Consensus recommendations on the management of toxicity associated with CD3×CD20 bispecific antibody therapy.

ABSTRACT: Bispecific antibodies (BsAb) that target CD3 and CD20 represent a new milestone in the treatment of patients with B-cell non-Hodgkin lymphoma. These drugs have demonstrated remarkable single-agent activity in patients with heavily pretreated disease, and 3 drugs have so far received regulatory approvals in various countries. However, BsAbs can potentially lead to severe toxicity associated with T-cell activation, particularly cytokine release syndrome (CRS). The anticipated widespread use of these off-the-shelf products poses challenges for implementation and highlights the need for guidance in anticipating, mitigating, and managing adverse events. In clinical trials, guidance for the evaluation and treatment of CRS and neurotoxicity associated with BsAb therapy has been modeled after algorithms originally created for chimeric antigen receptor (CAR) T-cell therapies and other immune effector therapies, yet notable differences in timing, quality, and severity exist between the toxicities of BsAbs and CAR T-cell therapies. We therefore convened an international panel of academic and community practice physicians, advanced practitioners, registered nurses, and pharmacists with experience using CD3×CD20 BsAbs in clinical trial and off-trial settings to provide comprehensive, consensus-based recommendations specific to the assessment and management of CD3×CD20 BsAb-related toxicities.

Administration of teclistamab in four patients with multiple myeloma requiring hemodialysis.

OBJECTIVE: Relapsed/refractory multiple myeloma (MM) has poor outcomes, especially in heavily pretreated patients. Limited data exists on the use of novel therapies in MM patients with renal dysfunction. This case series describes the successful initiation of teclistamab in four patients with heavily pre-treated MM on hemodialysis (HD). DATA SOURCES: The medical records of four adult MM patients on HD who received teclistamab were retrospectively reviewed. DATA SUMMARY: All patients completed teclistamab step-up dosing and received at least one full dose. HD runs were administered irrespective of teclistamab initiation. Patients tolerated therapy well, with only one patient experiencing grade 1 CRS, which was managed with supportive care. CONCLUSIONS: Due to the complexity of this patient population, close monitoring and multidisciplinary care are crucial. This approach is essential for effectively managing MM patients with renal dysfunction and for exploring novel treatment options.

NCCN Guidelines® Insights: Hematopoietic Growth Factors, Version 1.2022.

The NCCN Guidelines for Hematopoietic Growth Factors provide recommendations for the appropriate use of growth factors in the clinical management of febrile neutropenia (FN), chemotherapy-induced thrombocytopenia (CIT), and chemotherapy-induced anemia (CIA). Management and prevention of these sequelae are an integral part of supportive care for many patients undergoing cancer treatment. The purpose of these guidelines is to operationalize the evaluation, prevention, and treatment of FN, CIT, and CIA in adult patients with nonmyeloid malignancies and to enable the patient and clinician to assess management options for FN, CIT, and CIA in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for Hematopoietic Growth Factors, with particular emphasis on the incorporation of a newly developed section on CIT.

Incorporation of novel therapies for the management of sickle cell disease: A pharmacist's perspective.

Patients with sickle cell disease (SCD) experience significant disease-related morbidity including multiorgan damage, chronic anemia, and debilitating pain crises. While hydroxyurea has been the primary disease modifying modality in SCD, novel therapies with unique mechanism of action have recently been approved. This review article examines the evidence surrounding the available SCD therapies to guide pharmacists on potential treatment selection and management strategies for patients with SCD. A systematic search of online databases was performed to identify literature on the management of SCD. While the newly approved novel agents have demonstrated clinical benefit it remains unclear how these agents fit into the treatment paradigm. Pharmacists should be aware of the data supporting the use of these novel agents to optimize use on a patient-specific basis.

How to Choose An Appropriate Anticoagulant for Cancer-Associated Thrombosis.

