Safety and efficacy of ibrutinib in combination with rituximab and lenalidomide in previously untreated follicular and marginal zone lymphoma: An open label, phase 2 study.

BACKGROUND: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent non-Hodgkin lymphomas (iNHL). Median survival for iNHL is approximately 20 years. Because standard treatments are not curative, patients often receive multiple lines of therapy with associated toxicity-rationally designed, combination therapies with curative potential are needed. The immunomodulatory drug lenalidomide was evaluated in combination with rituximab for the frontline treatment of FL in the phase 3 RELEVANCE study. Ibrutinib, an oral Bruton tyrosine kinase inhibitor, is active in NHL and was evaluated in combination with lenalidomide, rituximab, and ibrutinib (IRR) in a phase 1 study. METHODS: The authors conducted an open-label, phase 2 clinical trial of IRR for previously untreated FL and MZL. The primary end point was progression-free survival (PFS) at 24 months. RESULTS: This study included 48 participants with previously untreated FL grade 1-3a (N = 38), or MZL (N = 10). Participants received 12, 28-day cycles of lenalidomide (15 mg, days 1-21 cycle 1; 20 mg, cycles 2-12), rituximab (375 mg/m2 weekly in cycle 1; day 1 cycles 2-12), and ibrutinib 560 mg daily. With a median follow-up of 65.3 months, the estimated PFS at 24 months was 78.8% (95% confidence interval [CI], 68.0%-91.4%) and 60-month PFS was 59.7% (95% CI, 46.6%-76.4%). One death occurred unrelated to disease progression. Grade 3-4 adverse events were observed in 64.6%, including 50% with grade 3-4 rash. CONCLUSIONS: IRR is highly active as frontline therapy for FL and MZL. Compared to historical results with lenalidomide and rituximab, PFS is similar with higher grade 3-4 toxicity, particularly rash. The study was registered with ClinicalTrials.gov (NCT02532257).

Long-term outcomes in patients with chronic lymphocytic leukemia treated with ibrutinib: Focus on hypertension and cardiovascular toxicity.

BACKGROUND: Continuous ibrutinib administration is needed to maintain efficacy in patients with chronic lymphocytic leukemia (CLL) and, as such, long-term toxicity is a concern. The authors report the 5-year follow-up of patients with CLL who received treatment with ibrutinib with a focus on hypertension and cardiovascular toxicities. METHODS: Patient characteristics were assessed, including blood pressure, cardiovascular disease, disease progression, and death. Univariate logistic regression analysis assessed the relation of patient characteristics and the development of new or worsened hypertension. The incidence of hypertensive outcomes was evaluated using competing risk. Survival was estimated using the Kaplan-Meier method. RESULTS: Three hundred patients with CLL who were treated with ibrutinib on clinical trials were included. The median patient age at study enrollment was 65 years (range, 29-83 years). Seventy percent of patients were men, and 88% were Caucasian. Sixty-nine percent of patients had hypertension at baseline, and 47% were on antihypertensive medication. Eighty-eight percent had relapsed or refractory CLL. New-onset and worsening hypertension were common, occurring in 68.5% and 38% of patients, respectively. Systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg was observed in 16.9% of patients. Hypertension was reversible after ibrutinib discontinuation. Older age, male sex, tobacco use, and chronic kidney disease were associated with ibrutinib-related hypertension. Baseline hypertension was not associated with major adverse cardiovascular events in ibrutinib-treated patients nor with event-free or overall survival. CONCLUSIONS: Hypertension is a common toxicity in patients with CLL who receive ibrutinib but is manageable in most patients. Other than chronic kidney disease, baseline cardiovascular disease did not affect ibrutinib-related hypertension nor was hypertension associated with major adverse cardiovascular events or survival. PLAIN LANGUAGE SUMMARY: Ibrutinib is an effective treatment for patients with chronic lymphocytic leukemia. Ibrutinib is a well tolerated therapy, however hypertension can develop or worsen in patients receiving ibrutinib and other cardiovascular events are significant challenges to the use of this drug. This may be particularly true in patients with heart disease. Short-term side effects may worsen heart disease, but the long-term impact is unknown. The long-term results of ibrutinib on heart disease and hypertension are described.

