Real-world evidence of obinutuzumab and venetoclax in previously treated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

Venetoclax-obinutuzumab (Ven-O) is frequently administered off-label in relapsed/refractory (r/r) CLL/SLL where venetoclax-rituximab is the approved regimen. We conducted this retrospective, real-world study to evaluate Ven-O in r/r CLL/SLL. Between 7/2019 and 6/2022, 40 patients with r/r CLL/SLL on Ven-O were included. The median age was 72, 28.2% had TP53 mutation and/or 17p deletion, median number of prior therapies was 1 (range, 1-6), and 55% had prior BTK inhibitor exposure. The overall response rate was 90% (complete response [CR] or CR with incomplete marrow recovery in 27.5% and partial response in 62.5%) of patients, and the 2-year progression-free survival was 81.2% (95% CI, 69.5-94.8). Therapy was well tolerated. No laboratory or clinical TLS occurred with venetoclax (Howard criteria). One (3%) patient experienced laboratory TLS with obinutuzumab initiation. In summary, this retrospective cohort study demonstrated that Ven-O achieves frequent, durable responses and can be safely administered in r/r CLL/SLL.

Combined analysis of the impact of second-generation BTK inhibitors on patient outcomes.

BTK inhibitors (BTKi) are highly effective in B-cell malignancies. Acalabrutinib and zanubrutinib have exhibited favorable safety profiles when compared with ibrutinib. We identified all published/presented randomized trials comparing a second-generation BTKi with ibrutinib and reconstructed individual patient-level, censored time-to-event data for adverse events to evaluate the impact of second-generation BTKi on safety outcomes including atrial fibrillation/flutter [AF], hypertension, bleeding, diarrhea, and infection. 1386 pts from ELEVATE-RR (n = 533), ALPINE (n = 652), and ASPEN (n = 201) trials were included in the analyses. Acalabrutinib or zanubrutinib were associated with significant reductions in cumulative event rates of AF (HR 0.28, 95% CI 0.18-0.42, p < 0.001), bleeding (HR 0.65, 95% CI 0.52-0.81, p < 0.001), diarrhea (HR 0.61, 95% CI 0.47-0.78, p < 0.001), hypertension (HR 0.40, 95% CI 0.27-0.61, p < 0.001), and infections (HR 0.83, 95% CI 0.70-0.98, p = 0.032). In summary, zanubrutinib and acalabrutinib have a favorable safety profile among pts with r/r B-cell malignancies. These data support use of acalabrutinib or zanubrutinib as preferred BTK inhibitors for approved indications.

Letermovir and tacrolimus interaction effects in hematopoietic cell transplantation recipients receiving moderate cytochrome P450 3A4 inhibitors for antifungal prophylaxis.

INTRODUCTION: Letermovir inhibits cytomegalovirus replication and is approved for the prevention of cytomegalovirus infection in cytomegalovirus seropositive hematopoietic cell transplantation recipients. Studies have found that letermovir coadministration has minimal effect on tacrolimus levels prior to the start of voriconazole, a strong cytochrome P450 (CYP) 3A4 inhibitor. However, data are lacking for hematopoietic cell transplantation recipients receiving letermovir and tacrolimus with moderate CYP 3A4 inhibitors as antifungal prophylaxis. METHODS: In this retrospective single-center analysis, we reviewed the charts of 92 consecutive adult allogeneic hematopoietic cell transplantation recipients receiving letermovir, tacrolimus, and moderate CYP3A4 inhibitors for antifungal prophylaxis. RESULTS: Tacrolimus concentration/dose (C/D) ratios were evaluated for the first 7 days pre-letermovir and for the first and second 7-day periods after letermovir. The tacrolimus mean C/D ratios [(ng/mL)/(mg/kg/day)] increased significantly with the addition of letermovir: 172.99 (95% confidence interval (CI): 158.2-187.78) pre-letermovir, 268.66 (95% CI: 244.34-292.98) first-week letermovir, and 312.19 (95% CI: 279.39-344.99) second-week letermovir (P < 0.001). The average dosages (mg/kg) of tacrolimus also decreased significantly across the three-time intervals (P < 0.001). Only four patients experienced clinically significant cytomegalovirus reactivation which required systemic treatment. CONCLUSION: These results demonstrate a reduction in tacrolimus dosing requirements for patients receiving tacrolimus and letermovir with concomitant moderate CYP3A4 inhibitors. The results of this interaction suggest that frequent monitoring of tacrolimus trough levels is warranted when starting letermovir and that empiric reduction of tacrolimus dosing upon letermovir initiation should be considered.

