Evaluation of second-generation Bruton's tyrosine kinase inhibitors for the treatment of mantle cell lymphoma.

INTRODUCTION: Second-generation Bruton's tyrosine kinase (BTK) inhibitors, acalabrutinib and zanubrutinib, are preferred agents for the treatment of relapsed and/or refractory mantle cell lymphoma (MCL) over first-generation BTK inhibitor, ibrutinib. The comparative safety and efficacy of these two agents have not been studied. Currently, the decision between using one second-generation BTK inhibitor over the other is largely dependent on provider preference, cost, organ dysfunction, presence of drug-drug interactions, adherence considerations, and theorized differences in safety outcomes due to the lack of head-to-head trials in MCL. METHODS: This retrospective, observational study seeks to provide real-world data on the safety and efficacy of second-generation BTK inhibitors in the setting of relapsed and/or refractory MCL. RESULTS: Thirty-eight patients treated with a second-generation BTK inhibitor were evaluated. Ten percent of patients experienced a select adverse drug event (ADE) in the acalabrutinib group that included hypertension and major hemorrhage with no patients experiencing a select ADE in the zanubrutinib group. CONCLUSIONS: Results support historical data that acalabrutinib and zanubrutinib have a more favorable safety profile compared to ibrutinib in MCL.

Ibrutinib for central nervous system lymphoma: the Australasian Lymphoma Alliance/MD Anderson Cancer Center experience.

Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression-free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8-16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies.

Corrected calcium versus ionized calcium measurements for identifying hypercalcemia in patients with multiple myeloma.

BACKGROUND: Dysregulated bone turnover is an important clinical manifestation of multiple myeloma (MM), and 30% of patients present with hypercalcemia. Serum calcium levels are routinely monitored using total calcium measurements corrected for albumin. However, myeloma-related paraproteins may bind calcium, confounding these measurements. PATIENTS AND METHODS: We retrospectively analyzed correlation between corrected calcium and ionized calcium in a sample of patients with MM and a control sample of patients with breast or non-small cell lung cancers (n = 200). Multiple linear regression was used to identify variables affecting corrected calcium measurements. RESULTS: Correlation between corrected calcium and ionized calcium was stronger in the control group compared to the MM group (Spearman correlation coefficient 0.85 versus 0.76, respectively). Sensitivity of corrected calcium in identifying hypercalcemia defined by elevated ionized calcium was 36% in patients with MM and 76% in the control group. Multiple linear regression did not reveal variables significantly influencing corrected calcium in the MM group, although serum paraprotein trended toward significance (p = 0.09). CONCLUSION: Ionized calcium may be better than corrected calcium for detecting hypercalcemia in patients with MM. Additional analyses are needed to better quantify the clinical impact of paraprotein calcium-binding.

Chimeric Antigen Receptor T Cells in Hematologic Malignancies.

Patients with B-cell hematologic malignancies who progress through first- or second-line chemotherapy have a poor prognosis. Early clinical trials with autologous anti-CD19 chimeric antigen receptor (CAR) T cells have demonstrated promising results for patients who have relapsed or refractory disease. Lymphodepleting conditioning regimens, including cyclophosphamide, fludarabine, pentostatin, bendamustine, interleukin-2, and total body irradiation, are often administered before the infusion of CAR T cells, allowing for greater T-cell expansion. The major toxicity associated with CAR T-cell infusions is cytokine release syndrome (CRS), a potentially life-threatening systemic inflammatory disorder. The quick onset and progression of CRS require rapid detection and intervention to reduce treatment-related mortality. Management with tocilizumab can help ameliorate the symptoms of severe CRS, allowing steroids, which diminish the expansion and persistence of CAR T cells, to be reserved for tocilizumab-refractory patients. Other toxicities of CAR T-cell therapy include neutropenia and/or febrile neutropenia, infection, tumor lysis syndrome, neurotoxicity and nausea/vomiting. A review of patients' medications is imperative to eliminate medications that may contribute to treatment-related toxicities. Studies are ongoing to help optimize patient selection, preparation, safety, and management of individuals receiving CAR T cells. Long-term follow-up will help establish the place of CAR T cells in therapy.

