Abstract: Lenalidomide is an immunomodulatory imide drug used broadly in the treatment of multiple myeloma and lymphoma. It continues to be evaluated in chronic lymphocytic leukaemia (CLL) at lower doses due to dose‐related toxicities including tumour flare and tumour lysis syndrome. This study aimed to develop a population pharmacokinetic model for lenalidomide in multiple cancers, including CLL, to identify any disease‐related differences in disposition. Methods Lenalidomide concentrations from 4 clinical trials were collated (1999 samples, 125 subjects), covering 4 cancers (multiple myeloma, CLL, acute myeloid leukaemia and acute lymphoblastic leukaemia) and a large dose range (2.5–75 mg). A population pharmacokinetic model was developed with NONMEM and patient demographics were tested as covariates. Results The data were best fitted by a 1‐compartment kinetic model with absorption described by 7 transit compartments. Clearance and volume of distribution were allometrically scaled for fat‐free mass. The population parameter estimates for apparent clearance, apparent volume of distribution and transit rate constant were 12 L/h (10.8–13.6), 68.8 L (61.8–76.3), and 13.5 h −1 (11.9–36.8) respectively. Patients with impaired renal function (creatinine clearance 〈 30 mL/min) exhibited a 22% reduction in lenalidomide clearance compared to patients with creatinine clearance of 90 mL/min. Cancer type had no discernible effect on lenalidomide disposition. Conclusions This is the first report of a lenalidomide population pharmacokinetic model to evaluate lenalidomide pharmacokinetics in patients with CLL and compare its pharmacokinetics with other B‐cell malignancies. As no differences in pharmacokinetics were found between the observed cancer‐types, the unique toxicities observed in CLL may be due to disease‐specific pharmacodynamics.

Abstract: Chronic lymphocytic leukemia (CLL) involves a profound humoral immune defect and tumor-specific humoral tolerance that directly contribute to disease morbidity and mortality. CD154 gene therapy can reverse this immune defect, but attempts to do this pharmacologically have been unsuccessful. The immune-modulatory agent lenalidomide shows clinical activity in CLL, but its mechanism is poorly understood. Here, we demonstrate that lenalidomide induces expression of functional CD154 antigen on CLL cells both in vitro and in vivo. This occurs via enhanced CD154 transcription mediated by a Nuclear Factor of Activated T cells c1 (NFATc1)/Nuclear Factor-κB (NF-κB) complex and also through phosphoinositide-3 (PI3)–kinase pathway-dependent stabilization of CD154 mRNA. Importantly, CD154-positive CLL cells up-regulate BID, DR5, and p73, become sensitized to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–mediated apoptosis, and promote costimulatory activation of normal B cells to produce antibodies. In CLL patients receiving lenalidomide, similar evidence of CD154 activation is observed including BID, DR5, and p73 induction and also development of anti-ROR1 tumor-directed antibodies. Our data demonstrate that lenalidomide promotes CD154 expression on CLL cells with subsequent activation phenotype, and may therefore reverse the humoral immune defect observed in this disease. This study is registered at http://clinicaltrials.gov as NCT00466895.