Venous thromboembolic disease can be a fatal complication of cancer. Despite advances in prevention, thousands of patients require treatment of cancer-associated thrombosis (CAT) each year. Guidelines have advocated low-molecular-weight heparin (LMWH) as the preferred anticoagulant for CAT for years, based on clinical trial data showing LMWH to be associated with a lower risk of recurrent thrombosis when compared with vitamin K antagonists. However, the potentially painful, subcutaneously administered LMWH injections can be expensive, and clinical practice has not been consistent with guideline recommendations. Recently, studies have compared LMWH to the direct oral anticoagulants (DOACs) for the management of CAT. Based on promising trial results outlined in this review, DOACs are now preferred anticoagulants for CAT occurring in patients without gastric or gastroesophageal lesions. For patients with gastrointestinal cancers, who may be at higher risk of hemorrhage with the DOACs, LMWH remains the anticoagulant of choice. Applying the latest data from this rapidly evolving field to care for diverse patient groups can be challenging. This article provides an evidence-based review of outpatient anticoagulant selection for lower-extremity deep vein thrombosis or pulmonary embolism in the setting of cancer, and takes into account special populations with cancer.

Impact of Extended-Interval Versus Standard Dosing of Zoledronic Acid on Skeletal Events in Non-Small-Cell Lung Cancer and Small-Cell Lung Cancer Patients With Bone Metastases.

BACKGROUND: Zoledronic acid every 4 weeks (Q4wk) reduces the incidence of skeletal-related events (SREs) in patients with metastatic lung cancer. Lung cancer patients were excluded from extended-interval dosing trials (every 12 weeks [Q12wk]) that demonstrated noninferiority of the 2 dosing schemes. To date, the optimal dosing of zoledronic acid in metastatic lung cancer remains unknown. OBJECTIVE: To determine whether zoledronic acid dosed Q12wk is similar to Q4wk dosing for prevention of SRE in patients with metastatic lung cancer. METHODS: A retrospective analysis was performed in patients with non-small-cell lung cancer and small-cell lung cancer with bone metastases who received Q12wk and Q4wk zoledronic acid. The primary outcome was incidence of SRE at 1 year. Secondary analyses included time to first SRE, overall survival (OS), incidence of osteonecrosis of the jaw (ONJ), kidney dysfunction, and hypocalcemia. RESULTS: A total of 34 patients received Q12wk and 46 patients received Q4wk zoledronic acid. Incidence of SRE at 1 year (Q12wk, 23.5%, vs Q4wk, 23.9%; 95% CI = -0.184 to 0.192; P = 0.968) and median time to SRE (not reached for either cohort; P = 0.530) did not differ. The Q12wk cohort had longer median OS (24.00 vs 8.97 months; P = 0.022). There were no differences in incidence of ONJ, kidney dysfunction, and hypocalcemia. CONCLUSION AND RELEVANCE: This is the first report examining extended-interval dosing of zoledronic acid in metastatic lung cancer. Incidence and time to SRE at 1 year were similar. This extended-interval dosing may be safe and reasonable for patients with lung cancer with bone metastases.

Implementation and outcomes of a pharmacist-led collaborative drug therapy management program for oncology symptom management.

INTRODUCTION: Nausea, vomiting, constipation, and diarrhea are common cancer and cancer therapy adverse effects. Pharmacists are uniquely positioned to optimize patient symptom control and minimize excess use of hospital resources, such as emergency department visits. METHODS: Michigan Medicine oncology clinical pharmacists have been independently providing patient symptom management through a collaborative drug therapy management (CDTM) program which established guidelines for management of gastrointestinal toxicities (nausea, vomiting, diarrhea, and/or constipation) secondary to a patient's cancer diagnosis or treatment of the cancer. Patients were referred to the pharmacist by the treating oncologist or hematologist. RESULTS: From June 2019 to May 2020, there were a total of 62 patient referrals. Ten of the 62 referrals did not meet the CDTM inclusion criteria, resulting in 52 patients who were managed by the pharmacists. The total number of individual pharmacist visits was 136, with a median of 2.2 (range, 0-11) visits per patient referred. A total of 169 categorized pharmacist interventions were captured. Most interventions (100/169, 59.2%) were related to nausea/vomiting. Diarrhea-related and constipation-related interventions accounted for 10 (5.9%) and 13 (7.7%) of the total interventions, respectively. Most patients (36/52, 69.2%) had a reduction in the severity of their referral diagnosis symptom(s) based on Common Terminology Criteria for Adverse Events grading. CONCLUSION: The Michigan Medicine Pharmacist CDTM program allowed pharmacists to independently manage gastrointestinal toxicities of patients with cancer and improved patient symptom severity. The CDTM program has the opportunity to improve quality of care.

