Investigating the Influence of Covariates on Axicabtagene Ciloleucel (axi-cel) Kinetics in Patients with Non-Hodgkin's Lymphoma.

BACKGROUND AND OBJECTIVE: Axicabtagene ciloleucel (axi-cel, Yescarta) is an autologous, anti-CD19, chimeric antigen receptor (CAR) T-cell therapy approved for patients with relapsed and refractory non-Hodgkin's lymphoma. Substantial inter-individual variability in cellular kinetics has been observed with CAR-T therapies and factors impacting CAR-T cellular kinetics remain poorly understood. This work reports a population cellular kinetic model of axi-cel in relapsed and patients with refractory non-Hodgkin's lymphoma and investigated the impact of covariates on early and late kinetic phases of CAR-T exposure. METHODS: A population cellular kinetic model (NONMEM® version 7.4) for axi-cel was developed using data from 410 patients (2050 transgene observations) after a single intravenous infusion of 2 × 106 anti-CD19 CAR+ T cells/kg in patients with non-Hodgkin's lymphoma (ZUMA-1, ZUMA-5, and ZUMA-7 clinical studies). A large panel of covariates was assessed to decipher the variability of CAR-T cell kinetics including patient characteristics, product characteristics, and disease types. RESULTS: Axi-cel cellular kinetics were well described by a piecewise model of cellular growth kinetics characterized by an exponential growth phase followed by a triphasic decline phase including a long-term persistence phase. The final cellular kinetic model retained in vitro doubling time during CAR-T cell manufacturing and total number of T cells infused as covariates impacting the duration of the growth phase, which, however, did not substantially influence maximum concentration, area under the concentration-time curve over the first 28 days, or long-term persistence. A statistically significant relationship was observed between maximum concentration and the probability to receive tocilizumab and/or corticosteroids. CONCLUSIONS: No covariates considered in this study were found to significantly and substantially predict the exposure profile of axi-cel. Tocilizumab and steroid use were related to maximum concentration, but they were used reactively to treat toxicities that are associated with a higher maximum concentration. Further CAR-T kinetic analyses should consider additional factors to explain the observed variability in cellular kinetics or help establish a dose-exposure relationship. CLINICAL TRIAL REGISTRATION: NCT02348216 (ZUMA-1), NCT03105336 (ZUMA-5), and NCT03391466 (ZUMA-7).

Impact of prior therapies and subsequent transplantation on outcomes in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3.

BACKGROUND: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported. METHODS: Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×106 CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided. RESULTS: Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7-58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups.Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22). CONCLUSIONS: In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel.

Treatment interruption and discontinuation of hormonal therapy in hormone receptor-positive breast cancer patients.

PURPOSE: To investigate predictors of treatment interruption and early discontinuation of adjuvant hormonal therapy (HT) in a retrospective cohort of women with newly diagnosed hormone receptor-positive (HR +) breast cancer. METHODS: Eligible cases were identified from a single institutional tumor registry from 2009 to 2015. Patients were followed from initiation of adjuvant HT for a minimum of one year through December 1, 2016. Predictors of treatment interruption or early discontinuation were analyzed with Cox proportional hazards regression models. RESULTS: With a median follow-up time of 3.0 years (IQR 1.5-4.5), 22 women (10.9%) discontinued HT early and 47 (23.4%) had at least one treatment interruption of > 14 days. Adjusted Cox proportional hazards regression models showed that women with pre-existing affective disorders were more likely to discontinue therapy early (HR 3.15; 95% CI 1.35-7.37), while those with pre-existing chronic pain disorders were at increased risk for treatment interruption (HR 2.24; 95% CI 1.20-4.19). HT-related symptoms were the most commonly reported reason for HT interruption or discontinuation. Women who experienced severe treatment-related symptoms were at increased risk for both HT interruption (HR 2.64; 95% CI 1.07-6.50) and HT discontinuation (HR 3.48; 95% CI 1.20-10.1). CONCLUSIONS: This study showed that HT interruptions and discontinuation were common, often associated with HT-related symptoms. Clinicians caring for breast cancer patients on HT should monitor closely for treatment-emergent symptoms, especially women with pre-existing disorders, and support them to continue therapy through aggressive symptom management and other patient-centered approaches.

