Chaitra Ujjani

Optimal Sequencing of Ibrutinib, Idelalisib, and Venetoclax in Chronic Lymphocytic Leukemia: Results from a Multi-Center Study of 683 Patients.

Background Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.BACKGROUND Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the US. However, there is no guidance as to their optimal sequence. PATIENTS AND METHODS We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). RESULTS A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81% respectively. With a median follow up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (vs. idelalisib) as first KI had a significantly better PFS in all settings; front-line (HR 2.8, CI1.3-6.3 p=.01), relapsed-refractory (HR 2.8, CI 1.9-4.1 p<.001), del17p (HR 2.0, CI 1.2-3.4 p=.008), and complex karyotype (HR 2.5, CI 1.2-5.2 p=.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS as compared to chemoimmunotherapy (CIT). Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, p=.06). CONCLUSIONS In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Further, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to CIT combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Elevation in serum lactate at the time of Febrile Neutropenia (FN) in hemodynamically-stable patients with Hematologic Malignancies (HM) is associated with the development of septic shock within 48 hours

Background: Hospitalized patients who develop febrile neutropenia (FN) are treated empirically with antibiotics due to a high risk of developing septic shock. Currently, there is no method to predict which patients are at greatest risk. This study was designed to determine whether serum lactate, measured at the time of FN, is associated with the development of septic shock in hospitalized hematologic malignancy (HM) patients. Methods: Vital signs and lactate were measured during episodes of FN. The primary endpoint was the development of septic shock. Using a prospective, nested, case-control design, controls were matched on length of stay at the time of septic shock to achieve 80% power to detect an OR of ≥ 2.5. Using logistic regression, we evaluated the association of vital signs and lactate with the subsequent development of septic shock. Results: Of the 547 patients enrolled, 46 (8.4%; 95% CI 6.2-10.9) developed septic shock. Baseline characteristics were similar between the groups. In univariate analysis, tachypnea (OR 5.9; 95% CI: 2.0-16.9, p =.001) and lactate (OR 18.4; 95% CI: 4.1-81.6, p

Ofatumumab and bendamustine in previously treated chronic lymphocytic leukemia and small lymphocytic lymphoma

Abstract Despite initial responses > 90% with fludarabine and rituximab-based regimens, patients with chronic lymphocytic leukemia (CLL) invariably relapse and require further treatment. Ofatumumab and bendamustine have each shown efficacy in relapsed/refractory CLL with overall response rates (ORRs) of 58% and 76%, respectively. Given excellent data with bendamustine and rituximab in relapsed/refractory CLL/small lymphocytic lymphoma (SLL), this phase II study evaluated the combination of ofatumumab and bendamustine in previously treated patients. Patients received ofatumumab 300 mg intravenously (IV) day − 7, followed by ofatumumab 1000 mg IV day 1 and bendamustine 70 mg/m2 days 1 and 2 of each 28-day cycle. Patients received 4–6 cycles depending on number of prior therapies, as long as well-tolerated or until progression. Of 10 patients enrolled, the ORR was 40% and complete response rate was 20%. The median progression-free and overall survivals were 8.1 months and 16.2 months. Three patients developed Richter transformation. The study was closed early due to unexpected adverse events including infusion-related reactions, infection and neurotoxicity.

The current status and future impact of targeted therapies in non-Hodgkin lymphoma

A number of new, biologic targeted therapies have been developed for the treatment of lymphoid malignancies. These include anti-CD20 monoclonal antibodies designed with greater binding affinities and different mechanisms of action profiles compared with rituximab. Other extracellular antigens on B cells and T cells are also being targeted. Monoclonal antibodies have been conjugated to radioisotopes and cellular toxins. In addition, several exciting new small-molecule kinase inhibitors are in development that target intracellular pathways that contribute to the pathogenesis of these diseases. Drugs that affect the tumor microenvironment are also under investigation. The advantage of these targeted agents compared with standard chemotherapy is greater tumor specificity, a more favorable toxicity profile, and, when combined with scientific rationale, and in the appropriate setting, perhaps a better long-term outcome.

Toxicities and outcomes of 621 ibrutinib-treated chronic lymphocytic leukemia patients in the United States: a real-world analysis

Clinical trials that led to ibrutinib’s approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.

