ALBERT

Description: Background: With advances in immunotherapeutic approaches and the recognition of antigen modulation as a mechanism of relapse, it is imperative to understand the impact of sequential targeting strategies and the role it may have on outcomes of future therapies to optimize timing of therapeutic interventions. We previously reported on the safety, feasibility, and efficacy on our phase I dose escalation anti-CD22 CAR protocol (clinicaltrials.gov/NCT02315612).1 Based on our initial experience, we identified CD22 loss or diminution of CD22 as a risk factor for relapse following CD22 directed CAR therapy. With development of other CD22 directed therapies, we retrospectively analyzed impact of prior CD22 targeted therapy on response to CD22 CAR in our ongoing clinical trial. Design: Children and young adults with relapsed/refractory CD22+ hematologic malignancies eligible for our phase I dose escalation anti-CD22 CAR protocol were enrolled on study (Clinicaltrials.gov NCT02315612). All had bone marrow evaluations at baseline, prior to lympho-depleting chemotherapy (Fludarabine 25 mg/m2 x 3 days and Cyclophosphamide 900 mg/m2 x 1 day) and again at day 28 (+/- 4 days) post-CAR infusion. We retrospectively analyzed the impact of prior CD22 directed therapy on outcomes following CD22 CAR and specifically looked at the variables of CD22 antigen expression prior to CAR infusion (% positive and antigen density) and compared responses to CD22 CAR for those who did and did not receive prior CD22 targeted therapy. Results: From December 2014 to July 2018, 43 subjects with ALL were treated. All had active bone marrow involvement at baseline, the majority with an M2 marrow (〉5% blasts) or higher disease burden. 34 had a prior transplant and 26 were previously treated with CD19 CAR. Fourteen subjects had received prior CD22 directed therapy, including CD22 CAR elsewhere (n=2) or inotuzumab ozagamicin (Ino) (n=13). Subjects received a median of 3 doses of Ino (3-6 doses) and the median time from last Ino exposure was 2 months (range 1-20 months). Median CD22 antigen expression on bone marrow leukemic blasts prior to planned lymphodepletion for those who had received prior CD22 therapy compared to those who did not was 2527 (882-9079) vs 3929 (846-13452), respectively (one-tailed p=0.05, Figure 1). (Figure 1). Complete remission (CR) rates following CAR-T infusion for those who had prior CD22 directed therapy compared to those who did not was 57% and 71%, respectively with MRD negativity by flow cytometry achieved in only 5/8 (62.5%) patients versus 18/20 (90%) respectively and residual disease in those not achieving MRD negativity was CD22 dim. Both subjects who had received prior CD22 CAR elsewhere were non-responders to our construct with a first-infusion, however one subject converted to a CR with an intensified lymphodepletion and a second infusion. Two subjects who had received prior Ino were noted to have partial CD22 expression on at least one time point (69-89% positivity) prior to enrollment. One of these patients with pre-existing CD22 partial positivity (69% positivity) had evidence for CAR-T cell expansion but had residual low CD22 expressing disease at restaging. Notably, another subject who received 6 doses of Ino prior to receiving CD22 CAR T-cells and had uniformly CD22+ disease at enrollment, emerged with CD22 negative disease following CD22 CAR. Durability of remission also significantly differed amongst the two groups. Median time to relapse in patients who received prior CD22 directed therapy was 2 months (range 2-5 months) versus 6 months (range 2-13 months) for those who did not receive prior CD22 targeted therapy, with the majority relapsing with CD22 negative disease. Conclusion: Sequential targeting of CD19 has anecdotally increased the possibility of CD19 negative relapses, and our data provide evidence for a similar phenomenon with sequential targeting of CD22. Most notably, CD22 expression in patients who had received prior CD22 targeted therapies was lower compared to those who did not. This may have ultimately contributed to both of the observed findings of decreased response rates and decreased durability of remission, the majority of whom relapsed with CD22 negative disease following sequential targeting. This observation contributes to the increasing fund of knowledge regarding optimization of targeted therapies. Disclosures No relevant conflicts of interest to declare.