Abstract: Background: In patients with chemo-sensitive relapsed diffuse large B-cell lymphoma (DLBCL), autologous hematopoietic cell transplant (ASCT) has long been the standard of care. Several recent studies have identified patient groups with poor post-transplant outcomes and in recent years chimeric antigen receptor (CAR)-T therapy has been utilized in patients who do not have adequate disease control to proceed with ASCT or who progress after ASCT. We hypothesized that the availability of CART to treat patients with aggressive lymphoma who were not ideal candidates for ASCT would lead to improved survival among lymphoma patients proceeding to transplant. We evaluated whether the demographics, baseline characteristics and post-ASCT outcomes for patients with relapsed non-Hodgkin lymphoma (NHL) have changed in the CAR-T era. Methods: We included patients initially diagnosed with DLBCL since 2012 who subsequently relapsed and received ASCT. Patients who completed ASCT without a documented relapse or who received CART therapy prior to an ASCT were excluded as were patients without adequate follow-up data. Patients who completed ASCT prior to January 1, 2018, were part of the pre-CART group while those completing ASCT on January 1, 2018 and later were part of the post-CART group. We compared demographics as well as disease and treatment-related variables of interest between the pre- and post-CART groups using Fisher's Exact or chi Square tests as appropriate for categorical and ANOVA for numeric variables. In addition, we determined progression-free (PFS) and overall survival (OS) from the date of ASCT using the Kaplan-Meier method and determined predictors of post-ASCT PFS and OS using the Cox Proportional Hazards model with backward elimination. Results: Of 84 included patients, 55 were in the pre-CART group and 29 were in the post-CART group. Median age at diagnosis for all patients was 55 years (range 22-73). 50 were male, and 60 had stage 3 or 4 disease. While there were no differences in demographics based on treatment group, the ECOG performance status for patients in the post-CART group was improved compared to those pre-CART (Table 1, p=0.040). There was also no difference in time from diagnosis to transplant between the two groups (Table 1, p=0.292). With a median follow-up post ASCT of 2.22 years for the pre-CART group and 1.24 years for the post-CART group, the median OS was 4.7 years (95% CI: 3.4 - Not Reached) for the entire cohort, 4.7 years (95% CI: 2.8 - Not Reached) for the pre-CART group and not reached (95% CI: NR-NR) for the post-CART group. The median PFS was not reached in either cohort (p=0.932). Neither univariate nor multivariable analysis showed any of covariates as being significant predictors of post-ASCT PFS. In the multivariable model for OS, receiving R-CHOP chemotherapy compared to other induction regimens (HR 0.28 [0.10-0.74], p=0.01) predicted improved OS while increased age (HR 1.06 [1.01-1.11] , p=0.03) predicted inferior OS. The receipt of ASCT after CART cell era, conditioning regimen, or first salvage regimen all did not impact PFS or OS. Conclusion: In comparison with those patients receiving autologous transplantation prior to the adoption of CAR T cell, patients receiving ASCT more recently had no change PFS or OS despite having better performance status prior to ASCT. Our findings suggest that selection of appropriate candidates for ASCT in the current era is critical and that patients who are at higher risk for early post-ASCT relapse should be considered for novel approaches including immune effector cell therapy. Additional follow-up will be needed to determine if newer currently approved therapies for post-ASCT relapse can improve OS in relapsed/refractory DLBCL who relapse after ASCT. Disclosures Waller: Verastem Oncology, Inc: Consultancy, Research Funding. Allen:Curio Sciences: Honoraria; Bayer: Consultancy, Other; Clinical Care Options: Speakers Bureau; Research to Practice: Speakers Bureau; Imbrium: Consultancy, Other. Lonial:JUNO Therapeutics: Consultancy; Amgen: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; Sanofi: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy; Onyx: Honoraria; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Takeda: Consultancy, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; GSK: Consultancy, Honoraria, Other: Personal fees; Merck: Consultancy, Honoraria, Other: Personal fees; Millennium: Consultancy, Honoraria; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Kaufman:Tecnopharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi/Genyzme: Consultancy, Honoraria. Hofmeister:Janssen: Honoraria, Research Funding; Oncolytics Biotech: Research Funding; Imbrium: Honoraria; Oncopeptides: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Nektar: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Dhodapkar:Janssen: Membership on an entity's Board of Directors or advisory committees, Other; Kite: Membership on an entity's Board of Directors or advisory committees, Other; Lava Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Other; Amgen: Membership on an entity's Board of Directors or advisory committees, Other; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other. Nooka:Oncopeptides: Consultancy, Honoraria; Spectrum Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Adaptive Technologies: Consultancy, Honoraria; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Klisovic:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Langston:Bristol Myers Squib: Research Funding; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding; Kadmon Corporation: Research Funding; Takeda: Research Funding; Chimerix: Research Funding. Cohen:Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy; Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding.