Timeliness of Treatment Initiation in Newly Diagnosed Patients With Breast Cancer.

BACKGROUND: Evidence-based timeliness benchmarks have been established to assess quality of breast cancer care, as delays in treatment are associated with poor clinical outcomes. However, few studies have evaluated how current breast cancer care meets these benchmarks and what factors may delay the timely initiation of treatment. PATIENTS AND METHODS: Demographic and disease characteristics of 377 newly diagnosed patients with breast cancer who initiated treatment at Tufts Medical Center (2009-2015) were extracted from electronic medical records. Time from diagnosis to initial surgery and time from diagnosis to initiation of hormone therapy were estimated with Kaplan-Meier curves. Multivariable regression analysis was used to identify factors associated with treatment delays. Thematic analysis was performed to categorize reasons for delay. RESULTS: Of 319 patients who had surgery recommended as the first treatment, 248 (78%) met the 45-day benchmark (median, 28 days; 25th-75th %, 19-43). After adjusting for potential confounders, multivariable regression analysis revealed that negative hormone receptor status (odds ratio, 3.48; 95% confidence interval, 1.44-8.43) and mastectomy (odds ratio, 4.07; 95% confidence interval, 2.10-8.06) were significantly associated with delays in surgery. Delays were mostly owing to clinical complexity or logistical/financial reasons. Of 241 patients eligible for hormone therapy initiation, 232 (96%) met the 1-year benchmark (median, 147 days; 25th-75th %, 79-217). CONCLUSION: Most patients met timeliness guidelines for surgery and initiation of hormone therapy, although risk factors for delay were identified. Knowledge of reasons for breast cancer treatment delay, including clinical complexity and logistical/financial issues, may allow targeting interventions for patients at greatest risk of care delays.

p35 is required for CDK5 activation in cellular senescence.

The retinoblastoma tumor suppressor gene (RB-1) is a key regulator of cellular senescence. Expression of the retinoblastoma protein (pRB) in human tumor cells that lack it results in senescence-like changes. The induction of the senescent phenotype by pRB requires the postmitotic kinase CDK5, the best known function of which is in neuronal development and postmitotic neuronal activities. Activation of CDK5 in neurons depends on its activators p35 and p39; however, little is known about how CDK5 is activated in non-neuronal senescent cells. Here we report that p35 is required for the activation of CDK5 in the process of cellular senescence. We demonstrate that: (i) p35 is expressed in osteosarcoma cells, (ii) p35 is required for CDK5 activation induced by pRB during senescence, (iii) p35 is required for the senescent morphological changes in which CDK5 is known to be involved as well as for expression of the senescence secretome, and (iv) p35 is up-regulated in senescing cells. Taken together, these results suggest that p35 is at least one of the activators of CDK5 that is mobilized in the process of cellular senescence, which may provide insight into cancer cell proliferation and future cancer therapeutics.

A requirement for cyclin-dependent kinase 6 in thymocyte development and tumorigenesis.

Cyclin-dependent kinase 6 (CDK6) promotes cell cycle progression and is overexpressed in human lymphoid malignancies. To determine the role of CDK6 in development and tumorigenesis, we generated and analyzed knockout mice. Cdk6-deficient mice show pronounced thymic atrophy due to reduced proliferative fractions and concomitant transitional blocks in the double-negative stages. Using the OP9-DL1 system to deliver temporally controlled Notch receptor-dependent signaling, we show that CDK6 is required for Notch-dependent survival, proliferation, and differentiation. Furthermore, CDK6-deficient mice were resistant to lymphomagenesis induced by active Akt, a downstream target of Notch signaling. These results show a critical requirement for CDK6 in Notch/Akt-dependent T-cell development and tumorigenesis and strongly support CDK6 as a specific therapeutic target in human lymphoid malignancies.