Relationships between T-lymphocytes and physical function in adults with chronic lymphocytic leukemia: Results from the HEALTH4CLL pilot study.

OBJECTIVE: Examine physical function and T-cell phenotype in patients with chronic lymphocytic leukemia (CLL) before and after a physical activity (PA) intervention. METHODS: Physical function measures and blood samples were collected from CLL patients (Rai stage 0-4, 50% receiving targeted therapy, N = 24) enrolled in a 16-week intervention of at-home aerobic and/or resistance exercise. Flow cytometry characterized T-cells in cryopreserved peripheral blood cells. Wilcoxon signed-rank test compared physical function and T-cell phenotype at baseline and 16-weeks; Kendall's Tau assessed associations between variables. RESULTS: Godin leisure-time PA score increased from baseline to 16-weeks (mean difference: 14.61, p < .01) and fatigue decreased (mean difference: 6.71, p < .001). At baseline, lower fatigue correlated with a lower proportion of CD8+ T-cells (τ = 0.32, p = .03) and cardiorespiratory fitness (CRF) inversely correlated with the percentage of PD-1+CD8+ T-cells (τ -0.31, p = .03). At 16-weeks, CRF inversely correlated with the proportion of PD-1+CD4+ T-cells (τ -0.34, p = .02). Reduced fatigue at 16-weeks correlated with an increased CD4:CD8 ratio (τ = 0.36, p = .02) and lower percentage of HLA-DR+PD-1+CD4+ T-cells (τ = -0.37, p = .01). CONCLUSIONS: This intervention increased leisure-time PA and decreased fatigue in CLL patients. These changes correlated with an increased CD4:CD8 T-cell ratio and reduced proportion of T-cells subsets previously associated with poor outcomes in CLL patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02194387.

Unusual complications in the management of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a common, indolent disease that typically presents with a proliferation of mature, immunologically dysfunctional CD5+ B-cells which preferentially occupy the bone marrow, peripheral blood and lymphoid organs. Immune dysfunction leads to an increase in autoimmune diseases which occur in approximately 10% of patients with CLL. Autoimmune cytopenias are the most common, but other organs may be affected as well. The treatment of these conditions typically depends on the extent of CLL and severity of symptoms, but generally consists of CLL-directed therapies, immunosuppression or both. CLL may also infiltrate extranodal sites in the body. Symptomatic extranodal CLL or extranodal disease which threatens normal organ function is an indication for initiation of CLL-directed therapy. The following review summarizes autoimmune and extranodal complications that can occur in patients with CLL and our suggested approach to their treatment.

Medical comorbidities in patients with chronic lymphocytic leukaemia treated with idelalisib: analysis of two large randomised clinical trials.

Comorbidities influence survival in patients with chronic lymphocytic leukaemia (CLL) treated with chemo-immunotherapy or ibrutinib. While idelalisib has been studied in patients with comorbidities, their impact has not been investigated. We analysed 481 patients treated with idelalisib on two randomised trials (NCT01659021 and NCT01539512). Comorbidities were assessed using the Cumulative Illness Risk Scale (CIRS). Patients received idelalisib + anti-CD20 (rituximab or ofatumumab; n = 284) or anti-CD20 alone (n = 197). The median age was 69 years. We found that comorbidities did not significantly affect outcomes of idelalisib therapy. The objective response rate (ORR) was 79·3% versus 85·8%, the median progression-free survival (PFS) was 16·3 versus 19·1 months, and the median overall survival (OS) was 39·8 versus 49·8 months in patients treated with idelalisib who had a CIRS score of >6 versus ≤6, correspondingly. Treatment with idelalisib + anti-CD20 was associated with superior PFS and ORR when compared to anti-CD20 monotherapy in patients who had high comorbidities (CIRS score of >6) or at least one severe comorbidity (median PFS 16·3 vs. 6·9 months and 16·6 vs. 6·5 months; odds ratio 20·1 and 33·2; P < 0·0001). Thus, comorbidities do not portend inferior outcomes in patients with CLL treated with idelalisib in combination with anti-CD20 therapy.