Description: Background: State of the art treatment for patients with NDMM involves induction with triplet-based regimens utilizing combinations of immunomodulatory drugs and proteasome inhibitors (PI) which improve time to progression (TTP), progression-free survival, and overall survival (OS) over doublet regimens. Carfilzomib is a selective PI with FDA approval in the KRd combination regimen for the treatment of patients with relapsed or refractory MM. Carfilzomib-based combinations are associated with increased clinical benefit over bortezomib-based combinations and carfilzomib does not cause neuropathy. This phase 2 study of 45 patients demonstrated that deep responses with KRd-r is achieved in the NDMM setting (Korde et al. JAMA Onc 2015). Here, we expand on our initial results in assessing response to present the long-term durability of minimal residual disease negativity (MRDneg) complete response (CR) and time to progression. We also characterize TTP by depth of response, age, and cytogenetic risk profile. Methods:Treatment-naïve patients with MM were treated for 8 cycles (28-day cycles) with carfilzomib 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg PO days 1-21, and dexamethasone 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles and then continued KRd treatment (i.e. without default autologous stem cell transplant (ASCT)). After 8 cycles of KRd, patients received 2 years of lenalidomide 10 mg PO maintenance on days 1-21. The primary objective of the study was to estimate the rate of ≥ Grade 3 peripheral neuropathy with secondary objectives of International Myeloma Working Group criteria for overall response rate (ORR), MRDneg CR, TTP, and response duration (DoR) assessed after every cycle during induction and subsequently after every 90 days of maintenance therapy. Assessment of MRDneg CR by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) was performed after 8 cycles of induction, 1 and 2 years of lenalidomide maintenance, and then annually. Results: Forty-five patients meeting eligibility criteria were enrolled (60% male; 42% ≥ age 65, range 40-89; race: 82% White, 13% Black, 4% Asian; isotypes: 51% IgG kappa, 16% IgG lambda, 13% IgA kappa, 9% IgA lambda, 9% free kappa, and 4% free lambda; 33% high risk cytogenetics, del(17p), t(4;14), t(14;16)or t(14;20)). The median potential follow up was 5.7 years (68.3 months). The ORR was 97.8% (95% Confidence Interval (CI): 88.2-99.9%) with a median DoR of 65.7 months (95% CI: 55.6-not reached (NR) months). Strikingly, 28 of the 45 patients, 62.2%, (95% CI: 46.5-76.2%) attained deep responses of MRDneg CR; durability of MRDneg CR was observed up to at least 70 months with a median duration of over 4 years (52.4 months; 95% CI: 35.3-61.6 months). Moreover, the median TTP was over five and a half years (67.3 months; 95% CI: 51.0-NR months) and the median OS was NR, however, at 80 months, 84.3% of patients were still alive. As expected, patients who attained MRDneg CR, by cycle 8, had a 78% reduction in the risk of progression (Hazard Ratio (HR): 0.22 (95% CI: 0.07-0.69); p=0.005) (Figure 1). Importantly, these deep responses of MRDneg CR and long progression free durations were observed regardless of age group or cytogenetic-based risk profile (Table 1). Toxicities have been previously reported and were generally manageable with no Grade ≥ 3 neuropathy or death due to toxicity. Conclusions: Upfront treatment of NDMM with the modern and highly efficacious KRd-r regimen incorporating a "by-default-delayed" ASCT strategy led to high rates of MRDneg CR (10-5 sensitivity) which even more importantly were sustained with a median duration of over 4 years. Moreover, attaining MRDneg CR, was strongly associated with a delay in progression. Clinically important, we observed that these deep responses and long progression-free durations are observed regardless of age or cytogenetic risk and stress the importance of utilizing highly efficacious triplet-based regimens for these sub-categories of NDMM. Lastly, our results with KRd-r in NDMM compare favorably to ASCT-based regimens and question the use of upfront ASCT for all patients. Our observed median TTP of 67 months is approximately 17 months longer than published data using the regimen of bortezomib, lenalidomide, and dexamethasone with ASCT (Attal et al. NEJM 2017). Updated results will be presented at the Annual Meeting. Disclosures Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Juno: Research Funding; Takeda: Research Funding; Physician Education Resource: Honoraria. Landgren:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Key Points Ibrutinib allows for partial reconstitution of normal B cells and humoral immunity in patients with chronic lymphocytic leukemia. Infection rate decreased with time on ibrutinib and was inversely correlated with improvements in serum IgA.