A phase 1 trial of ibrutinib plus palbociclib in previously treated mantle cell lymphoma.

Single-agent ibrutinib is active in patients with previously treated mantle cell lymphoma (MCL); however, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human MCL cells and MCL cell lines expressing wild-type Bruton's tyrosine kinase (BTK). Therefore, we conducted a phase 1 trial to evaluate the dosing, safety, and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. From August 2014 to June 2016, a total of 27 patients (21 men, 6 women) were enrolled. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1 to 21 of each 28-day cycle. The dose-limiting toxicity was grade 3 rash. The most common grade 3 to 4 toxicities included neutropenia (41%), thrombocytopenia (30%), hypertension (15%), febrile neutropenia (15%), and lung infection (11%). The overall and complete response rates were 67% and 37%, and with a median follow-up of 25.6 months, the 2-year progression-free survival was 59.4% and the 2-year response duration was 69.8%. A phase 2 multicenter clinical trial to further characterize efficacy is now ongoing. The current trial was registered at www.clinicaltrials.gov as #NCT02159755.

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.

A phase I trial of palbociclib plus bortezomib in previously treated mantle cell lymphoma.

In mantle cell lymphoma (MCL), cyclin D1 combines with CDK4/6 to phosphorylate Rb, releasing a break on the G1 to S phase cell cycle. Palbociclib is a specific, potent, oral inhibitor of CDK4/6 capable of inducing a complete, prolonged G1 cell cycle arrest (pG1) in Rb+ MCL cells. The proteasome inhibitor bortezomib is approved by the US Food and Drug Administration for treatment of mantle cell lymphoma. Palbociclib-induced pG1 appears to sensitize MCL cells to killing by low-dose bortezomib, potentially improving its activity and tolerability. We conducted a phase 1 trial of palbociclib plus bortezomib in patients with previously treated MCL (NCT01111188). Patients received palbociclib at 75 mg (dose level 1), 100 mg (dose level 2), or 125 mg (dose levels 3 and 4) on days 1-12 of each 21-day cycle in addition to intravenous bortezomib 1.0 mg/m2 (dose levels 1, 2, 3) or 1.3 mg/m2 (dose level 4) on days 8, 11, 15 and 18. A total of 19 patients with a median age of 64 and an average of 2 prior therapies were enrolled. Two subjects experienced dose limiting toxicity (DLT): thrombocytopenia (dose level 1) and neutropenia (dose level 3). Although no DLTs were seen at dose level 4, all patients required dose delays during cycle 2 due to cytopenias, and the study team decided to stop the trial. Four of 19 patients achieved a clinical response, including one patient with a complete response. Three patients received treatment for more than one year, including one patient receiving single-agent palbociclib for more than 6 years. The combination of palbociclib 125 mg on days 1-12 plus bortezomib 1.0 mg/m2 on days 8, 11, 15, and 18 of a 21-day cycle is feasible and active in previously treated MCL, with the primary toxicity being myelosuppression. The regimen may be worthy of further evaluation in patients with non-blastoid MCL following failure of other newer agents.

MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin.

PURPOSE: The type I Melanoma Antigen GEnes (MAGEs) are commonly expressed in cancers, fueling speculation that they may be therapeutic targets with oncogenic potential. They form complexes with RING domain proteins that have E3 ubiquitin ligase activity and promote p53 degradation. MAGE-A3 was detected in tumor specimens from patients with multiple myeloma and its expression correlated with higher frequencies of Ki-67(+) malignant cells. In this report, we examine the mechanistic role of MAGE-A in promoting survival of proliferating multiple myeloma cells. EXPERIMENTAL DESIGN: The impact of MAGE-A3 expression on survival and proliferation in vivo was examined by immunohistochemical analysis in an independent set of tumor specimens segregated into two groups: newly diagnosed, untreated patients and patients who had relapsed after chemotherapy. The mechanisms of MAGE-A3 activity were investigated in vitro by silencing its expression by short hairpin RNA interference in myeloma cell lines and primary cells and assessing the resultant effects on proliferation and apoptosis. RESULTS: MAGE-A3 was detected in a significantly higher percentage of relapsed patients compared with newly diagnosed, establishing a novel correlation with progression of disease. Silencing of MAGE-A showed that it was dispensable for cell cycling, but was required for survival of proliferating myeloma cells. Loss of MAGE-A led to apoptosis mediated by p53-dependent activation of proapoptotic Bax expression and by reduction of survivin expression through both p53-dependent and -independent mechanisms. CONCLUSIONS: These data support a role for MAGE-A in the pathogenesis and progression of multiple myeloma by inhibiting apoptosis in proliferating myeloma cells through two novel mechanisms.

Outcome of deferred initial therapy in mantle-cell lymphoma.

PURPOSE: Treatment of mantle-cell lymphoma (MCL) is nonstandardized, though patients are commonly treated immediately at diagnosis. Because data on observation, or "watch and wait," have not been previously reported, we analyzed the outcome of deferred initial therapy. PATIENTS AND METHODS: Inclusion criteria in this retrospective analysis were a diagnosis of MCL between 1997 and 2007 and known date of first treatment. Hospital and research charts were reviewed for prognostic and treatment-related information. Date of death was derived from hospital records and confirmed using an online Social Security death index. RESULTS: Of 97 patients with MCL evaluated at Weill Cornell Medical Center, 31 patients (32%) were observed for more than 3 months before initial systemic therapy, with median time to treatment for the observation group of 12 months (range, 4 to 128 months). The observation group (median follow-up, 55 months) had a median age of 58 years (range, 40 to 81 years). Prognostic factors in assessable patients included advanced stage (III/IV) in 75%, elevated lactate dehydrogenase in 25%, and intermediate- or high-risk Mantle Cell International Prognostic Index in 54%. Better performance status and lower-risk standard International Prognostic Index scores were more commonly present in those undergoing observation. Although time to treatment did not predict overall survival in a multivariate analysis, the survival profile of the observation group was statistically superior to that of the early treatment group (not reached v 64 months, P = .004). CONCLUSION: In selected asymptomatic patients with MCL, deferred initial treatment ("watch and wait") is an acceptable management approach.

The cancer-testis antigens CT7 (MAGE-C1) and MAGE-A3/6 are commonly expressed in multiple myeloma and correlate with plasma-cell proliferation.

Multiple myeloma is a malignancy of plasma cells. Vaccine immunotherapy is among the novel therapeutic strategies under investigation for this disease. To identify myeloma-associated antigens as potential targets for vaccine immunotherapy, we surveyed a comprehensive panel of bone marrow specimens from patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma for expression of cancer-testis (CT) antigens. Immunohistochemistry (IHC) demonstrated that 82% of stage-III myeloma specimens expressed the CT antigen CT7 (also known as melanoma antigen C1 [MAGE-C1]) and 70% expressed MAGE-A3/6. Messenger RNA for CT7 and MAGE-A family members was detected in 87% and 100% of stage-III samples, respectively. CT7 protein expression increased with advanced stage of disease. Higher levels of CT7 and MAGE-A3/6 proteins also correlated with elevated plasma-cell proliferation. These results show that CT7 and MAGE-A3/6 are promising myeloma-associated antigens for application in vaccine immunotherapy. Furthermore, the common expression and correlation with proliferation suggest a possible pathogenic role for these proteins in myeloma.