Outcomes of Burkitt lymphoma with central nervous system involvement: evidence from a large multicenter cohort study.

Central nervous system (CNS) involvement in Burkitt lymphoma (BL) poses a major therapeutic challenge, and the relative ability of contemporary regimens to treat CNS involvement remains uncertain. We described prognostic significance of CNS involvement and incidence of CNS recurrence/progression after contemporary immunochemotherapy using real-world clinicopathologic data on adults with BL diagnosed between 2009 and 2018 across 30 US institutions. We examined associations between baseline CNS involvement, patient characteristics, complete response (CR) rates, and survival. We also examined risk factors for CNS recurrence. Nineteen percent (120/641) of patients (age 18-88 years) had CNS involvement. It was independently associated with HIV infection, poor performance status, involvement of ≥2 extranodal sites, or bone marrow involvement. First-line regimen selection was unaffected by CNS involvement (P=0.93). Patients with CNS disease had significantly lower rates of CR (59% versus 77% without; P<0.001), worse 3-year progression-free survival (adjusted hazard ratio [aHR], 1.53, 95% confidence interval [CI], 1.14-2.06, P=0.004) and overall survival (aHR, 1.62, 95%CI, 1.18-2.22, P=0.003). The 3-year cumulative incidence of CNS recurrence was 6% (95%CI, 4-8%). It was significantly lower among patients receiving other regimens (CODOX-M/IVAC, 4%, or hyperCVAD/MA, 3%) compared with DA-EPOCH-R (13%; adjusted sub-HR, 4.38, 95%CI, 2.16-8.87, P<0.001). Baseline CNS involvement in BL is relatively common and portends inferior prognosis independent of first-line regimen selection. In real-world practice, regimens with highly CNS-penetrant intravenous systemic agents were associated with a lower risk of CNS recurrence. This finding may be influenced by observed suboptimal adherence to the strict CNS staging and intrathecal therapy procedures incorporated in DA-EPOCH-R.

Intensive induction regimens after deferring initial therapy for mantle cell lymphoma are not associated with improved survival.

INTRODUCTION: While most patients with mantle cell lymphoma (MCL) receive therapy shortly after diagnosis, a subset of patients with indolent-behaving disease can safely defer treatment. In this subgroup, we evaluated the importance of treatment intensity in patients with MCL who defer initial therapy. METHODS: Out of 1134 patients with MCL from 12 academic centers, we analyzed 219 patients who initiated therapy at least 90 days after diagnosis. Patients who received induction with high-dose cytarabine and/or autologous stem cell transplantation (ASCT) in first remission were considered to have received intensive therapy (n = 88) while all other approaches were non-intensive (n = 131). RESULTS: There was no difference in progression-free (PFS; P = .224) or overall survival (OS; P = .167) in deferred patients who received non-intensive vs. intensive therapy. Additionally, univariate and multivariate Cox proportional hazards models were performed for PFS and OS. Treatment at an academic center (HR 0.43, P = .015) was associated with improved OS in both univariate and multivariate models, while intensity of treatment was not associated with improved OS in either model. CONCLUSIONS: These results indicate that intensified initial treatment is not associated with improved survival after deferring initial therapy, although prospective studies are needed to determine which of these patients with MCL may benefit from intensive therapy.

Multi-center analysis of practice patterns and outcomes of younger and older patients with mantle cell lymphoma in the rituximab era.

Clinical outcomes and predictors of survival in patients with newly diagnosed mantle cell lymphoma (MCL) treated in the rituximab era (2000-2015) at 12 US academic centers were assessed to identify determinants of survival across age groups. Objectives were to characterize and compare practice patterns, outcomes and prognostic factors for survival in younger patients (age < 65) and older patients (age ≥ 65 years). Among 1162 patients included, 697 were younger and 465 were older. In younger patients, 2-year progression free survival (PFS) and overall survival (OS) rates were 79% and 92% respectively; blastoid histology, ECOG ≥ 2, and lack of maintenance rituximab (MR) remained statistically relevant to poor OS on univariate analysis (UVA) and multivariate analysis (MVA). In older patients, 2-year PFS and OS rates were 67% and 86% respectively; lack of maintenance rituximab remained significantly associated with inferior PFS and OS on UVA and MVA (p < 0.001). Two-year PFS rates were 79%, and 67% and 2-year OS rates were 92% and 86% for ages < 65 and ≥ 65 respectively (p < 0.001). First-line high-dose cytarabine exposure and/or MR lessened the negative impact of age on survival. Taken collectively, survival outcomes for older patients remain inferior to those of younger patients in the rituximab era. However, maintenance rituximab and potentially high-dose cytarabine-based induction can mitigate the negative impact of age on survival.