The efficacy and safety of cardio-protective therapy in patients with 5-FU (Fluorouracil)-associated coronary vasospasm.

BACKGROUND: Coronary vasospasm is a known side effect of 5-FU (fluorouracil) therapy. Beyond switching to non-5FU-based chemotherapy, there are no established treatments for 5-FU associated coronary vasospam. Our objective was to assess the safety and efficacy of re-challenge with 5-FU after pre-treatment with calcium channel blockers (CCBs) and long-acting nitrates among patients 5-FU associated coronary vasospasm. METHODS: We conducted a retrospective study of patients with 5-FU coronary vasospasm at a single academic center. By protocol, those referred to cardio-oncology received pre-treatment with either combination [nitrates and CCBs] or single-agent therapy [nitrates or CCBs]) prior to re-challenge with 5-FU. Our primary outcome was overall survival. Other important outcomes included progression-free survival and safety. RESULTS: Among 6,606 patients who received 5-FU from January 2001 to Dec 2020, 115 (1.74%) developed coronary vasospasm. Of these 115 patients, 81 patients continued 5-FU therapy, while 34 stopped. Of the 81 who continued, 78 were referred to cardio-oncology and prescribed CCBs and/or nitrates prior to subsequent 5-FU, while the remaining 3 continued 5-FU without cardiac pre-treatment. Of the 78, 56.4% (44/78) received both nitrates and CCBs, 19.2% (15/78) received CCBs alone, and 24.4% (19/78) received nitrates alone. When compared to patients who stopped 5-FU, those who continued 5-FU after pre-treatment (single or combination therapy) had a decreased risk of death (HR 0.42, P = 0.005 [95% CI 0.23-0.77]) and a trend towards decreased cancer progression (HR 0.60, P = 0.08 [95% CI 0.34-1.06]). No patient in the pre-treatment group had a myocardial infarct after re-challenge; however, chest pain (without myocardial infarction) recurred in 19.2% (15/78) among those who received cardiac pre-treatment vs. 66.7% (2/3) among those who did not (P = 0.048). There was no difference in efficacy or the recurrence of vasospasm among patients who received pre-treatment with a single agent (nitrates or CCBs) or combination therapy (14.7% (5/34) vs. 25.0% (11/44), P = 0.26). CONCLUSION: Re-challenge after pre-treatment with CCBs and nitrates guided by a cardio-oncology service was safe and allowed continued 5-FU therapy.

Humoral and cellular immunogenicity of SARS-CoV-2 vaccines in chronic lymphocytic leukemia: a prospective cohort study.

Chronic lymphocytic leukemia (CLL), the most common leukemia worldwide, is associated with increased COVID-19 mortality. Previous studies suggest only a portion of vaccinated CLL patients develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibodies. Whether the elicited antibodies are functional and/or accompanied by functional T-cell responses is unknown. This prospective cohort study included patients with CLL who received SARS-CoV-2 and PCV13 vaccines (not concurrently). The primary cohort included adults with CLL off therapy. Coprimary outcomes were serologic response to SARS-CoV-2 (receptor binding domain [RBD] immunoassay) and PCV13 vaccines (23-serotype IgG assay). Characterization of SARS-CoV-2 antibodies and their functional activity and assessment of functional T-cell responses was performed. Sixty percent (18/30) of patients demonstrated serologic responses to SARS-CoV-2 vaccination, appearing more frequent among treatment-naïve patients (72%). Among treatment-naïve patients, an absolute lymphocyte count ≤24 000/µL was associated with serologic response (94% vs 14%; P < .001). On interferon-γ release assays, 80% (16/20) of patients had functional spike-specific T-cell responses, including 78% (7/9) with a negative RBD immunoassay, a group enriched for prior B-cell-depleting therapies. A bead-based multiplex immunoassay identified antibodies against wild-type and variant SARS-CoV-2 (α, ß, γ, and δ) in all tested patients and confirmed Fc-receptor binding and effector functions of these antibodies. Of 11 patients with negative RBD immunoassay after vaccination, 6 (55%) responded to an additional mRNA-based vaccine dose. The PCV13 serologic response rate was 29% (8/28). Our data demonstrate that SARS-CoV-2 vaccination induces functional T-cell and antibody responses in patients with CLL and provides the framework for investigating the molecular mechanisms and clinical benefit of these responses. This trial was registered at www.clinicaltrials.gov as #NCT05007860.