Abstract: Incorporation of rATG in RIC regimens not only reduces rates of graft-versus-host disease (GVHD), but it also promotes effective engraftment of donor cells. However rATG at doses ≥7.5mg/kg, is associated with significant infectious complications (Hamadani M. ASH 2007). We hence embarked on a strategy designed to evaluate lower dose (6mg/kg) rATG in patients (pts) undergoing RIC with FBA. All pts (n=47) were conditioned with F (30 mg/m2/day, days-7 to -3), B (0.8 mg/kg/dose IV × 8 doses) and either 7.5mg/kg of rATG (7.5rA) (n=39) or 6mg/kg of rATG (6rA) (n=8), followed by micro-dose methotrexate and tacrolimus. Criteria for selection included advanced age ( & gt;55yrs), prior autograft, and/or high co-morbidity index (median 1, range 0–4). There were 31 male and 16 female pts with a median age of 57 years (range 24–70 yrs). Diagnoses included AML (N=17), NHL (N=10), Hodgkin’s lymphoma (N=4), CML (N=5), advanced CLL (N=8), and others (N=3). 74% (N=35) had high-risk disease. Six pts had previously undergone autologous SCT. 36% had a Karnofsky performance status of 70 or 80% at the time of transplant. 9 pts (19%) had one or more antigen or allele level mismatches with their donors. Stem cell source included peripheral blood (N=43) or bone marrow (N=4). 42 pts (89%) received grafts from unrelated donors. All pts engrafted neutrophils and platelets promptly (median 15 and 17 days, respectively). One patient had secondary graft failure, and another AML patient previously only treated with decitabine experienced secondary graft rejection. Both of these patients received 7.5rA. Overall rates of grade II–IV and III–IV acute GVHD were 27% (N=13) and 17% (N=8) respectively. 17 pts (41%) developed chronic GVHD but extensive chronic GVHD was seen in only 21% (N=9). Day 100 and overall non-relapse mortality (NRM) was 6% (N=3) and 23% (N=11). Causes of death included disease progression=6, post-transplant lymphoproliferative disorder (PTLD)=2, GVHD=3, infection=4, and others=2. CMV, EBV, and BK-virus reactivation occurred in 55% (N=26), 25% (N=12) and 21% (n=10) respectively. Compared to pts receiving 7.5rA, ones receiving 6rA had fewer CMV (61% vs. 25%; p-value=0.05) and BK-viral (25% vs. 0%; p-value=0.03) reactivations and lower rate of relapse (33% vs. 12.5%; p-value=0.20), NRM (28% vs. 0%; p-value=0.01), and acute GVHD (33% vs. 0%; p-value=0.01). None of the 6rA pts developed PTLD. Overall lineage-specific chimerism analysis showed 100% donor CD33+ chimerism at all time points (days 30, 60, 90, and 180) and median donor CD3+ chimerism of 94%, 97%, 99% and 100% at days +30, +60, +90 and +180. No difference was seen in the two rATG doses. 36 pts (76%) were in CR after ASCT. The median follow-up of surviving patients is 12 months (range 3–26 months). Rates of overall survival (OS) and progression free survival (PFS) at 1year are 66% and 52% respectively. Using the Log-Rank test, OS and PFS was not statistically significant between recipients of matched and mismatched grafts, and between pts with high-risk or standard-risk disease. In conclusion, our preliminary data suggests that 6rA promotes effective donor cell engraftment, without compromising GVHD control, and may be associated with lower rates of infectious complications and disease relapse. Systematic evaluation of rATG dose de-escalation is continuing at our institution.

