, translocation (14;16) or (4;14). Results: We included 66 patients with NDMM (n=39) and RRMM (n=27) who achieved VGPR or better. In patients with RRMM the median number of treatment lines was 2 (range 2-11). Fifteen patients suffered from high-risk disease. Median age at NGF diagnostics was 64 years (range 31-83). Among patients achieving VGPR (n=27), CR (n=10) and sCR (n=29) seventeen (26%) were MRD-negative by NGF testing. CR or better was significantly associated NGF MRD-negativity (p=0.04). Notably, rates of NGF MRD-negativity were similar among patients with NDMM (28%) and RRMM (26%). Even some heavily pretreated patients who underwent ≥ 4 lines of therapy achieved MRD-negativity on NGF (2 of 9). Functional imaging was performed in 46 (70%) patients with DW-MRI (n=22) and PET (n=26). Median time between NGF and imaging assessment was 2 days (range 0-147). Combining results from imaging and NGF, 12 out of 46 (26%) patients were MRD-negative with both methods (neg/neg). Three patients displayed disease activity as measured with both, imaging and NGF (pos/pos). Twenty-nine of the remaining patients were MRD-positive only according to NGF (pos/neg), while two patients were positive on imaging only (neg/pos). More patients demonstrated combined MRD-negativity on NGF and imaging (neg/neg) in the NDMM setting than in RRMM (32% versus 19%). We also observed that 30% of the patients with high-risk genetics showed MRD-negativity on both imaging and NGF. Of note, none of the patients with very advanced disease (≥4 previous lines) was MRD-negative on both techniques. Conclusion In the clinical routine, MRD diagnostics could be used to tailor maintenance and consolidation approaches for patients achieving deep responses by traditional IMWG criteria. Our real-world experience highlights that MRD-negativity can be achieved in patients suffering from high-risk disease and also in late treatment lines, supporting its value as endpoint for clinical trials. However, our data also support MRD diagnostics to be combined with functional imaging at least in the RRMM setting to rule out residual focal lesions. Future studies using MRD for clinical decision-making are highly warranted. Disclosures Einsele: Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rasche:Celgene/BMS: Honoraria; GlaxoSmithKline: Honoraria; Oncopeptides: Honoraria; Skyline Dx: Research Funding; Janssen: Honoraria; Sanofi: Honoraria.

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Over-Expression of CRLF2 By Flow Cytometry (FC) Impacts on Overall Survival (OS) in Mexican Patients with Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood-2021-153309 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3367-3367

Author(s):

Emmanuel Almanza Huante ◽

Juan Rangel-Patiño ◽

Rosana Daniela Córdova-Serrano ◽

Karla Adriana Espinosa ◽

Roberta Demichelis

Keyword(s):

Flow Cytometry ◽

Overall Survival ◽

High Risk ◽

Research Funding ◽

Negative Group ◽

High Tendency ◽

Over Expression ◽

Treatment Naïve ◽

Mexican Patients

Abstract Introduction: "Philadelphia like" ALL has been related to poor prognosis. CRLF2 over-expression (cytokine receptor like factor-2) has been found in up to 50% of patients with Philadelphia-like ALL and its expression can be measured by Flow Cytometry (FC). CRLF2 over-expression is more common in Hispanic population (45-68%) however, there is no current recommendation in using it as a prognostic marker. Objectives: Find the prevalence of CRLF2 overexpression measured by FC, in adult Mexican patients with treatment-naïve ALL Describe the outcomes of the patients who over-expressed CRLF2 by Complete Response (CR), Minimal Residual Disease (MRD), Leukemia-Free Survivale (LFS) and Overall Survival (OS). Methodology: This is a retrospective cohort study in adults with newly diagnosed ALL from two reference centers in Mexico City. We measured CRLF2 expression by FC in fresh bone marrow samples from treatment-naïve patients at one location; to define over-expression, samples were first analyzed by two different experts who grouped the cases in over-expression or no overexpression using Mean Fluorescence Intensity (MFI) between two populations, blasts and controls (normal B cells). Outcomes were compared using chi-square test for binary variables and log-rank test for time-to-event variables with a p value <0.05 as significant. Results: From April 2018 to January 2020 46 patients with treatment-naïve B-cell ALL were evaluable; the median age was 29.5 years, 38 (82.6%) were Adolescents and Young Adults (AYA), 22 (47.8%) had leukocytosis, 15 (53.5%) of the evaluable karyotypes, were assigned to high-risk group. The median time of follow-up was 24.5 months and 19 (41.3%) patients were positive for CRLF2-overexpression. For the follow-up cohort all of the patients were evaluable for outcomes. CNS disease was detectable in 11(24.5%) patients which was higher in CRLF2-overexpresed patients (15.5% vs 8.9%, p=0.015). We found no difference in Complete Remission (CR) in CRLF2 status but a high tendency for R/R (Relapse/Refractory) disease (83.3% in CRLF2-overexpression vs 60% in CRLF2 negative group; p=0.09) and dead (63.2% in CRLF2-overexpression vs 37% in CRLF2 negative group; p=0.07). MRD1, 2 and 3 (1=after induction, 2= week 16 and 3= before maintenance) was significantly worse in patients with CRLF2 overexpression (1=15.8% vs 58.3%, p<0.01; 2=7.1% vs 52.6%, p<0.01; 3=0% vs 55.6%, p<0.05). Overall Survival was significantly worse in patients with CRLF2 overexpression (Median Not Reached vs 11.05 months; p=0.04) (Figure 1); Disease-Free Survival (DFS) had a tendency towards worse outcome in patients with CRLF2 overexpression (18.48 vs 5.82 months, p=0.07) (Figure 2). Conclusion: Survival in patients who have CRLF2 overexpression is significantly worse when measured by FC, this might be related to early high-risk markers as MRD. CRLF2 overexpression in this hispanic sample was higher (41%) than other reports. CRLF2 measured as a prognostic factor by FC needs to be further considered due to the high availability of this technique across Latin-America. Figure 1 Figure 1. Disclosures Rangel-Patiño: Abbvie: Speakers Bureau; Bristol: Consultancy. Espinosa: Pfizer: Consultancy; Amgen: Speakers Bureau; Janssen: Consultancy. Demichelis: Novartis: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy; Bristol/Celgene: Consultancy, Speakers Bureau; Jazz: Consultancy; ASH: Research Funding; Astellas: Consultancy; AMGEN: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau.

