Faculty Bibliography

Introduction: Pola-G-Len may enhance anti-tumor immune response in R/R FL. We report a pre-planned interim analysis of the safety/efficacy of induction and maintenance with Pola-G-Len in pts with R/R FL in a phase Ib/II study (NCT02600897).
Method(s): Pts received induction treatment with 6x 28-day (D) cycles (C) of: G 1000mg IV (C1: D1, D8, D15; C2-6: D1); Pola 1.4mg/kg or 1.8mg/kg dose escalation (DE) or recommended phase 2 dose (RP2D; expansion) IV (D1); and Len 10-20mg (DE) or RP2D (expansion) PO (D1-21). Pts with complete response (CR)/partial response (PR)/stable disease (SD) at the end of induction (EOI) received G 1000mg (D1 every 2mo, for 24mo), and Len (10mg, D1-21 monthly, 12mo). Primary endpoints were C1 dose-limiting toxicities (DLTs), safety/tolerability, CR rate at EOI (modified Lugano criteria). Results At the interim data cut-off (6 July 2018), 52 pts were enrolled: 9 discontinued the study (adverse events [AE], n=3; death due to PD, n=4; pt withdrawal, n=1; other, n=1). At baseline, the median pt age was 62 (range 32-87) years; 60% were male; 58% had FLIPI score 3-5; 79% had received >=2 prior therapy lines; 50% were refractory to their last treatment; 17% had bulky disease (>=7cm). Two DLTs were reported in the cohort receiving Pola 1.8mg/kg + Len 10mg during the DE period (Gr 4 lipase/amylase elevation; asymptomatic, resolved with supportive care; Gr 3 thrombocytopenia leading to a delay in the initiation of cycle 2). Gr >=3 AEs were experienced by 75% of pts: neutropenia (46%), thrombocytopenia (17%), anemia (12%) and infections (12%) were the most common AEs. Len dose reduction or interruption occurred in 31% and 52% of pts, respectively. One Gr 5 AE was reported (septic shock after PD in pt receiving subsequent therapy). The RP2D was determined as Pola 1.4mg/kg + Len 20mg. Preliminary efficacy data suggest high activity, with an independent review committee-assessed Modified Lugano response rate of 89% and a CR rate of 67% (Table). Median progression-free survival was not reached (median follow-up duration 8.95 mo in the efficacy-evaluable population). Conclusions The safety profile of Pola-G-Len is consistent with known profiles of the individual drugs. Response rates at EOI with Pola-G-Len are promising, with high CR comparedwith available R/R FL treatments. (Table Presented)

Background: Relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical problem. We hypothesized that activating the immune microenvironment, and concurrently targeting tumor cells with brentuximab vedotin (B) could overcome tumor resistance. Here we report the extended follow-up for all patients treated on Phase 1 of E4412 with the combinations of B (1.2 or 1.8 mg/kg), nivolumab (N) 3mg/kg and ipilimumab (I) (1 or 3mg).
Method(s): Patients with confirmed R/R HL were enrolled sequentially in cohorts of B-I (n=21), B-N (n=18), and B-N-I (n=22). Schedule was: B-N q 21 days for 16 cycles and N an additional 12 months; I q 3 weeks for 4 cycles and then q 3 months (B-I), or every 12 weeks for up to 24 months (B-N-I). Dose limiting toxicity (DLT) was defined within the first cycle of therapy.
Result(s): As of 3/1/2019, 64 patients were enrolled of which 61 were eligible, 3 were ineligible due to prior treatment or laboratory values. The median age was 33; median prior therapies 2 (excluding SCT) across all cohorts, range: 1-9 (B-I), 1-6 (B-N), and 1-5 (B-N-I). Twentyfive patients (40%) had prior SCT: 9 (B-I), 7 (B-N), and 9 (B-N-I). Seven patients: 3 (B-I), 4 (B-N) and 1 (B-N-I) had prior BV. Safety: All enrolled patients are evaluable for safety. There were 2 grade 5 pneumonitis deaths, one each in B-N and B-N-I. There were 5 DLTs: pneumonitis and typhlitis (B-N), and one each grade 4 diabetic ketoacidosis and hyperglycemia, transient grade 3 AST elevation, and post AlloSCT grade 4 GVHD (B-N-I). Significant grade 3 AEs included rash (12%), and colitis, gastritis, pancreatitis, and arthritis each in 1 patient. Common toxicities considered at least possibly related to drug, included: fatigue (28%), transaminitis (36%), rash predominantly with B-I (25%) versus 8% combined B-N, and B-N-I, peripheral neuropathy (53%) and diarrhea (43%), primarily grade 1-2. Response: Five patients: (1 each B-I, B-N, and 3 B-N-I) were unevaluable for response. For the entire cohort the ORR/CR is 76%/57% (B-I), 88%/61% (B-N), and 82%/73% (B-N-I). For patients with at least 2 cycles of therapy and one imaging time point the ORR/CR is 80%/60%, 94%/64%, and 95%/84% for B-I, B-N and B-NI respectively. With a median follow-up of 2.98 years, 2 years, and 1.35 years the 1 year PFS is 60%, 68%, and 72% for B-I, B-N and BN- I respectively The median OS has not been reached for any of the arms (Figure 1).
Conclusion(s): All combinations were well tolerated, with mainly grade 1-2 immune toxicities, however deaths secondary to pneumonitis were noted in N containing cohorts. The ORR and CR rate in the N containing cohorts is superior to that of B-I doublet; the CR of B-N-I is higher than both doublet combinations and some patients have durable responses. It remains to be seen if a higher CR rate will eventually translate into more durable response rates. The ongoing randomized phase 2 study (E4412) is comparing the B-N doublet to the B-N-I triplet (NCT01896999)