Evaluating the incidence of chemotherapy-induced nausea and vomiting in patients with B-cell lymphoma receiving dose-adjusted EPOCH and rituximab.

BACKGROUND: Studies evaluating antiemetic prophylaxis have primarily focused on the solid tumor setting and single-day regimens. This study evaluates antiemetic prophylaxis and chemotherapy induced nausea and vomiting (CINV) in patients with lymphoma receiving a multiday doxorubicin-cyclophosphamide containing regimen. METHODS: This was a retrospective, single center, cohort study evaluating patients with aggressive non-Hodgkin B-cell lymphoma receiving dose-adjusted R-EPOCH in the hospital. Data was collected from the electronic medical record from April 2016 to September 2019. Complete response over 120 hours was the primary outcome. Secondary outcomes included complete response during the acute and delayed phases as well as complete control. RESULTS: A total of 73 patients who received dose adjusted R-EPOCH were identified. Most patients (n = 39, 53%) were male with a the median age was 63 years (range: 21-81). Most patients received ondansetron 16 mg once daily (n = 48, 66%) on days 1-5 as antiemetic prophylaxis with a minority receiving either dexamethasone (n = 8) or an NK1 antagonist (n = 13) in addition to ondansetron. Complete response rate was 32% and the complete response in the acute and delayed phase was also 32%. CONCLUSION: Control of CINV in patients with lymphoma hospitalized to receive dose-adjusted R-EPOCH was suboptimal, with only 32% of patients achieving complete response. Nearly three-quarters of patients received only a 5HT3 receptor antagonist as scheduled antiemetic therapy without an NK1 receptor antagonist. This data supports the importance of improving awareness of regarding multiday CINV guidelines and ensuring timely update and implementation of these evidence-based guidelines.

The Incidence, Risk Factors, and Outcomes With 5-Fluorouracil-Associated Coronary Vasospasm.

BACKGROUND: Coronary vasospasm is a recognized side effect of 5-FU (fluorouracil). There are limited and conflicting data on the incidence, risk factors and prognostic effect of 5-FU associated vasospasm. OBJECTIVES: To assess the incidence, risk factors and prognostic implications of 5-FU coronary vasospasm among patients receiving 5-FU regimens at a single tertiary care center. METHODS: We conducted a retrospective analysis of all patients who received 5-FU at a single academic center from January 2009 to July 2019. Vasospasm was defined as the occurrence of a typical chest pain syndrome in the presence of 5-FU. The presence of associated electrocardiogram (ECG) changes and/or elevated biomarkers was used to further confirm the diagnosis. Patients with vasospasm were compared to patients treated with 5-FU without vasospasm in a 1:2 ratio. Data regarding demographics, medical history, and follow-up were collected by manual chart review. RESULTS: From approximately 4019 individual patients who received 5-FU from 2009 to 2019 at a single center, 87 (2.16%) developed vasospasm. Patients who developed vasospasm were younger (58±13 vs. 64±13 years, P = 0.001), and were less likely to have any cardiovascular risk factors (70.1% vs. 84.5%, P = 0.007). Patients with vasospasm and patients without vasospasm were otherwise similar in terms of types of cancer, stage of cancer, sex, and race. There was no significant difference in progression-free survival, overall mortality or cancer specific mortality between patients who developed vasospasm versus those who did not. CONCLUSION: In a large, single-center report of 5-FU associated vasospasm, patients who developed vasospasm were younger, had lower rates of traditional cardiovascular risk factors and had no significant difference in progression-free or overall survival compared to those who did not develop vasospasm.