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Preliminary Results from a Phase II Study of the Combination of Pevonedistat and Azacitidine in the Treatment of MDS and MDS/MPN after Failure of DNA Methyltransferase Inhibition

Blood ◽

10.1182/blood-2019-130003 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4236-4236 ◽

Cited By ~ 5

Author(s):

Tamara K Moyo ◽

Justin M. Watts ◽

Barry S. Skikne ◽

Jason H. Mendler ◽

Virginia M. Klimek ◽

...

Keyword(s):

High Risk ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Dna Methyltransferase ◽

Phase Ii Study ◽

Median Number ◽

Advisory Committees ◽

Treatment Naïve ◽

Experienced Grade

After failure of DNA methyltransferase inhibition (DNMTi) there is no standard of care therapy for high-risk myelodysplastic syndromes (MDS), and median survival for higher risk disease is less than 6 months (Prebet et al, JCO 2011; Jabbour et al, Cancer 2015). Pevonedistat, a first in human small molecule inhibitor of the NEDD8 activating enzyme (NAE), downregulates Cullin ring ligases (CRL) which interferes with the shuttling and degradation of proteins in the proteasome and leads to accumulation of CRL substrates. Combining pevonedistat (Pev) with azacitidine (AZA) resulted in synergistic cell killing in in vitro and xenograft models of acute myeloid leukemia (AML) (Smith et al, Blood 2011), elicited favorable response rates in treatment naïve elderly or unfit AML patients (Swords et al Blood 2018), and is currently under study in treatment-naïve MDS. The study presented herein (NCT03238248) investigates the utility of adding pevonedistat to azacitidine (PevAz) after DNMTi failure in MDS and MDS/MPN overlap syndromes. Methods: In this on-going single-arm phase II study, MDS and MDS/MPN patients were eligible if they were refractory to DNMTi treatment, progressing after at least 2 cycles of therapy; had failed to achieve a complete remission (CR) after at least 4 cycles of DNMTi therapy; or had relapsed after an initial response to DNMTi therapy. Enrolled subjects received AZA 75mg/m2 sc/iv daily on days 1-5 and Pev 20mg/m2 iv on days 1, 3 and 5 of each 28-day cycle. Survival is the primary endpoint and is assessed at regularly scheduled study visits and every 3 months after ending protocol-directed therapy. Hematologic and bone marrow response rates are secondary endpoints. Responses to treatment are determined by the MDS International Working Group (IWG) response criteria (Cheson et al, Blood 2006) or for MDS/MPN, by the modified MDS/MPN IWG response criteria (Savona et al, Blood 2015). Results: As of the data cutoff on 15 MAR 2019, 23 subjects (21 with MDS, 2 with MDS/MPN) had enrolled and initiated treatment. Subjects had previously been treated with AZA (n=11/23), decitabine (n=11/23), and ASTX727 (n=4/23); some subjects had been treated with more than one DNMTi prior to enrollment. Median number of cycles of any prior DNMTi therapy was 7 (range 2-35). 65% of subjects were female. Median age at enrollment was 67 years (range 51 - 85). 65% had Intermediate-2 or High risk disease by IPSS at time of enrollment. Median number of PevAz cycles completed prior to the data cutoff was 4 (range 1-19). One subject had not reached the first response assessment at the time of the data cutoff and data was unavailable for one subject. The overall response rate including complete and partial remission, hematologic improvement and clinical benefit (CB) was 42.9% (9/21), and CR rate (including 1 CR + 4 marrow CR) was 23.8% (5/21) with a median duration of response (DOR) of 8.7m (range 2.8m-15.7m). An additional 38.1% (8/21) had stable disease as best response (Table 1). The most common Grade >2 adverse events (any attribution) include thrombocytopenia (39%), anemia (35%), leukopenia (26%), neutropenia (22%), infections (17%), and febrile neutropenia (13%). Six subjects experienced Grade ≤ 2 elevations in AST/ALT and 4 had Grade ≤ 2 elevation in bilirubin, whereas only one subject experienced Grade > 2 LFT abnormality (increase in ALT). There was one death on study due to intracerebral hemorrhage related to a previously undiagnosed metastatic carcinoma. PevAz treatment was discontinued in other subjects due to disease progression (n=7), adverse event (n=1), lack of response (n=1), or to pursue allogeneic stem cell transplant after achieving a satisfactory response to PevAz (n=3). Ten subjects were continuing PevAz therapy on study as of the data cutoff. Summary: PevAz was well-tolerated in MDS and MDS/MPN patients who had previously failed DNMTi, with the most common adverse events of cytopenias, which are a common feature of these diseases. 5/21 subjects achieved CR/mCR with meaningful DOR, and the ORR of 42.9% exceeded expectations for MDS patients with previous failure of DNMTi therapy; both MDS/MPN patients responded with CR and CB. For these patients whose treatment options are limited and prognosis very poor, these preliminary data are especially encouraging and warrant further investigation. This therapy combination is being tested in a phase 3 study in treatment naïve high risk MDS, CMML and low-blast AML. Disclosures Watts: Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding. Strickland:Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Research Funding; AbbVie: Consultancy; Jazz: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Byrne:Karyopharm: Research Funding. Bradley:AbbVie: Other: Advisory Board. Savona:Sunesis: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: 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; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties.

