Tycel Phillips

Postibrutinib outcomes in patients with mantle cell lymphoma

Despite unprecedented clinical activity in mantle cell lymphoma (MCL), primary and acquired resistance to ibrutinib is common. The outcomes and ideal management of patients who experience ibrutinib failure are unclear. We performed a retrospective cohort study of all patients with MCL who experienced disease progression while receiving ibrutinib across 15 international sites. Medical records were evaluated for clinical characteristics, pathological and radiological data, and therapies used pre- and postibrutinib. A total of 114 subjects met eligibility criteria. The median number of prior therapies was 3 (range, 0-10). The Mantle Cell Lymphoma International Prognostic Index (MIPI) scores at the start of ibrutinib were low, intermediate, and high in 46%, 31%, and 23% of patients, respectively. Of patients with available data prior to ibrutinib and postibrutinib, 34 of 47 and 11 of 12 had a Ki67 >30%. The median time on ibrutinib was 4.7 months (range 0.7-43.6). The median overall survival (OS) following cessation of ibrutinib was 2.9 months (95% confidence interval [CI], 1.6-4.9). Of the 104 patients with data available, 73 underwent subsequent treatment an average of 0.3 months after stopping ibrutinib with a median OS of 5.8 months (95% CI, 3.7-10.4). Multivariate Cox regression analysis of MIPI before postibrutinib treatment, and subsequent treatment with bendamustine, cytarabine, or lenalidomide failed to reveal any association with OS. Poor clinical outcomes were noted in the majority of patients with primary or secondary ibrutinib resistance. We could not identify treatments that clearly improved outcomes. Future trials should focus on understanding the mechanisms of ibrutinib resistance and on treatment after ibrutinib.

RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106.

Aggressive induction chemotherapy followed by autologous haematopoietic stem cell transplant (auto‐HCT) is effective for younger patients with mantle cell lymphoma (MCL). However, the optimal induction regimen is widely debated. The Southwestern Oncology Group S1106 trial was designed to assess rituximab plus hyperCVAD/MTX/ARAC (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone, alternating with high dose cytarabine and methotrexate) (RH) versus rituximab plus bendamustine (RB) in a randomized phase II trial to select a pre‐transplant induction regimen for future development. Patients had previously untreated stage III, IV, or bulky stage II MCL and received either 4 cycles of RH or 6 cycles of RB, followed by auto‐HCT. Fifty‐three of a planned 160 patients were accrued; an unacceptably high mobilization failure rate (29%) on the RH arm prompted premature study closure. The estimated 2‐year progression‐free survival (PFS) was 81% vs. 82% and overall survival (OS) was 87% vs. 88% for RB and RH, respectively. RH is not an ideal platform for future multi‐centre transplant trials in MCL. RB achieved a 2‐year PFS of 81% and a 78% MRD negative rate. Premature closure of the study limited the sample size and the precision of PFS estimates and MRD rates. However, RB can achieve a deep remission and could be a platform for future trials in MCL.

Challenges and opportunities for checkpoint blockade in T-cell lymphoproliferative disorders

The T-cell lymphoproliferative disorders are a heterogeneous group of non-Hodgkin’s lymphomas (NHL) for which current therapeutic strategies are inadequate, as most patients afflicted with these NHL will succumb to disease progression within 2 years of diagnosis. Appreciation of the genetic and immunologic landscape of these aggressive NHL, including PD-L1 (B7-H1, CD274) expression by malignant T cells and within the tumor microenvironment, provides a strong rationale for therapeutic targeting this immune checkpoint. While further studies are needed, the available data suggests that responses with PD-1 checkpoint blockade alone will unlikely approach those achieved in other lymphoproliferative disorders. Herein, we review the unique challenges posed by the T-cell lymphoproliferative disorders and discuss potential strategies to optimize checkpoint blockade in these T-cell derived malignancies.

Surveillance Scans in Lymphoma: Friend or Foe?