Management strategies and outcomes for very elderly patients with diffuse large B-cell lymphoma.

BACKGROUND: The number of elderly patients with diffuse large B-cell lymphoma (DLBCL) in our aging society continues to rise, although the optimal management of very elderly patients with DLBCL is unknown. METHODS: This study evaluated 207 patients who were 80 years old or older at the diagnosis of DLBCL from 2002 to 2014 at The University of Texas MD Anderson Cancer Center. Analyzed features included clinical characteristics, treatment outcomes, and tolerability of therapy. Cox proportional hazards models examined relations between the treatment regimen and survival. RESULTS: The median age was 83 years (range, 80-96 years). Fifty-four percent of the patients had intermediate- to high-risk or high-risk International Prognostic Index scores. Fifteen percent had scores of 4 or higher on the Charlson Comorbidity Index (CCI). The initial therapies included rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 70%); rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH; 6%); and non-anthracycline-based therapies, including rituximab, cyclophosphamide, etoposide, vincristine, and prednisone (R-CEOP) and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP; 10%). With a median follow-up of 38.1 months, the 3-year failure-free survival (FFS) and overall survival (OS) rates were 55% and 54%, respectively. Eighty-eight patients experienced relapse during the follow-up, but only 3 patients (3.4%) experienced relapse beyond 3 years. Patients who received R-CHOP or R-EPOCH had significantly longer FFS than those who received R-CEOP or R-CVP, with 3-year FFS rates of 63% for R-CHOP, 74% for R-EPOCH, and 23% for R-CEOP and R-CVP. Male sex, a monocyte count ≥ 500 × 107 /L, and a CCI score ≥ 4 were significantly associated with inferior OS. Extranodal disease (≥2) and a higher CCI score were associated with a high risk of treatment-related mortality. CONCLUSIONS: With anthracycline-based regimens such as R-CHOP and R-EPOCH, very elderly patients with DLBCL had superior outcomes similar to those achieved for younger patients with DLBCL. Cancer 2016;122:3145-51. © 2016 American Cancer Society.

Idelalisib for treatment of B-cell malignancies.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety and tolerability, dosing and administration, and place in therapy of idelalisib, a targeted therapy for certain types of non-Hodgkin's lymphoma (NHL), are reviewed. SUMMARY: Historically, conventional cancer chemotherapy agents were recommended for the management of progressive lymphomas requiring systemic treatment; in recent years, however, emerging targeted therapies have altered the landscape of lymphoma treatment. Idelalisib, a novel oral phosphatidylinositol 3-kinase (PI3K) inhibitor, disrupts downstream signaling pathways involved in cancer cell growth and survival. Inhibition of PI3K has been demonstrated to produce durable treatment responses and improved survival outcomes in clinical trials involving patients with indolent forms of NHL. Idelalisib is indicated for use in combination with rituximab for treatment of relapsed chronic lymphocytic leukemia (CLL) and as monotherapy for relapsed small lymphocytic leukemia and follicular lymphoma after the failure of at least two systemic treatments. The recommended dosage of idelalisib is 150 mg orally twice daily; the medication can be taken without regard to mealtimes. The most common adverse effects of idelalisib include diarrhea, nausea, fatigue, cough, and pyrexia. Severe hepatotoxicity and gastrointestinal toxicities, including colitis and intestinal perforation, have also been reported in association with idelalisib use. Ongoing clinical studies are exploring the potential for expanded use of idelalisib in the management of other B-cell malignancies. CONCLUSION: Idelalisib is a well-tolerated and effective treatment for patients with relapsed or refractory CLL or indolent NHL, providing a novel targeted therapeutic option for the management of these hematologic malignancies.