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Residual Disease Monitoring By High Throughput Sequencing Provides Risk Stratification in Childhood B-ALL and Identifies a Novel Subset of Patients Having Poor Outcome

Blood ◽

10.1182/blood.v128.22.1086.1086 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1086-1086 ◽

Cited By ~ 2

Author(s):

Brent L. Wood ◽

David Wu ◽

Ilan M. Kirsch ◽

Beryl Crossley ◽

David Williamson ◽

...

Keyword(s):

Flow Cytometry ◽

High Risk ◽

High Throughput ◽

Research Funding ◽

High Throughput Sequencing ◽

Residual Disease ◽

Early Response ◽

Laboratory Services ◽

Disease Threshold ◽

Standard Risk

Abstract Background Early response to induction chemotherapy is a significant prognostic factor in the outcome of children with acute lymphoblastic leukemia (ALL). High throughput sequencing (HTS) of rearranged immune receptor (TCR and Ig) genes offers the possibility of a more accurate, sensitive, and standardized approach to determination of early response to therapy.In this study, we investigate the ability of an HTS assay to risk stratify children with B-ALL at the end of induction therapy in comparison with flow cytometry (FC), assess the impact of increased MRD sensitivity on risk group assignment, evaluate the significance of MRD discordance between HTS and FC, and identify a novel subset of patients having an inferior outcome. Methods 619 paired Pretreatment and End of Induction (Day 29) samples from patients with B-ALL enrolled on Children's Oncology Group (COG) clinical trials AALL0331 (standard-risk, SR) and AALL0232 (high-risk, HR) having minimal residual disease (MRD) at Day 29 of less than 0.1% by flow cytometry were assayed by high throughput sequencing of CDR3 regions of IGH and TCRG. Dominant clonal CDR3 sequences in the pretreatment samples were quantitated in the paired Day 29 samples as residual disease of total nucleated cells without knowledge of the FC results. The relationship of residual disease determined by HTS and FC to 5-year event-free and overall survival (EFS and OS) was evaluated using Kaplan-Meier statistics. Results HTS detected a dominant clonal sequence in 93.2% of Pretreatment B-ALL samples, providing an informative cohort of standard-risk (N=282) and high-risk (N=297) patients. Using a threshold of 0.01% on the combined cohort, HTS and FC show identical EFS and OS for MRD positive (77.7% ± 0.04, 91.6% ± 0.03) and negative (92.5% ± 0.02, 96.3% ± 0.01) subsets, see Figure 1. Interestingly, reducing the HTS threshold from 0.01% to 0.0001% results in an improvement in EFS for the HTS MRD positive subset in both standard (80.1% -> 88.2%) and high-risk (75.3% -> 84.8%) patients, likely due to major reductions in the number of patients otherwise scored as MRD negative using the higher threshold of 0.01%(70.9% -> 27.0% SR and 78.5% -> 36.7% HR). This reflects the much more favorable outcome of the large cohort of patients with MRD between 0.0001% and 0.01% compared to those >0.01%. Little improvement in EFS is seen for HTS MRD negative patients with a reduction in MRD threshold. Maximal difference in EFS is achieved at an HTS threshold of 0.01%. Importantly, the subset of SR patients with no detectable residual clonal sequence at any level (19.9% of total) show an excellent EFS (98.1% ± 0.02) and OS (100% ± 0), different from the similar subset of HR patients (30.0% of total) showing less favorable EFS (92.7% ± 0.04) and OS (95.1% ± 0.03). Patients discordant for MRD at a threshold of 0.01%, either HTS+/FC- (N=55) or HTS-/FC+ (N=17), show intermediate EFS compared with concordantly positive or negative patients. Of interest, patients lacking a detectable clonal IgH sequence (N=42) show a significantly inferior EFS (78.5% ± 0.08 vs. 89.3% ± 0.02, p=0.01) but not OS. Conclusions HTS is equivalent to FC in its ability to risk stratify patients with childhood B-ALL at End of Induction therapy using a MRD threshold of 0.01%. Reducing the HTS MRD threshold below 0.01% does not improve risk stratification, but does allow identification of a small subset of MRD negative standard-risk patients virtually certain to be cured with current therapy. Patients discordant for MRD between HTS and FC have an outcome intermediate between that seen for concordant patients. Patients lacking a detectable clonal IgH sequence, presumably representing a more primitive form of leukemia, show a significantly inferior outcome. Figure 1. Equivalence of outcomes by high throughput sequencing and flow cytometry for B-ALL patients at a residual disease threshold of 0.01%. Figure 1. Equivalence of outcomes by high throughput sequencing and flow cytometry for B-ALL patients at a residual disease threshold of 0.01%. Disclosures Wood: Pfizer: Honoraria, Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement; Seattle Genetics: Honoraria, Other: Laboratory Services Agreement; Juno: Other: Laboratory Services Agreement. Kirsch:Adaptive Biotechnology: Employment. Crossley:Adaptive: Employment, Equity Ownership. Williamson:Adaptive Biotechnology: Employment. Borowitz:HTG Molecular: Consultancy; BD Biosciences: Research Funding; Bristol-Myers Squibb: Research Funding; MedImmune: Research Funding. Loh:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding. Robins:Adaptive Biotechnology: Employment.