18F‐FDG PET‐CT and trephine biopsy assessment of bone marrow involvement in lymphoma

The ability of positron emission tomography‐computerized tomography (PET‐CT) to accurately detect bone marrow involvement (BMI) has been suggested in Hodgkin lymphoma (HL) and diffuse large B‐cell lymphoma (DLBCL), but its abilities in other histologies is less established. The aim of this retrospective study was to confirm the role of PET‐CT in detecting BMI in DLBCL and HL, and to explore its usefulness in other subtypes. Of the 149 newly diagnosed patients, common subtypes included DLBCL, follicular lymphoma (FL) and HL. In DLBCL, the sensitivity and specificity of PET‐CT at diagnosis were 75% and 92%. In FL, the sensitivity and specificity of PET‐CT were 67% and 85% at diagnosis, and 73% and 89% at relapse. In HL, the sensitivity and specificity were 100% and 74%. PET‐CT was able to detect BMI in patients with negative biopsies. Most of the patients in which PET‐CT failed to identify BMI were already advanced stage by imaging. In this analysis, PET‐CT was highly accurate for detecting BMI at diagnosis in DLBCL and HL and highly specific in FL at diagnosis and relapse. Results also suggested the diagnostic advantage of PET‐CT over bone marrow biopsy in detecting BMI. Prospective evaluation is necessary and may eliminate biopsies in future patients.

The Optimal Management of Follicular Lymphoma: An Evolving Field

Follicular lymphoma consists of a heterogeneous group of diseases that can vary dramatically in clinical course. As with other indolent lymphomas, follicular lymphoma is felt to be highly treatable, but ultimately incurable. The appropriate management of this disease ranges from close observation to chemoimmunotherapy based on presenting symptoms and comorbidities. In this article, we focus on the optimal management of follicular lymphoma, including prognostication, indications for treatment, and current treatment options. While a number of front-line chemoimmunotherapy options exist, R-CHOP (rituximab, cyclophosphamide, vincristine, prednisone) and BR (bendamustine, rituximab) tend to be favored due to efficacy and tolerability. Post-induction options include maintenance rituximab and radioimmunotherapy, but neither has demonstrated an overall survival benefit. In relapsed disease, patients can receive an alternative chemoimmunotherapy regimen or radioimmunotherapy, or participate in a clinical trial. There are a number of new biologic targeted therapies with promising activity in follicular lymphoma that have the potential to change our approach to this disease.

Bendamustine in chronic lymphocytic leukemia and non-Hodgkin’s lymphoma

Bendamustine (Treanda®; Pharmachemie BV, The Netherlands for Cephalon, Inc., PA, USA) is a unique cytotoxic agent with both alkylating and antimetabolite properties. A growing body of evidence demonstrates its efficacy in a number of hematologic malignancies, and as such, it has been US FDA approved for the treatment of chronic lymphocytic leukemia and non-Hodgkin’s lymphoma that has not responded to, or progressed within 6 months of, a rituximab-based regimen. Bendamustine has efficacy both as a single agent as well as in combination with other chemotherapeutics and immunotherapeutics. Here, we will discuss in the detail the molecular properties, clinical efficacy and safety profile of bendamustine.

Utility of the systemic inflammatory response syndrome (SIRS) criteria in predicting the onset of septic shock in hospitalized patients with hematologic malignancies.

Background: The systemic inflammatory response syndrome (SIRS) criteria have not been validated in patients with hematologic malignancies (HM). Objective: To determine whether daily assessment of SIRS criteria allows early identification of HM patients who will develop septic shock (SS). Design: Observational, single-center, nested case-control study. Setting: Oncology unit of a tertiary care center. Patients: 547 consecutive, hospitalized, HM subject were enrolled. Using incidence-density sampling, 184 controls were matched to 46 SS cases. Measurements: The study exposure was the SIRS score. The study outcome was the development of SS during the hospitalization. Main Results: 8.4% of subjects developed SS. SIRS scores measured 24 hours prior to SS were significantly higher in cases than in controls (2.1 vs. 1.4, p

Comparable outcomes in chronic lymphocytic leukaemia (CLL) patients treated with reduced-dose ibrutinib: results from a multi-centre study

Additional Supporting Information may be found in the online version of this article: Data S1. Supplementary methods. Fig S1. Computed tomography, macroscopic, and loupe images. Table S1. Abberations common to both the malignant phyllodes tumour and myeloid sarcoma components detected by array comparative genomic hybridization. Table S2. Variants common to both the malignant phyllodes tumour and myeloid sarcoma components detected by whole-exome sequencing. Table S3. Variants only in the myeloid sarcoma component detected by whole-exome sequencing. Table S4. Antibodies used for immunohistochemistry and results. Table S5. Primer sequences.