Clinical controversies in the treatment of cancer-associated venous thromboembolism.

Cancer-associated venous thromboembolism (VTE) is a common complication of malignancy. Patients with cancer exhibit risk factors for both recurrent VTE and major or minor bleeding. Direct oral anticoagulants (DOACs) are an attractive treatment option; however, there is a lack of consensus among national guidelines for choice between DOACs and LMWH, agent selection, dosing strategy, and duration of anticoagulation. Characteristics of the thrombotic event, the malignancy, the patient, and the anticoagulant must be considered. A systematic search of online databases was performed to identify literature on the management of cancer-associated VTE. Multiple controversies remain surrounding the optimal treatment of cancer-associated VTE.

Successful rechallenge of rituximab following severe rituximab-induced acute thrombocytopenia in a patient with splenic marginal zone lymphoma.

Rituximab-induced acute thrombocytopenia (RIAT) is a relatively rare complication of rituximab treatment that has been infrequently reported in a number of patients with malignant lymphoma. Most commonly encountered in mantle cell lymphoma, the extent to which RIAT occurs in splenic marginal zone lymphoma is unknown. In this report, we describe a case of RIAT in a patient with splenic marginal zone lymphoma. Rituximab was safely rechallenged with increased premedications and slowed infusion rate. While the exact mechanism of this phenomenon has yet to be elucidated, diligent monitoring of platelet counts following rituximab infusion can be considered in high-risk patients to avoid potential adverse events. Split dose rituximab for high-risk patients may provide an alternative approach to improve patient safety.

Outcomes of previously untreated elderly patients with AML: a propensity score-matched comparison of clofarabine vs. FLAG.

The 5-year overall survival (OS) in patients ≥ 60 years old with acute myeloid leukemia (AML) remains < 10%. Clofarabine-based induction (CLO) provides an alternative to low-intensity therapy (LIT) and palliative care for this population, but supporting data are conflicted. Recently, our institution adopted the FLAG regimen (fludarabine, cytarabine, and granulocyte colony-stimulating factor) based on data reporting similar outcomes to CLO in elderly patients with AML unable to tolerate anthracycline-based induction. We retrospectively analyzed the efficacy and safety of patients ≥ 60 years old with AML treated with FLAG or CLO over the past 10 years. We performed a propensity score match that provided 32 patients in each group. Patients treated with FLAG had a higher CR/CRi rate (65.6 vs. 37.5%, P = 0.045) and OS (7.9 vs. 2.8 months, P = 0.085) compared to CLO. Furthermore, FLAG was better tolerated with significantly less grade 3/4 toxicities and a shorter duration of neutropenia (18.5 vs. 30 days, P = 0.002). Finally, we performed a cost analysis that estimated savings to be $30,000-45,000 per induction with FLAG. Our study supports the use of FLAG both financially and as an effective, well-tolerated high-dose treatment regimen for elderly patients with AML. No cases of cerebellar neurotoxicity occurred.

Incidence and risk factors for bacterial infection using bortezomib, lenalidomide, and dexamethasone (RVd) in newly diagnosed multiple myeloma.

Infections are an important cause of morbidity and mortality in newly diagnosed multiple myeloma (NDMM), but the real-world risk using modern induction regimens such as bortezomib, lenalidomide, and dexamethasone (RVd) is not well described. We performed a retrospective single-center cohort study to identify infections and risk factors in patients treated with first-line RVd from January 2014 to January 2020 and collected demographic and clinical data. Of 144 patients treated with RVd for NDMM, 21 patients (14.5%) experienced a bacterial infection during induction, of which 8 (5.5%) were grade 3 infections despite a low rate of antibiotic prophylaxis use (12%). Grade 3 neutropenia occurred in 11% of patients, 2% had febrile neutropenia and there were no deaths from infection. On multivariable analysis, age, smoking history, diabetes, antibiotic use in the 60 days preceding the start of RVd, and high-risk cytogenetics were associated with higher risk of bacterial infection.

Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a rare, incurable hematological malignancy with a heterogeneous presentation and clinical course. A wide variety of chemotherapy-based regimens are currently used in patients who are untreated. Over the last several years, several targeted or small-molecule therapies have shown efficacy in the relapsed/refractory setting and have since been explored in the frontline setting. Lenalidomide plus rituximab was explored in a phase 2 study of 38 patients with MCL who were untreated and ineligible to receive transplantation, in which the combination produced durable remissions. We looked to build upon this regimen by adding venetoclax to the combination. We conducted a multicenter, open-label, nonrandomized, single-arm study to evaluate this combination. We enrolled 28 unselected patients with untreated disease irrespective of age, fitness, or risk factors. Lenalidomide was dosed at 20 mg daily from days 1 to 21 of each 28-day cycle. The dose of venetoclax was determined using the time-to-event continual reassessment method. Rituximab was dosed at 375 mg/m2 weekly, starting on cycle 1, day 1 until cycle 2, day 1. No dose-limiting toxicities were noted. All patients were treated with venetoclax at the maximum tolerated dose of 400 mg daily. The most common adverse events were neutropenia and thrombocytopenia. The overall and complete response rates were 96% and 86%, respectively. In total, 86% of patients achieved minimal residual disease undetectability via next-generation sequencing. The median overall and progression-free survivals were not reached. The combination of lenalidomide, rituximab, and venetoclax is a safe and effective regimen in patients with untreated MCL. This trial was registered at www.clinicaltrials.gov as #NCT03523975.

Evaluating the Role of Novel Oncology Agents: Oncology Stewardship in Relapsed/Refractory Diffuse Large B-Cell Lymphoma.

Novel treatment strategies have shifted the treatment landscape for patients with diffuse large B-cell lymphoma, particularly for those with relapsed/refractory disease. However, uncertainty remains regarding the therapeutic value of these novel agents compared to existing salvage chemotherapy regimens. In addition, the high cost associated with these agents puts both patients and health systems at risk of financial toxicity, further complicating their use. The development of clinical pathways incorporating oncology stewardship principles are necessary in order to maximize value-based care. This comprehensive review assesses the efficacy and safety data available for novel treatment options in relapsed/refractory diffuse large B-cell lymphoma and applies stewardship principles to evaluate their optimal place in therapy, with the aim of optimizing safe, effective, and financially responsible patient care.

Chemotherapy Remote Care Monitoring Program: Integration of SMS Text Patient-Reported Outcomes in the Electronic Health Record and Pharmacist Intervention for Chemotherapy-Induced Nausea and Vomiting.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a common cause of unplanned healthcare utilization. The University of Michigan Rogel Cancer Center initiated the chemotherapy remote care monitoring program (CRCMP) to proactively identify patients experiencing CINV and intervene before the need for urgent evaluation. METHODS: High-risk patients for CINV are identified by neurokinin-1 (NK-1) antagonist administration, enrolled in the CRCMP, and received a daily text message survey for 7 days after chemotherapy administration to report symptoms. Responses above a set threshold trigger a message to the team pharmacist for intervention. The primary outcome of 14-day unplanned healthcare use was evaluated before and after CRCMP implementation. RESULTS: In 8 months, 652 patients received an NK-1 antagonist (2,244 cycles) and 387 patients were enrolled in the CRCMP (59%). Text message response rate was 94%. Clinical pharmacists provided 248 interventions in 121 patient episodes meeting threshold criteria. Fourteen-day unplanned healthcare use was decreased in the CRCMP-enrolled NK-1 episodes (6.68% v 4.53%, P = .02). Admissions were numerically lower for those enrolling in CRCMP when only admissions for nausea were considered (0.63% v 0.35%, P = .33). CONCLUSION: The CRCMP allowed for real-time management of patient-reported CINV symptom burden based on patient-reported outcomes (PROs) and an electronic medical record-integrated SMS text questionnaire. Clinical pharmacists were key team members to manage patient symptoms. Enrollment in CRCMP significantly reduced overall unplanned healthcare utilization. Although these changes were numerically small, any reduction in unnecessary care utilizing PROs can contribute to high-value care for patients with cancer.