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A Phase II Single Arm Study of Nivolumab As Maintenance Therapy after Autologous Stem Cell Transplantation in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression

Blood ◽

10.1182/blood-2021-148139 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2455-2455

Author(s):

Carlos Bachier ◽

Henning Schade ◽

Behyar Zoghi ◽

Aravind Ramakrishnan ◽

Nirav N. Shah

Keyword(s):

Stem Cell ◽

High Risk ◽

Maintenance Therapy ◽

Board Of Directors ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Residual Disease ◽

Refractory Disease ◽

Advisory Committees ◽

Extranodal Disease

Abstract Introduction: Autologous stem cell transplants (ASCT) are standard of care for patients with primary refractory or recurrent Hodgkin lymphoma (HL). While transplant results in cure for some patients, others relapse and succumb from their disease. Studies have found high expression of programmed death ligand 1 (PD-L1) in HL cells. The anti-PD-1 monoclonal antibody, nivolumab, has been safe and efficacious in the treatment of relapsed, refractory HL (Ansell et al. 2015). We evaluated the safety and efficacy of nivolumab maintenance therapy post-ASCT in high risk for relapse Hodgkin disease. Methods: Patients with HL with high risk of residual disease following ASCT ( high risk defined as refractory disease, relapse <12 months, or relapse ≥12 months with extranodal disease after frontline therapy) received nivolumab (240 mg IV every 2 weeks) starting 45-180 days post-transplant for a maximum of 6 months of treatment. Patients were followed for AEs through 100 days after the last dose of drug. PET-CT response assessments were performed 1-3 month, 6 month, and 12 month post-ASCT. The primary objective was to evaluate the safety and tolerability of nivolumab as maintenance therapy early after ASCT. The secondary objective was to evaluate progression-free survival (PFS) at 12 months post-transplant. Results: To date, 37 patients were enrolled; median age 36 years; 25 patients (68%) male. The median number of prior systemic regimens was 2 (range 2-4). 25 patients (68%) had relapsed disease, and 12 patients (32%) had primary refractory disease. 18 patients (49%) had extranodal disease at relapse, 6 patients (16%) had B-symptoms at relapse, and 11 patients (30%) had residual disease after salvage, including 10 patients (27%) of whom had 2-3 prior salvage therapies. 22 patients (60%) had received prior brentuximab, and 3 patients (8%) had received prior nivolumab or pembrolizumab. 36 patients received ASCT and 1 patient received tandem ASCT. At the time of data cutoff, 28 patients (76%) had discontinued nivolumab treatment, 22 patients (60%) because they had completed the 6-month treatment course, 4 patients (11%) due to an adverse event (AE) (1 patient each with pain, pneumonitis, rhabdomyolysis, or hypothyroidism), and 2 patients (5%) due to disease progression. The median duration of treatment was 22.1 weeks. 17 patients (46%) experienced a treatment-related AE (TRAE), of which 5 patients (14%) experienced a ≥Grade 3 TRAE. The most common (≥5%) TRAEs were diarrhea, fatigue, bone pain, neutrophil count decreased, pruritus, rash, and vomiting. 2 patients experienced a treatment-related serious AE (pneumonitis, rhabdomyolysis). There were no treatment-related deaths. With a median follow up of 9.2 months, the median PFS and overall survival (OS) have not been reached. The 6 month PFS is 92.1% and the 12-month OS is 100%. There were no differences in OS when stratified based on prior treatment. Conclusions: The use of nivolumab maintenance early after ASCT is safe and tolerable in this high risk patient population. Early efficacy data is promising, but data need to mature to determine the 12 month PFS. Figure 1 Figure 1. Disclosures Bachier: CRISPR: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Shah: Umoja: Consultancy; Incyte: Consultancy; Legend: Consultancy; Kite: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy.

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Prognosis Impact of Positive Minimal Residual Disease By Flow Cytometry Prior to Transplant According to the Cut-Off Threshold in Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-139954 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 15-16

Author(s):

Claudia Nunez-Torron ◽

Fernando Martin Moro ◽

Juan Marquet Palomanes ◽

Miguel Piris-Villaespesa ◽

Ernesto Roldan ◽

...