Opinion StatementAdvancements in the treatment of lymphoma over the last few decades have allowed more patients to achieve a remission after the completion of therapy. Due to the improvement in response rates, methods to detect recurrence early and accurately during follow-up, especially in patients with potential curable aggressive lymphomas, are a key. Observation has always involved close clinical follow-up with the use of physical exams and routine labs, but rapid changes in technology have allowed CT scans, PET scans, and MRIs to become an integral part of managing patients with lymphoma. While the utility of scans in initial staging and immediately after completion of therapy is well established, the use of these imaging modalities for monitoring recurrence in lymphoma patients is still controversial. Patient advocacy groups and other regulatory committees have questioned the frequency and in some cases even the need for these tests in patients without evidence of active disease given the concern for radiation-associated health risks. Additionally, the extent to which this form of testing impacts the psyche of our patients is not completely known. Given the numerous questions raised about the benefits, safety, and cost-effectiveness of CT imaging, firm guidelines are needed at this time in standard practice and within our clinical trials to limit the use of surveillance imaging. Such efforts are expected to improve the utility of these scans in asymptomatic patients, reduce healthcare costs, and reduce patient exposure to radiation.

Phase 1 study of the PI3Kδ inhibitor INCB040093 ± JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma

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.

ONGOING PHASE 1/2 STUDY OF INCB050465, A SELECTIVE PI3Kδ INHIBITOR, FOR THE TREATMENT OF PATIENTS (PTS) WITH RELAPSED/REFRACTORY (R/R) B-CELL MALIGNANCIES (CITADEL-101)

279 ONGOING PHASE 1/2 STUDY OF INCB050465, A SELECTIVE PI3Kδ INHIBITOR, FOR THE TREATMENT OF PATIENTS (PTS) WITH RELAPSED/ REFRACTORY (R/R) B‐CELL MALIGNANCIES (CITADEL‐101) P. Caimi* | R. Ramchandren | T.J. Phillips | M.S. Wertheim | M.E. Gutierrez | W.J. Edenfield | L.P. Akard | J.A. Call | D.O. Persky | D.J. DeMarini | L. Zhou | S. Yeleswaram | A. Forero‐Torres Department of Medicine‐Gastroenterology, University Hospitals Seidman Cancer Center, Cleveland, OH, USA; Hematology/Oncology, Karmanos Cancer Center, Detroit, MI, USA; Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA; Hematology/Oncology, Hematology/ Oncology Associates of Treasure Coast, Port St Lucie, FL, USA; Drug Discovery and Phase I Unit, Hackensack University Medical Center, Hackensack, NJ, USA; Hematology, Greenville Health System Cancer Institute, Greenville, SC, USA; Hematology, Indiana Blood & Marrow Transplantation, LLC, Indianapolis, IN, USA; Hematology/Oncology, Utah Cancer Specialists‐Network, Salt Lake City, UT, USA; Hematology/ Oncology, University of Arizona Cancer Center, Tucson, AZ, USA; Clinical Development, Incyte Corporation, Wilmington, USA; Hematology/Oncology, University of Alabama Birmingham, Birmingham, AL, USA

Pegasparaginase silent inactivation during therapy for NK/T cell lymphoma

Abstract Natural Killer/T cell (NK/T cell) lymphoma is a rare, yet aggressive T cell lymphoma, which often displays resistance to traditional chemotherapies. Asparagainse (ASNase), through its unique mechanism of action, has become a vital component in the treatment of NK/T cell lymphoma. However, because ASNase is of bacterial origin, antibody formation can render the therapy ineffective, even in the absence of clinical hypersensitivity, which has been coined ‘silent inactivation.’ While the phenomenon of silent inactivation of PEG-ASNase is well documented in the treatment of ALL, it has not been described in NK/T cell lymphoma patients. Herein, we report a case series of six patients treated for NK/T cell lymphoma with PEG-ASNase who subsequently developed silent inactivation identified using therapeutic drug monitoring (TDM). The goal of this manuscript is to alert clinicians of this phenomenon, and review the importance of TDM in NK/T cell lymphoma patients receiving ASNase.