The bone marrow microenvironment has a key role in regulating haematopoiesis, but its molecular complexity and response to stress are incompletely understood. Here we map the transcriptional landscape of mouse bone marrow vascular, perivascular and osteoblast cell populations at single-cell resolution, both at homeostasis and under conditions of stress-induced haematopoiesis. This analysis revealed previously unappreciated levels of cellular heterogeneity within the bone marrow niche and resolved cellular sources of pro-haematopoietic growth factors, chemokines and membrane-bound ligands. Our studies demonstrate a considerable transcriptional remodelling of niche elements under stress conditions, including an adipocytic skewing of perivascular cells. Among the stress-induced changes, we observed that vascular Notch delta-like ligands (encoded by Dll1 and Dll4) were downregulated. In the absence of vascular Dll4, haematopoietic stem cells prematurely induced a myeloid transcriptional program. These findings refine our understanding of the cellular architecture of the bone marrow niche, reveal a dynamic and heterogeneous molecular landscape that is highly sensitive to stress and illustrate the utility of single-cell transcriptomic data in evaluating the regulation of haematopoiesis by discrete niche populations.

BACKGROUND:Antibody-drug conjugates (ADCs) polatuzumab vedotin (pola) and pinatuzumab vedotin (pina) showed clinical activity and tolerability in phase 1 trials. The aim of this multicentre, open-label, phase 2 study was to compare rituximab plus pola (R-pola) or pina (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. METHODS:rituximab plus 2·4 mg/kg ADCs) every 21 days until disease progression or unacceptable toxicity up to 1 year. Treatment allocations were not masked to the investigator, patients or sponsor after the patients were enrolled and randomly assigned. The primary objectives were safety and tolerability, and antitumour response. The study is registered with ClinicalTrials.gov, number NCT01691898, and is closed to accrual. FINDINGS/RESULTS:81 patients with diffuse large B-cell lymphoma and 42 with follicular lymphoma were recruited between Sept 27, 2012, and Oct 10, 2013, and were assigned to treatment. 81 patients with diffuse large B-cell lymphoma and 41 patients with follicular lymphoma were eligible for analysis. Of the 42 patients with diffuse large B-cell lymphoma who received R-pina, 25 (60%, 95% CI 43-74) achieved an objective response and 11 (26%, 95% CI 14-42) achieved a complete response. Of the 39 patients in this cohort who received R-pola, 21 (54%, 95% CI 37-70) achieved an objective response, and eight (21%, 95% CI 9-36) achieved a complete response. Of the 21 patients in the follicular lymphoma cohort who received R-pina, 13 (62%, 95% CI 38-82) achieved an objective response, and one (5%, 95% CI 0·1-24) achieved a complete response. Of the 20 patients in this cohort who received R-pola, 14 (70%, 95% CI 46-88) achieved an objective response, and nine (45%, 95% CI 23-68) achieved a complete response. In the diffuse large B-cell lymphoma cohort, grade 3-5 adverse events occurred in 33 (79%) of 42 patients receiving R-pina (most common were neutropenia [29%] and hyperglycaemia [10%]; nine [21%] grade 5 adverse events, five of which were infection-related), and in 30 (77%) of 39 patients receiving R-pola (most common were neutropenia [23%], anaemia [8%] and diarrhoea [8%]; no grade 5 adverse events). In the follicular lymphoma cohort, grade 3-5 adverse events occurred in 13 (62%) of 21 patients receiving R-pina (most common were neutropenia [29%] and hyperglycaemia [14%]; no grade 5 adverse events) and in ten (50%) of 20 patients receiving R-pola (most common were neutropenia [15%] and diarrhoea [10%]; one grade 5 adverse event). INTERPRETATION/CONCLUSIONS:R-pina and R-pola are potential treatment options in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. Pola was selected by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response than pina, and an overall benefit-risk favouring R-pola. FUNDING/BACKGROUND:F Hoffmann-La Roche.