Keyword(s):

Flow Cytometry ◽

Myeloid Leukemia ◽

Research Funding ◽

Residual Disease ◽

Allogeneic Transplant ◽

Group 3 ◽

Baseline Characteristics ◽

Group 2 ◽

Minimal Residual ◽

Group 1

Introduction: Patients with Acute Myeloid Leukemia (AML) and positive Minimal Residual Disease (MRD) prior to allogeneic transplant are currently considered to be a group at high risk of relapse. Multiparameter flow cytometry is a standard technique to measure MRD, and generally we use a 0.1% threshold for positivity. The clinical significance of those patients with an MRD levels >0% but <0.1% is uncertain and it is recommended to define the prognosis of this subgroup. Material and methods: We performed a single-center retrospective analysis of 88 patients transplanted between 2012 and 2020. All patients achieved complete remission (CR) with or without hemoperipheral recovery prior to allogeneic transplant. We have divided our cohort into three groups according to MRD state by flow cytometry: Group 1 patients with negative MRD, Group 2 patients with MRD level >0% but <0.1% and Group 3 patients with MRD ≥ 0.1%. The baseline characteristics of each group were compared using the Chi2 test. The survival analysis was performed through Kaplan-Meier method and the risk was calculated with Cox regression. The Overall Survival (OS) was defined as the time from transplantation to death and the Relapse-Free Survival (RFS) as the time from transplantation to either relapse or death. P<0.05 was defined as statistically significant difference. Results: The baseline characteristics of our cohort are reflected in Table 1. We did not find statistical significant differences except for the response to induction. The median follow-up of the entire cohort was 13.5 months (range 6-43.5). The 4-year RFS (4y-RFS) was 47% and the 4-year OS (4y-OS) 50%. The 4y-RFS was 52.5% in Group 1 vs 59% in Group 2 vs 30% in Group 3. The 4y-OS was 60% in Group 1 vs 60% in Group 2 vs 31% in Group 3 (Image 1). The Hazard Ratio (HR) for RFS and OS comparing Group 1 vs Group 2 was 0.9 [95% CI ((0.3-2.5)] and 1.1 [95% CI (0.4-3)] respectively. The HR for the RFS and OS comparing Group 1 vs 3 was 1.2 [95% CI (0.9-1.7)] and 1.2 [95% CI (0.8-1.6)]. We have stratified patients according to the European LeukemiaNet risk classification. In Group 1, the 4y-RFS was 79% in patients with Favorable Risk (FR) vs 55% in those with Intermediate Risk (IR) and 53% in patients with Adverse Risk (AR) [HR 1.2, 95% CI (0.6-2.3)] and the 4y-OS was 79% vs 54% vs 53% respectively [HR 1.3, 95% CI (0.6-2.5)]. In Group 2, the 4y-RFS was 100% in those with FR vs 83% in IR vs 33% in AR [HR 3.9, 95% CI (0.4-30)] and the 4y-OS was 100% vs 82% vs 36% respectively [HR 4, 95% CI (0.5-32%)]. In Group 3, the 4y-RFS in patients with FR was 82% vs 0% in IR vs 0% in AR [HR 2.1, 95% CI (1.1-4.1)] and the 4y-OS was 82% vs 0% vs 0% respectively [HR 1.6, 95% CI (0.8-3.3)] (Image 2). Conclusions: In our cohort, positive MRD >0.1% prior to transplant identified a group with worse RFS and OS compared to those with negative MRD or positive MRD level >0% but <0.1%. Positive MRD >0.1% is especially relevant in the IR and AR groups of the European LeukemiaNet risk classification. In the AR subgroup even any detectable level of positive MRD could identify patients with unfavorable post-transplant OS and RFS outcomes. We must establish post-transplant strategies in these patients to improve survival. Disclosures Garcia-Gutiérrez: Pfizer: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Incyte: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding.

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Combination Chemoimmunotherapy with Pentostatin, Cyclophosphamide and Rituximab Shows Significant Clinical Activity with Low Accompanying Toxicity in Previously Untreated B-Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v108.11.35.35 ◽

2006 ◽

Vol 108 (11) ◽

pp. 35-35

Author(s):

Neil Kay ◽

Susan Geyer ◽

Timothy Call ◽

Tait Shanafelt ◽

Clive Zent ◽

...

Keyword(s):

Flow Cytometry ◽

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Residual Disease ◽

Progression Free Survival ◽

Lymphocytic Leukemia ◽

Clinical Activity ◽

Hematologic Toxicity ◽

Free Survival ◽

Significant Clinical Activity

Abstract BACKGROUND: B-Chronic Lymphocytic Leukemia (CLL) is still uncurable but very powerful new tools are available with the use of chemoimmunotherapy (CIT). Purine nucleoside-based regimens that incorporate rituximab have generated very high levels of overall responses (OR) with significant percentage of those complete responses (CR) in previously untreated CLL. Here we report and update our experience with a phase 2 pentostatin-based CIT regimen for previously untreated CLL as conducted at 2 medical centers. We also studied the association of outcome based on risk stratification parameters and achievement of minimal residual disease. METHODS: Building on prior work of pentostatin in CLL by us (Kay ASH, 2004) and others, we initiated a trial of combined pentostatin (P)(2 mg/m2), cyclophosphamide (C)(600 mg/m2) and rituximab (R)(375 mg/m2) for symptomatic, previously untreated patients (n=65). This PCR regimen is given on a 21-day, 6-cycle schedule. However, the initial cycle of treatment uses thrice weekly rituximab as described by us earlier. In brief, this was rituximab at 100 mg/m2 on day 1, 375 mg/m2 on days 3 and 5 of the first week only. Prophylactic Sulfamethoxazole/Trimethoprim and Acyclovir were given to all patients for 1 year starting on the first cycle of therapy with PCR. All patients were risk stratified using CD38, ZAP-70, immunoglobulin heavy chain variable region gene (IgVH) and FISH panel assessments at entry. RESULTS: These patients were characterized as mostly in high-risk categories. Of 64 evaluable patients, 34 (53%) were high Rai risk (stage 3–4), 71% were non mutated for the IgVH gene, 34% were CD38+ and 34% were ZAP-70+. Thirty patients (52%) had one FISH anomaly, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs, and no major infections. NCI Working Group Criteria Responses occurred in 58 (91%) with 26 (41%) complete responses (CR), 14 (22%) nodular partial responses (nodular PR), and 18 (28%) partial responses (PR) patients. Outcome for all 64 patients demonstrates a median progression-free survival of 32.6 months. Importantly, no high risk factor (i.e., age, FISH, IgVH status, CD38+, ZAP-70+) except for del (17p) defect (n=3) precluded attaining a CR or NPR. In contrast, we found this regimen was equally effective in young vs. elderly (>70 yrs) patients and in del(11)(q22.3) vs. other favorable prognostic FISH factors. Examination of outcome among CR and nodular PR patients for PFS by flow cytometry status (negative vs. positive, i.e., ≤ 1 % CD5+/CD19+ vs. ≥ 1 % CD5+/CD19+) demonstrated improvement in progression free survival for patients who attained flow cytometry negativity (p = 0.009). Conclusion: This novel regimen of pentostatin, cyclophosphamide and rituximab for previously untreated CLL demonstrated significant clinical activity despite poor risk-based prognoses with minimal toxicity in terms of bone marrow suppression and/or infections. The additional feature of this approach is the ability to have durable responses for all age groups and even CLL patients with a del(11)(q22.3).