Incidence of Invasive Fungal Infections in Acute Myeloid Leukemia Without Antifungal Prophylaxis.

BACKGROUND: Antifungal prophylaxis during induction for acute myeloid leukemia (AML) varies according to local rates of invasive fungal infections (IFIs). We evaluated fluconazole prophylaxis and no antifungal prophylaxis, as a natural interrupted time-series study to assess survival and infection complications. PATIENTS AND METHODS: We identified patients with AML ≥ 18 years old undergoing induction chemotherapy during 2 time periods: period 1, fluconazole prophylaxis from August 1, 2013 to September 30, 2015, and period 2, no prophylaxis from October 1, 2015 to December 31, 2017. The primary outcome was incidence of proven or probable IFI. Secondary outcomes included types of IFIs and 60-day overall survival (OS). IFI was defined by the 2002 European Organization for Research and Treatment of Cancer/Mycoses Study Group Consensus criteria. RESULTS: One hundred forty-four patients received induction chemotherapy over the 2 time periods. In the prophylaxis versus no-prophylaxis groups, the rate of proven or probable IFIs was 4 (5%) of 87 versus 12 (21%) of 57 (P = .01). The total number of proven IFIs was 3 (3%) of 87 versus 4 (7%) of 57 (P = .44), whereas probable IFIs were 1 (1%) of 87 versus 8 (14%) of 57 (P < .01). No difference was observed in fungemia. Incidence of IFIs was too low to detect resistance patterns. OS at 60 days was improved in with fluconazole prophylaxis compared with no prophylaxis (hazard ratio, 0.329; 95% confidence interval, 0.12-0.89; P = .028). CONCLUSION: Observed rates of proven or probable IFI were lower in the fluconazole prophylaxis group versus the no-prophylaxis group. Sixty-day OS was higher with fluconazole prophylaxis. Further study is required to evaluate how fluconazole may impart the differences in survival seen in this analysis.

CAR T-Cell-Associated Neurotoxicity: Current Management and Emerging Treatment Strategies.

Axicabtagene ciloleucel and tisagenlecleucel are 2 chimeric antigen receptor (CAR) T-cell immunotherapies targeting CD19 for the treatment of B-cell acute lymphoblastic leukemia and non-Hodgkin lymphoma. Two commonly recognized complications associated with CAR T-cell therapies are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). ICANS can occur in isolation or concomitantly with CRS following CAR T-cell therapy and may be due to disruption of the blood-brain barrier and the effects of elevated cytokine levels on the central nervous system. Presently, the optimum management of ICANS remains elusive, as there lacks consensus guidelines. The objective of this review is to provide a comprehensive summary of ICANS and strategies for prompt identification and management of patients presenting to the intensive care unit with this syndrome.

Current Treatment Strategies for Multiple Myeloma.

The treatment of multiple myeloma (MM) continues to evolve with the approval of numerous agents over the past decade. Advances in treatment have led to the incorporation of these newer therapies into the treatment paradigm, with improvements in overall survival and the possibility of deep responses including a minimal residual disease-negative state. The strategy of triplet therapies for patients with newly diagnosed MM, followed by high-dose chemotherapy and autologous stem-cell transplantation for eligible patients, and subsequently consolidation and maintenance therapy, is the current treatment roadmap for patients. However, patients with MM will ultimately develop refractoriness to antimyeloma therapies. In this article, we summarize our current practice of managing patients with MM. We highlight our approach to patients with newly diagnosed MM who are transplantation eligible and ineligible and highlight risk-adapted strategies for these patients. In addition, we discuss our approach to the management of patients with relapsed or refractory MM. Last, we review standard therapies and emerging strategies such as targeted approaches, immune-based therapies, and drugs with novel mechanisms of action. Trials evaluating chimeric antigen receptor T cells targeting B-cell maturation antigen are ongoing and are only one of several novel approaches targeting cell maturation antigen, which include the use of bispecific T-cell engager antibodies and antibody drug conjugates. Emerging therapies offer the promise of more individualized approaches in the management of patients with MM and ultimately may result in the possibility of being one step closer to curing patients with MM.

Current management and emerging treatment strategies for multiple myeloma.