Comorbidities predict inferior outcomes in chronic lymphocytic leukemia treated with ibrutinib.

BACKGROUND: Most patients with chronic lymphocytic leukemia (CLL) present with multiple comorbidities. Although comorbidities negatively affect outcomes for patients treated with chemoimmunotherapy, their impact on patients who receive targeted therapies is unknown. METHODS: This multicenter, retrospective analysis evaluated the significance of comorbidities, as assessed by the Cumulative Illness Rating Scale (CIRS), among patients with CLL treated with ibrutinib. RESULTS: One hundred forty-five patients received ibrutinib (80% in a relapsed/refractory setting). A high burden of comorbidities (CIRS score ≥ 7) was associated with inferior median event-free survival (EFS; 24 vs 37 months; P = .003) and 2-year overall survival (OS; 79% vs 100%; P = .005). In an adjusted Cox model, both EFS and OS worsened with an incremental increase in the CIRS score. Furthermore, comorbidities were associated with an increased risk of ibrutinib dose reduction and therapy discontinuation. CIRS was predictive in both frontline and relapsed CLL, regardless of patient age. CONCLUSIONS: Comorbidities portend a poor prognosis among patients with CLL treated with ibrutinib. Prospective studies are needed to optimize the treatment of patients with CLL who have comorbidities. Cancer 2018. © 2018 American Cancer Society.

Complex karyotype in patients with mantle cell lymphoma predicts inferior survival and poor response to intensive induction therapy.

BACKGROUND: Risk stratification of newly diagnosed patients with mantle cell lymphoma (MCL) primarily is based on the MCL International Prognostic Index (MIPI) and Ki-67 proliferative index. Single-center studies have reported inferior outcomes in patients with a complex karyotype (CK), but this remains an area of controversy. METHODS: The authors retrospectively reviewed 483 patients from 5 academic centers in the United States and described the effect of a CK on survival outcomes in individuals with MCL. RESULTS: A CK was found to be associated with inferior overall survival (OS) (4.5 vs 11.6 years; P<.01) and progression-free survival (PFS) (1.9 vs 4.4 years; P<.01). In patients who underwent high-intensity induction followed by autologous stem cell transplantation (ASCT) in first remission, a CK was associated with poor OS (5.1 vs 11.6 years; P = .04) and PFS (3.6 vs 7.8 years; P<.01). Among patients with a CK, high-intensity induction had no effect on OS (4.5 vs 3.8 years; P = .77) nor PFS (2.3 vs 1.5 years; P = .46). Similarly, ASCT in first remission did not improve PFS (3.5 vs 1.2 years; P = .12) nor OS (5.1 vs 4.0 years; P = .27). On multivariable analyses with Ki-67 and MIPI, only CK was found to be predictive of OS (hazard ratio [HR], 1.98; 95% confidence interval [95% CI], 1.12-3.49 [P = .02]), whereas both CK (HR, 1.91; 95% CI, 1.17-3.12 [P = .01]) and Ki-67 >30% (HR, 1.86; 95% CI, 1.06-3.28 [P = .03]) were associated with inferior PFS. Multivariable analysis did not identify any specific cytogenetic abnormalities associated with inferior survival. CONCLUSIONS: CK appears to be independently associated with inferior outcomes in patients with MCL regardless of the intensity of induction therapy and receipt of ASCT. Cytogenetics should be incorporated into the workup of a new diagnosis of MCL and novel therapeutic approaches should be investigated for patients with CK. Cancer 2018;124:2306-15. © 2018 American Cancer Society.