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Purpose:To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT).Experimental Design:We performed a retrospective analysis of outcomes of 606 patients with CLL who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research.Results:On the basis of multivariable models, disease status, comorbidity index, lymphocyte count, and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low-, intermediate-, high-, and very-high-risk [4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, P < 0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, P < 0.0001]. We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or ≥5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high (P < 0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4 years) and OS (75% at 4 years).Conclusions:In this large cohort of patients with previously treated CLL who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic-based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.

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Purpose:ADCT-402 (loncastuximab tesirine) is an antibody–drug conjugate comprising a CD19-targeting antibody and pyrrolobenzodiazepine dimers. A first-in-human study evaluated the safety and preliminary clinical activity of loncastuximab tesirine in patients with B-cell non-Hodgkin lymphoma (NHL).Patients and Methods:A multicenter, phase I, dose-escalation and dose-expansion study enrolled patients ages ≥18 years with relapsed/refractory (R/R) B-cell NHL. Patients received loncastuximab tesirine every 3 weeks at doses assigned by a 3+3 dose-escalation design. Dose escalation was used to assess the safety and tolerability of loncastuximab tesirine to determine the dose for expansion. Secondary objectives evaluated clinical activity, characterized the pharmacokinetic profile, and evaluated antidrug antibodies.Results:During dose escalation, 88 patients with R/R B-cell NHL were treated with loncastuximab tesirine at doses 15 to 200 μg/kg. Treatment-emergent adverse events (TEAEs) were experienced by 87/88 (98.9%) patients. Most common TEAEs (≥20% of patients) were hematologic abnormalities, fatigue, edema, liver test abnormalities, nausea, rash, and dyspnea. Grade ≥3 TEAEs (≥5% of patients) included hematologic abnormalities, liver test abnormalities, fatigue, and dyspnea. Overall response rate at doses ≥120 μg/kg was 59.4% (41 of 69 patients; 40.6% complete response; 18.8% partial response). Median duration of response, progression-free survival, and overall survival (all doses) were 4.8, 5.5, and 11.6 months, respectively. Drug exposure increased with increasing dose, showing moderate accumulation with multiple doses ≥150 μg/kg. There was no evidence of immunogenicity.Conclusions:Loncastuximab tesirine had promising activity with acceptable safety in this dose-escalation study. A phase II study with initial dosing at 150 μg/kg has been initiated based on these results.

Purpose: To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT). Experimental Design: We performed a retrospective analysis of outcomes of 606 patients with CLL who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research. Results: On the basis of multivariable models, disease status, comorbidity index, lymphocyte count, and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low-, intermediate-, high-, and very-high-risk [4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, P < 0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, P < 0.0001]. We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or ≥5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high (P < 0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4 years) and OS (75% at 4 years). Conclusions: In this large cohort of patients with previously treated CLL who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic-based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.

Lonca is an antibody (Ab) drug conjugate comprising a humanized monoclonal Ab directed against B-cell antigen CD19, conjugated with a potent pyrrolobenzodiazepine (PBD) dimer toxin. In a Phase 1 (NCT02669017) study in relapsed or refractory (R/R) B-NHL, a recommended Phase 2 dosing regimen for Lonca of 150 µg/kg once every 3 weeks (Q3W) for two doses, followed by 75 µg/kg Q3W was identified then evaluated in a Phase 2 (NCT03589469) study in R/R diffuse large B-cell lymphoma (DLBCL). A population pharmacokinetic (PPK) model was developed to characterize the pharmacokinetics (PK) of the Lonca dosing regimen and evaluate exposure covariates. The integrated PPK model was used to describe drug concentrations for Lonca PBD-conjugated Ab (5,301 samples), total Ab (5,241 samples), and unconjugated warhead SG3199 (239 samples) in serum from 328 patients. Samples were taken pre-dose, at end of infusion and at pre-determined timepoints post-infusion throughout the trials. Analysis was performed using non-linear mixed-effects modeling (NONMEM, v7.4 [ICON Solutions]). Subgroup analyses were conducted on model-predicted exposure metrics derived from simulation of Lonca PK profiles based on empirical Bayesian estimates of individual PK parameters. Concentration-time data of Lonca PBD-conjugated Ab and total Ab were best characterized by a two-compartment model with parallel linear clearance (0.218 L/day), and a time-dependent clearance component which approached zero by ~15 weeks. The estimated volume of distribution of central compartment was 3.86 L and the estimated typical half-life at steady state of Lonca is ~3 weeks. The effect of body weight, age, sex, race, renal impairment, drug formulation, anti-drug Ab, ECOG, and concomitant P-gp inhibitors did not show clinically important influence on exposure (< ±30% change relative to reference). Based on model-predicted Cycle 1 average concentration (Cavg) patients with low albumin (1 were noted but did not appear to be of clinical relevance. In conclusion, Lonca exposure was well described by a two-compartment model with linear and time-dependent clearance; the latter is thought to reflect reduction of tumor cells. Lonca exposure was lower in non-DLBCL patients, and lower in patients with hypoalbuminemia secondary to enhanced protein clearance in patients with critical illness. Overall, modeling demonstrates rapid attainment of steady-state exposure for Lonca given 150 µg/kg Q3W for two doses, and a sustaining profile for Lonca given 75 µg/kg Q3W thereafter for patients with DLBCL. Citation Format: Melhem Solh, Juan Pablo Alderuccio, Anastasios Stathis, David Ungar, Sam Liao, Lisa Khouri, Xiaoyan Zhang, Joseph Boni. Integrated population modeling of loncastuximab tesirine (Lonca) exposure in B-cell non-Hodgkin lymphoma (B-NHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1366.