Multiple myeloma is a malignant plasma cell neoplasm that is incurable despite significant progress in treatment over the past several decades. The incorporation of novel agents and combinations into the MM treatment paradigm has resulted in improved survival and tolerability, as well as deeper responses including achieving a minimal residual disease negative state. The addition of new treatment options and combinations has added complexity in treatment selection for myeloma patients. The current strategy for newly diagnosed myeloma involves induction, consolidation, and maintenance therapy. However, nearly all myeloma patients will develop refractory disease. This highlights the need for more effective therapies targeting the myeloma cells and their microenvironment. In this article, we summarize current management of transplant eligible and ineligible newly diagnosed patients in both the upfront and relapsed refractory setting, highlighting risk adapted strategies. We also summarize emerging therapies, such as immune and targeted approaches, as well as drugs with novel mechanisms of action. Emerging strategies offer individualized treatment options and may ultimately offer the possibility of a cure for myeloma patients.

Evaluation of the impact of thyroiditis development in patients receiving immunotherapy with programmed cell death-1 inhibitors.

PURPOSE: We evaluated if the development of thyroiditis in patients who received treatment with immune checkpoint inhibitors across various tumor types was associated with tumor response. METHODS: In this retrospective, single-center, cross-sectional study, patients with various tumor types who received treatment with nivolumab or pembrolizumab as standard of care were evaluated. The primary endpoint was to evaluate the objective response rate in patients who developed thyroiditis compared with patients who did not develop thyroiditis. Secondary endpoints included disease control rate, progression-free survival, and overall survival. RESULTS: One hundred and three patients were included for analysis with a median follow-up duration of 12.8 months (range, 4.0-21.6). The data cutoff was 31 December 2016. The objective response rate was 38.2% among the 34 patients in the thyroiditis group and 17.4% in the 69 patients in the non-thyroiditis group (p = 0.028). Progression-free survival was longer in the thyroiditis group than in the non-thyroiditis group. The median progression-free survival was 10.1 months (95% CI, 1.6-18.5) in the thyroiditis group and 3.7 months (95% CI, 2.5-4.9) in the non-thyroiditis group (hazard ratio, 0.45; 95% CI, 0.27-0.76; p = 0.002). CONCLUSION: Patients with various tumor types who received treatment with immune checkpoint inhibitors and developed thyroiditis had a higher objective response rate than those who did not develop thyroiditis. The development of thyroiditis should be investigated further in the context of prospective randomized trials as a surrogate marker for tumor response to treatment with immune checkpoint inhibitor therapies.

Safety and efficacy of a urine alkalinization protocol developed for high-dose methotrexate patients during intravenous bicarbonate shortage.

PURPOSE: Urinary alkalinization with intravenous sodium bicarbonate is standard during high-dose methotrexate administration. Due to a national intravenous sodium bicarbonate shortage, a urinary alkalinization protocol involving hyperhydration with intravenous fluids, oral bicarbonate, and intravenous or oral acetazolamide was utilized from 10 April to 30 May 2017 ("shortage protocol"). This study compared outcomes between protocols. METHODS: A single-center, retrospective chart review was conducted for adults who received methotrexate ≥500 mg/m2 on ≥ two occasions, at least once during each protocol, between 19 February and 19 July 2017. RESULTS: Eighteen patients (50% male), median age 65 years, received 76 total high-dose methotrexate cycles. Shortage protocol was used in 37 cycles (48.7%). Mean time to methotrexate clearance did not differ between groups (p = ns). Mean time to urinary alkalinization and duration of hospitalization were not statistically different (p = 0.49 and 0.23, respectively). Average total bicarbonate administered per 24 hours was higher in standard protocol (p < 0.05), but hydration rates were similar (p = 0.73). Creatinine clearance and urine output on days 1 and 2 post-high-dose methotrexate did not significantly differ (creatinine clearance day 1, p = 0.27; creatinine clearance day 2, p = 0.55; urine output day 1, p = 0.62; urine output day 2, p = 0.60). Interruptions in alkalinization were significantly higher during shortage (0.41 ± 0.75 instances of urine pH < 7 during standard vs. 1.3 ± 1.7 under shortage, p < 0.05).