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Correlates of Lenalidomide Induced Immune Stimulation and Response in CLL: Analysis in Patients on Treatment

Blood ◽

10.1182/blood.v118.21.979.979 ◽

2011 ◽

Vol 118 (21) ◽

pp. 979-979 ◽

Cited By ~ 1

Author(s):

Georg Aue ◽

Stefania Pittaluga ◽

Delong Liu ◽

Larry Stennett ◽

Susan Soto ◽

...

Keyword(s):

Gene Expression ◽

Flow Cytometry ◽

Expression Profiling ◽

Research Funding ◽

Immune Stimulation ◽

Intramural Research Program ◽

Pre Treatment ◽

Program Research

Abstract Abstract 979 Lenalidomide's mechanism of action in chronic lymphocytic leukemia (CLL) is not well understood. In vitro data suggest that anti-leukemic immune responses are important. Tumor flare reactions during treatment have been associated with response in some but not other studies. In vivo data that mechanistically link immune stimulation to clinical responses are lacking. We designed an independent, single center, phase II trial of lenalidomide in relapsed/refractory CLL (clinicaltrials.gov: NCT00465127). Here we report final clinical data and results of multiple translational analyses that indicate that an IFNy centered immune response is critical for response. A 3 week on, 3 weeks off treatment scheme (42 day cycles) was chosen to pulse immune stimulation while trying to minimize myelosuppression. The starting dose was 20 mg daily for the first 10 patients and 10 mg for the subsequent 23. Response was measured at 24 weeks. 5 patients, 4 with del 17p, achieved a PR by IWCLL criteria (16%) and were eligible to continue drug for 4 more cycles; the PFS in these patients was 16 months compared to 7 months for all other (p<0.001). Myelosupression remained the limiting side effect. A cytokine release syndrome often accompanied by tumor flare reactions was seen in 78% of patients in cycle 1 and often recurred in subsequent cycles. Compared to other studies it appears that the long treatment free period increased the inflammatory reaction upon restarting of L. All correlative analyses reported here were performed on PBMCs, lymph node (LN) core biopsies and serum obtained from patients during cycle 1 and 2 and included flow cytometry, gene expression profiling (Affymetrix arrays), and cytokine measurements. Nine patients with decreased lymphadenopathy ≥10% (10–85%) on CT after 4 cycles were considered responders (R) for correlative studies. There was a significant decrease in CLL count (median 14% on day 8 and 49% on day 22, p<0.01) and in the number of circulating T (CD3, CD4, CD8) and NK-cells (n=22, p<0.05) with no difference between R and non-responders (NR). In contrast, the CD3 count in LN core biopsies increased 1.4 fold in R compared to matched pre-treatment biopsies (p<0.05) with no change in NR (0.95 fold). In the L free interval CLL cells rebounded to pre-treatment levels. A rapid rebound of CLL counts during treatment interruptions has been previously described but its mechanism is not well understood. In migration assays we observed a 3-fold increased migration towards SDF-1 for L compared to control cells (p=0.03), indicating that increased homing of lymphocytes to tissue sites may be responsible for the rapid decrease in peripheral counts. The cell surface molecules CD40, 54, 86, 95, DR5 were upregulated (p<0.05) while CD5 and 20 were downregulated (p<0.001) on circulating CLL cells. Effects on CD54 and CD5 were stronger in R than NR (p<0.05). Next we performed gene expression profiling on purified PB-CLL cells and LN core biopsies obtained on day 8. L induced upregulation of 95 genes, many of which are known to be regulated by interferon gamma (IFNγ). The comparison with a gene expression signature induced by recombinant IFNγ in CLL cells cultured in vitro confirmed the significant induction of a typical IFNγ response by L in vivo (n=24, p<0.0001). The IFNγ response in PB-CLL cells was no different in R vs NR (n=12, p=0.78), but in LN biopsies it was more prominent in R (n=7) than NR (n=5) (p<0.05). Consistently the IFNG gene was upregulated in LN biopsies of R but actually decreased in NR (p=0.001). Serum IFNγ levels were elevated on L (n=14 at all time points, day 4 p=0.03, day 8 p=0.01, day 22 p=0.02, day 49 p<0.01), but off drug returned to pretreatment levels. Next we sought to determine the source of IFNγ. The tumor cells are ruled out as IFNG was not expressed in purified CLL cells. By flow cytometry the number of IFNγ secreting CD4 T-cells increased on day 8 from 0.8% to 1.5%, p=0.006), an effect that was stronger in R had than NR (p<0.05). IFNγ positive NK cells did not increase on L. These data provide a first mechanistic link between the degree of Lenalidomide induced immune activation to clinical response in CLL. Based on our experience we suggest that continued dosing of L may be superior to dose interruptions. Disclosures: Aue: NHLBI, Intramural Research Program: Research Funding. Off Label Use: Lenalidomide is not FDA approved for CLL. Wiestner:NHLBI, Intramural Research Program: Research Funding.