Late-onset complications with bendamustine versus CHOP or CVP based chemoimmunotherapy in indolent Non-Hodgkin's lymphoma.

Bendamustine is a preferred first-line chemoimmunotherapy regimen for indolent non-Hodgkin's lymphoma (iNHL). Emerging evidence suggests an increased incidence of late-onset complications with bendamustine-based regimens compared with CHOP/CVP; however, this evidence is limited. We retrospectively compared late-onset complications from January 2005 to May 2020 in adults with previously untreated iNHL who received rituximab or obinutuzumab with CHOP, CVP, or bendamustine. Forty-six patients received CHOP/CVP; 119 received bendamustine. No difference in incidence of late-onset infections was observed. Bendamustine led to a higher rate of prolonged and unresolved lymphocytopenia and a greater incidence of late-onset neutropenia. Many patients receiving bendamustine did not have lymphocyte recovery even three years following administration. Ongoing infection prophylaxis with bendamustine-based regimens may offset translation of these laboratory findings to late-onset infectious risk.

Optimal sequence of daratumumab and elotuzumab in relapsed and refractory multiple myeloma.

Daratumumab and elotuzumab have demonstrated improvements in overall response rates (ORR) and progression-free survival (PFS) in relapsed/refractory multiple myeloma (RRMM). There is a lack of comparative clinical trials and an even larger lack of consensus on the optimal integration of these novel agents into the treatment paradigm. Clinical outcomes were compared retrospectively in 37 patients who received daratumumab before elotuzumab (dara-first, n = 23) and patients who received elotuzumab before daratumumab (elo-first, n = 14). ORR to the first monoclonal antibody was not different (dara-first 56.5% vs. elo-first 64.3%, p = .641). ORR to the second antibody differed when daratumumab was given second compared to when elotuzumab was given second (64.3% vs. 34.8%, respectively; p = .081). Cumulative PFS for elo-first was significantly longer than dara-first (22.67 months vs. 10.5 months, respectively; p = .001). Response rates to daratumumab may be preserved irrespective of sequence. However, response rates to elotuzumab may diminish with prior daratumumab exposure.

Contemporary treatment options for a classical disease: Advanced Hodgkin lymphoma.

Advanced classical Hodgkin lymphoma (cHL) is a rare lymphoid disease characterized by the presence of Hodgkin and Reed-Sternberg (HRS) cells. Each year, cHL accounts for 0.5% of all new cancer diagnoses and about 80% are diagnosed with advanced stage disease. Given the significant improvement in cure rates, the focus of treatment has shifted towards minimization of acute and long-term toxicities. PET-adapted strategies have largely been adopted as standard of care in the United States in an attempt to balance toxicities with adequate lymphoma control. However, the appropriate upfront chemotherapy regimen (ABVD versus eBEACOPP) remains controversial.

Impact of a vincristine dose cap on the incidence of neuropathies with DA-EPOCH-R for the treatment of aggressive lymphomas.

The CALGB/Alliance 50303 trial found a fivefold increase in the rate of severe neuropathies with DA-EPOCH-R compared to R-CHOP. A likely cause is a higher, uncapped dose of vincristine which is unique to DA-EPOCH-R. Due to a potential for increased toxicity and a paucity of literature confirming improved efficacy with higher vincristine doses, our institution implemented a 2 mg vincristine dose cap with DA-EPOCH-R. We conducted a single-center, retrospective cohort study assessing rates of neuropathy in patients receiving DA-EPOCH-R with or without a 2 mg vincristine dose cap. Patients who received a 2 mg vincristine dose cap had a significant reduction in the incidence of grade 2+ neuropathy (40.9% vs. 84.1%, p = .001) and a significantly longer time to onset of grade 2+ neuropathy (not reached vs. 63 days, p = .001). A vincristine dose cap of 2 mg per cycle may reduce the neurotoxicity-associated morbidity of DA-EPOCH-R.