PURPOSE/OBJECTIVE:Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger. PATIENTS AND METHODS/METHODS:We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score-weighted (PSW) analysis were performed. RESULTS:Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2). CONCLUSION/CONCLUSIONS:In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.

While up to 80% of patients with Hodgkin's lymphoma (HL) are cured with first-line therapy, relapsed/refractory (R/R) disease remains a clinical challenge and is fatal for many young patients. HL is unique in that the tumor cells (Hodgkin Reed-Sternberg; HRS cells) are a small fraction (<1%) of the tumor bulk, with the remaining tumor composed of the cells of the tumor microenvironment (TME). The support and integrity of the TME is necessary for HRS cell growth and survival. Targeting the programmed death 1 pathway has shown exciting activity in relapsed HL and led to United States Food and Drug Administration approval of the checkpoint inhibitors, nivolumab and pembrolizumab, for R/R HL. Novel combinations with checkpoint blockade therapy (CBT), targeted approaches such as combinations of CBT with brentuximab vedotin or chemotherapy, chimeric antigen receptor T-cells, and the use of CBT to potentially sensitize to subsequent therapy are being investigated as treatment approaches. As understanding of the HL TME grows, hopefully this will increase the number of rational therapeutic targets.

The activity of T cell mediated immunotherapies in B cell lymphoma has been limited to date. The novel bi-specific antibody CD20-TCB, has a 2:1 antibody design to maximize T cell engagement, and demonstrates activity in preclinical models. This may represent a novel therapeutic approach for patients with relapsed/refractory NHL.

Because both phosphatidylinositol 3-kinase δ (PI3Kδ) and Janus kinase (JAK)-signal transducer and activator of transcription pathways contribute to tumor cell proliferation and survival in B-cell malignancies, their simultaneous inhibition may provide synergistic treatment efficacy. This phase 1 dose-escalation/expansion study assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of INCB040093, a selective PI3Kδ inhibitor, as monotherapy or combined with itacitinib (formerly INCB039110), a selective JAK1 inhibitor, in adult patients with relapsed or refractory (R/R) B-cell lymphomas. Final results are reported. Overall, 114 patients were treated (monotherapy, n = 49; combination therapy, n = 72 [7 patients crossed over from monotherapy to combination]). INCB040093 100 mg twice daily (monotherapy) and INCB040093 100 mg twice daily + itacitinib 300 mg once daily (combination) were the recommended phase 2 doses. One dose-limiting toxicity (gastrointestinal bleed secondary to gastric diffuse large B-cell lymphoma [DLBCL] regression) occurred with monotherapy. The most common serious adverse events with monotherapy were pneumonia (n = 5) and pyrexia (n = 4), and with combination Pneumocystis jiroveci pneumonia (n = 5), pneumonia (unrelated to P jiroveci; n = 5), and pyrexia (n = 4). Grade 3 or higher transaminase elevations were less common with combination. INCB040093 was active across the B-cell lymphomas; 63% of patients (5/8) with follicular lymphoma responded to monotherapy. Adding itacitinib provided promising activity in select subtypes, with responses of 67% (14/21) in classic Hodgkin lymphoma (vs 29% [5/17] with monotherapy) and 31% (4/13) in nongerminal center B-cell-like DLBCL. INCB040093 with/without itacitinib was tolerated and active in this study, and is a promising treatment strategy for patients with select R/R B-cell lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT01905813.