Successful use of cytarabine and bendamustine in a patient with mantle cell lymphoma and acute renal failure using intermittent hemodialysis: A case report:

Mantle cell lymphoma is a mature B-cell non-Hodgkin lymphoma characterized by the hallmark (11;14) chromosomal translocation, which often presents with lymphadenopathy and extra-nodal involvement. Young, fit patients are generally treated with chemotherapy approaches that incorporate high-dose cytarabine (e.g. the Nordic regimen) followed by autologous hematopoietic cell transplantation. Because of the significant activity of cytarabine in mantle cell lymphoma, increasingly, high- and intermediate-dose cytarabine are being used in the treatment of elderly mantle cell lymphoma patients. In practice, many patients present with significant organ dysfunction and there is limited data on the use of high- to intermediate-dose cytarabine and bendamustine in this setting. Here, we report a case of a critically ill, elderly patient with mantle cell lymphoma and concomitant acute kidney injury and oliguria who was successfully treated with a cycle of cytarabine (Ara-C) and bendamustine accompanied by intermittent hemodialysis.

Survival following salvage therapy for primary refractory peripheral T-cell lymphomas (PTCL)

Optimal salvage therapy for primary refractory peripheral T‐cell lymphomas (PTCL) and the role of hematopoietic stem cell transplant (SCT) remain poorly defined. We conducted a retrospective review of clinical outcomes and prognostic factors in a single‐center cohort of 93 patients with primary refractory PTCL, defined as progression during first‐line therapy or relapse within 6 months of its completion. Clinical outcomes were poor in this population, with median event‐free survival (EFS) of 3.5 months, median overall survival (OS) of 9.1 months, and 34% 3‐year survival. Outcomes were comparable in patients who progressed through first‐line therapy and patients who achieved CR/PR and subsequently relapsed within 6 months. A majority exhibited high‐risk features and had intermediate to high risk IPI, which correlated with inferior outcomes. There was no difference in outcomes between patients who received single‐agent salvage regimens and patients who underwent traditional, multi‐agent salvage regimens. Thus, participation in well‐designed clinical trials should be encouraged in this population. Additionally, there may be a trend toward improved EFS and OS in patients who underwent autologous or allogeneic SCT compared to patients who achieved CR or PR but were not transplanted.

Polo-like-kinase 1 (PLK-1) and c-myc inhibition with the dual kinase-bromodomain inhibitor volasertib in aggressive lymphomas

Survival following anthracycline-based chemotherapy remains poor among patients with most T-cell lymphoproliferative disorders. This may be attributed, at least in part, to cell-autonomous mechanisms of chemotherapy resistance observed in these lymphomas, including the loss of important tumor suppressors and the activation of signaling cascades that culminate in the expression and activation of transcription factors promoting cell growth and survival. Therefore, the identification of novel therapeutic targets is needed. In an effort to identify novel tumor dependencies, we performed a loss-of-function screen targeting ≈500 kinases and identified polo-like kinase 1 (PLK-1). This kinase has been implicated in the molecular cross-talk with important oncogenes, including c-Myc, which is itself an attractive therapeutic target in subsets of T-cell lymphomas and in high-grade (“double hit”) diffuse large B-cell lymphomas. We demonstrate that PLK-1 expression is prevalent among these aggressive lymphomas and associated with c-myc expression. Importantly, PLK-1 inhibtion with the PLK-1 inhibitor volasertib significantly reduced downstream c-myc phosphorylation and impaired BRD4 binding to the c-myc gene, thus inhibiting c-myc transcription. Therefore, volasertib led to a nearly complete loss of c-myc expression in cell lines and tumor xenografts, induced apoptosis, and thus warrants further investigation in these aggressive lymphomas.