Abstract: We report here for the first time a case of “decitabine-induced differentiation syndrome” in a patient (pt) with acute myeloid leukemia (AML). The cytosine analog decitabine, after incorporating into DNA, irreversibly binds DNA methyltransferase (DNMT) enzymes where cytosine residues are targeted for methylation. This allows replication of unmethylated DNA with subsequent re-expression of genes previously silenced by promoter methylation. It has been suggested that decitabine at low doses may have differentiating effects, as compared to cytotoxic effects at higher doses. A previous phase I trial demonstrated clinical activity of low dose decitabine in patients with myeloid malignancies (Issa, et al., Blood 2004). Given the close relationship of DNA methylation and histone deacetylation in modulating gene expression, we are currently conducting a phase I trial (OSU 0336) of low dose decitabine (15mg/m2 IV over 1 hour on days 1–10) alone (step 1) or in combination with escalating doses of the histone deacetylase inhibitor valproic acid (step 2) in AML. An 82 year old male pt with untreated, secondary AML (65% bone marrow blasts, 95% marrow cellularity) was enrolled on step 1 of the study and given 15mg/m2/day of decitabine for 10 consecutive days. At the time of initiation of therapy, the pt had a white blood cell (WBC) count of 8,700/uL with absolute neutrophil count (ANC) of 1,500/uL and absolute blast count (ABC) of 3,200/uL. At day 11, the pt had WBC 1,000/uL with ANC of 450/uL and ABC of 150/uL and was clinically well. However, at day 17, he presented with cough and shortness of breath, without fever. WBC had risen to 18,700/uL with ANC of 11,000/uL and ABC of 750/uL. The patient developed worsening hypoxia and required mechanical ventilation. Chest radiograph demonstrated diffuse interstitial infiltrates, but bronchoscopy and lavage (on day 18 and repeated on day 24) did not identify an infectious etiology. Due to clinical concern for a differentiation syndrome similar to the “retinoic acid syndrome” occurring in acute promyelocytic leukemia patients treated with all-trans-retinoic-acid (ATRA), the pt was started on dexamethasone 10mg IV q12 hours beginning on day 18, in addition to broad spectrum antimicrobial coverage. Peripheral blood smears during the following week showed evidence of myeloid differentiation, and by day 25 no circulating blasts were found (WBC 4,300/uL, ANC 3,000/uL) while the overall clinical condition improved. The pt was finally extubated on day 38 but within 24 hours required emergent re-intubation due to nasogastric feeding aspiration and died at day 53. In summary, these preliminary data support the biological activity of low dose decitabine in AML and suggest that clinical precautions similar to those implemented for the “retinoic acid syndrome” in ATRA-treated APL should be considered in decitabine-treated AML when myeloid differentiation and rising neutrophil counts are observed.

Abstract: Background: Patients (pts) with chemo-refractory (Cref) and/or progressive aggressive non-Hodgkin’s lymphomas (A-NHL) generally have a poor clinical outcome. Autologous stem cell transplantation (SCT) has limited efficacy in this setting. Studies reporting outcomes of allogeneic (Allo) SCT in pts with Cref A-NHL are limited. Methods: 108 pts with A-NHL underwent Allo-SCT between 1988 and 2007 at our institution. 46 A-NHL pts with Cref (i.e pts with 〈 50% reduction in tumor size and/or persistent bone marrow involvement following chemotherapy) or progressive disease (PD) by CT-criteria were eligible for this analysis. Positron emission tomography (PET) or PET/CT scans were not performed to assess response. Results: The median age was 46 years (range 22–63 yrs). 39 pts received matched sibling allografts, while 7 underwent unrelated donor SCT. All except 3 pts received myeloablative conditioning. 38 pts received BU/CY-based conditioning, while BEAM (n=5) or Flu/Bu (n=3) was employed in the remaining pts. Diagnosis included diffuse large B-cell lymphoma (n=18), Burkitt’s lymphoma (n=3), transformed lymphoma (n=5), mantle cell lymphoma (n=11) and T-cell lymphomas (n=9). The median number of prior therapies was 3 (range 1–8). 32 pts had Cref disease, while 14 had PD. 41 pts had stage III/IV disease, 23 had elevated LDH, while 36 had extranodal involvement. Median follow-up of surviving pts following Allo-SCT is 5-yrs. The 5-yr overall survival (OS), progression free survival (PFS), and relapse rate for the whole cohort (n=46) was 38%, 34%, and 35% respectively. Rate of grade II-IV acute graft-versus-host disease (GVHD) was 43% (n=20). Among the 33 evaluable pts rate of chronic GVHD was 75%. Overall non-relapse mortality rate was 37%. No significant difference in the baseline characteristics of pts with Cref and PD was present. The 5-yr OS and PFS rates for pts with Cref and PD were 46% vs. 21% (p-value=0.01; log-rank test), and 46% vs. 7% (p-value=0.0002; log-rank test) respectively. On multivariate analysis only PD at the time of SCT predicted for worse OS and PFS. Conclusion: Our study shows encouraging efficacy of Allo-SCT in a group of A-NHL pts with Cref disease by CT scan-criteria who often fail following Auto-SCT. However outcomes of pts with PD remain dismal despite Allo-SCT, and our data question the practice to perform allografting in A-NHL pts with PD. We hypothesize that PET scans may help better define patients with aggressive NHL appearing not to have responded to salvage chemotherapy by standard CT criteria that still may derive significant benefit from allografting.