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Long-Term Follow Up Of a Randomized Phase II Study Of The JAK2-Selective Inhibitor Fedratinib (SAR302503) In Patients With Myelofibrosis (MF)

Blood ◽

10.1182/blood.v122.21.4047.4047 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4047-4047 ◽

Cited By ~ 4

Author(s):

Animesh Pardanani ◽

Ayalew Tefferi ◽

Catriona HM Jamieson ◽

Nashat Y Gabrail ◽

Claudia Lebedinsky ◽

...

Keyword(s):

High Risk ◽

Disease Progression ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

Hematologic Toxicity ◽

Costal Margin ◽

Spleen Volume ◽

Randomized Phase Ii ◽

Grade 3

Abstract Background We previously reported that patients with MF enrolled in a randomized Phase II study of fedratinib (SAR302503) (ARD11936; NCT01420770) had clinically meaningful reductions in splenomegaly and improvements in MF-associated constitutional symptoms after 24 weeks of treatment (Haematologica 2013;98:S1113). Here, we report updated efficacy and safety results from this study after 48 weeks of treatment (end of Cycle 12). Methods Patients with intermediate risk-2 or high-risk MF were randomized to receive once-daily fedratinib at doses of 300 mg, 400 mg, or 500 mg, for consecutive 4-weekly cycles, until disease progression or unacceptable toxicity. Eligible patients were aged ≥18 years, with palpable splenomegaly (5 cm below costal margin), and a platelet count ≥50 × 109/L. The primary measure for this study was percent change in spleen volume from baseline at the end of Cycle 3 (Blood 2012:120;Abstract 2837. Haematologica 2013;98:S1113). Endpoints for the current analysis included spleen response (≥35% reduction in spleen volume from baseline, assessed by a blinded independent central review by MRI), safety, and changes in bone marrow fibrosis (BMF). Results A total of 31 patients were randomized and treated: median age 63 years, 52% male, 58% primary MF, 58% high-risk MF, 90% JAK2V617F positive. The median numbers of treatment cycles were 12, 14, and 13 in the 300 mg, 400 mg and 500 mg dose groups, respectively, with median durations of exposure of 48.2, 56.2, and 52.4 weeks. At the cut-off date for this analysis, 21 patients (68%) remained on treatment; the most common reasons for treatment discontinuation were adverse events (AEs) (n=5) and withdrawal of consent (n=2). Overall, 58% (18/31) of patients achieved a spleen response at any time during treatment. The median spleen response duration was >35 weeks at all doses (Table). At Week 48, a spleen response was achieved by 30% (3/10), 80% (8/10), and 45% (5/11) of patients in the 300 mg, 400 mg, and 500 mg groups, respectively. Responses were generally maintained across all treatment groups. From Week 24 to Week 48 two additional patients achieved a spleen response (both in the 400 mg group), while one patient in the 500 mg group did not maintain a response (this patient had a fedratinib dose reduction to 200 mg). Changes in BMF up to Week 48 are being evaluated. The most common non-hematologic AE was diarrhea, with a Grade 3 rate of 13% (4/31 patients) but no Grade 4 cases were recorded. The rates of diarrhea decreased after the first cycle of treatment; from Cycle 2, the incidence of diarrhea (any grade) did not exceed 16% (5/31) at any cycle, and only one case of diarrhea was reported at Week 48 (end of Cycle 12). Anemia was the most-common hematologic toxicity, with a Grade 3 rate of 58% (18/31); no Grade 4 cases were reported. All Grades thrombocytopenia occurred in 55% (17/31) of patients, Grade 3 in three patients, and Grade 4 in two patients. Discontinuation of treatment due to AEs occurred in five patients over the 48 weeks (300 mg [n=2]; 400 mg [n=2]; 500 mg [n=1]), with two cases reported after Week 24 (dyspnea and leukocytosis [400 mg]; anemia and thrombocytopenia [500 mg]). There were 2 deaths (one in the 300 mg group due to unknown reasons [85 days after fedratinib discontinuation] and one in the 500 mg group due to disease progression [36 days after fedratinib discontinuation]). No cases of leukemic transformation were reported. Conclusions This updated analysis of the ARD11936 Phase II trial shows that treatment with fedratinib results in durable reductions in splenomegaly in patients with MF. No additional safety signals were observed with prolonged exposure to fedratinib. This study was sponsored by Sanofi. Disclosures: Pardanani: Sanofi, Bristol Myers Squibb, PharmaMar and JW Pharma: Clinical trial support Other. Jamieson:J&J, Roche: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Lebedinsky:Sanofi: Employment. Gao:Sanofi: Employment. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau.

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Ublituximab, a Novel Glycoengineered Anti-CD20 Monoclonal Antibody (mAb), in Combination with TGR-1202, a Next Generation Once Daily PI3kδ Inhibitor, Demonstrates Activity in Heavily Pre-Treated and High-Risk Chronic Lymphocytic Leukemia (CLL) and B-Cell Lymphoma

Blood ◽

10.1182/blood.v124.21.801.801 ◽

2014 ◽

Vol 124 (21) ◽

pp. 801-801 ◽

Cited By ~ 1

Author(s):

Matthew A. Lunning ◽

Julie M. Vose ◽

Marshall T. Schreeder ◽

Nathan Fowler ◽

Loretta J. Nastoupil ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Next Generation ◽

Employment Equity ◽

Once Daily ◽

Richter's Transformation ◽

Equity Ownership ◽

Anti Cd20 ◽

Ecog Ps ◽

11Q Deletion

Abstract Introduction: Ublituximab (UTX) is a novel chimeric mAb targeting a unique epitope on the CD20 antigen, glycoengineered to enhance affinity to FcγRIIIa receptors, thereby demonstrating significantly greater ADCC than rituximab. UTX monotherapy in patients (pts) with rituximab relapsed/refractory NHL and CLL has reported a 43% ORR (ASCO 2014). TGR-1202 is a next generation, once daily, oral PI3Kδ inhibitor which notably lacks the hepatotoxicity associated with other PI3Kδ inhibitors, and is active in pts with relapsed and refractory hematologic malignancies (EHA 2014). UTX and TGR-1202 have shown synergistic activity in-vitroin various lymphoid cell lines (Lugano 2013). This Phase 1 trial evaluates safety and efficacy of the combination of a glycoengineered anti-CD20 (UTX) and a PI3Kδ inhibitor (TGR-1202) in pts with heavily pre-treated relapsed or refractory CLL and NHL. Methods: Eligible pts have relapsed/refractory CLL or NHL with an ECOG PS ≤ 2. A 3+3 design evaluates cohorts of CLL and NHL pts independently with UTX dosed on Days 1, 8, 15 of Cycles 1 & 2 followed by maintenance therapy. UTX starts at 600 mg in Cohort 1 and increases to 900 mg for pts with CLL and is fixed at 900 mg for pts with NHL. TGR-1202 starts at 800 mg QD in Cohort 1 and is increased in subsequent cohorts. An amendment in July 2014 was introduced to include an improved micronized formulation of TGR-1202, starting at 400 mg once daily and increasing in subsequent cohorts. There are no limits on prior therapy, and patients with Richter’s Transformation or who are refractory to prior PI3Kδ inhibitors or BTK inhibitors are eligible. Primary endpoints: Safety and Dose Limiting Toxicities (DLT). Secondary endpoints: Efficacy (ORR, CR rate). Results: As of August 2014, 21 pts have been enrolled: 8 CLL/SLL, 7 DLBCL, 5 Follicular Lymphoma, and 1 patient with Richter’s Transformation. Median age is 64 years (range 35-82); 12 male/9 female. Median prior Tx = 3 (range 1-9); median ECOG PS = 1. All pts are evaluable for safety. Adverse events have been manageable with no safety concerns noted. Day 1 infusion related reactions (IRR) were the most common treatment related adverse event (48%), with all but one event Grade 1 or 2 in severity, followed by neutropenia (38%), diarrhea (29%), and nausea (29%). Notably, no events of TGR-1202 related hepatotoxicity have been reported to date. All IRR and neutropenia events have been manageable with dose delays. One neutropenia related dose delay in a CLL patient at UTX 600 mg + TGR 800 mg met the criteria for a DLT, necessitating enrollment of additional pts into this cohort. No other DLTs have been reported, including at higher dose levels. Fifteen pts were evaluable for efficacy with 6 pts too early for response assessment. Among evaluable pts, 80% displayed a reduction in tumor burden at first efficacy assessment, despite pts exhibiting a number of high-risk characteristics, including 3/5 CLL pts having 17p/11q deletion and a median of 6 prior lines of therapy amongst pts with FL. Objective responses are summarized below: Table TypePts (n)PRn (%)ORRn (%)PD(n)% pts ≥ SD for 12 wksMedian Prior Rx CLL/SLL54 (80%)4 (80%)-5 (100%)2 (1 – 3) Richter’s1---1 (100%)1 FL4---4 (100%)6 (3 – 8) DLBCL52 (40%)2 (40%)14 (80%)3 (1 – 6) Total156 (40%)6 (40%)114 (93%)3 (1 – 8) Amongst pts with CLL, 2/2 pts with normal cytogenetics achieved a PR including a patient with prior treatment with a BTK inhibitor, while 2/3 pts with presence of 17p/11q deletion achieved a PR, with the remaining patient having SD with a 44% nodal reduction at first assessment. Conclusions: Preliminary data suggests the combination of UTX + TGR-1202 is well tolerated with early signs of clinical activity in heavily pre-treated and high-risk patient subsets. Enrollment is ongoing with at least 30 patients anticipated. Disclosures Lunning: Onyx: Consultancy; Alexion: Consultancy; Gilead: Consultancy; Spectrum Pharmaceuticals: Consultancy. Schreeder:TG Therapeutics, Inc.: Research Funding. Pauli:TG Therapeutics, Inc.: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership. Vakkalanka:Rhizen: Employment, Equity Ownership. Viswanadha:Incozen: Employment. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding.

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