PD-1/PD-L1 inhibitor-induced immune thrombocytopenia: A pharmacovigilance study and systematic review.

INTRODUCTION: Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitors (ICIs) are used for a variety of cancers and are associated with a risk of developing immune-related adverse events, most commonly dermatitis, colitis, hepatitis, and pneumonitis. Immune-mediated hematologic toxicities have been reported, but are less well-described in the literature. Immune thrombocytopenia (ITP) is a rare autoimmune, hematologic adverse event that has been reported with PD-1/PD-L1 inhibitors. METHODS: We performed a retrospective observational analysis of the United States Food and Drug Administration Adverse Event Reporting System (FAERS) data. We searched for cases of ITP reported with exposure to PD-1/PD-L1 inhibitors from initial FDA approval for each agent to September 30, 2022. Disproportionality signal analysis was done by calculating the reporting odds ratio (ROR). Oxaliplatin was used as a positive control for sensitivity analysis as it is an anticancer therapy that has been associated with drug-induced ITP. A systematic review of the PubMed database was also conducted to identify published cases of PD-1/PD-L1 inhibitor-induced ITP. RESULTS: There were 329 reports of ITP with ICIs in the FAERS database that were reviewed for a disproportionality signal, including atezolizumab (n = 27), durvalumab (n = 17), nivolumab (n = 160), and pembrolizumab (n = 125). The ROR was significant for atezolizumab (ROR 5.39, 95 % CI 3.69-7.87), avelumab (ROR 10.32, 95 % CI 4.91-21.69), durvalumab (ROR 7.91, 95 % CI 4.91-12.75), nivolumab (ROR 9.76, 95 % CI 8.34-11.43), and pembrolizumab (ROR 12.6, 95 % CI 10.55-15.06). In our systematic review, we summated 57 cases of ICI-induced ITP. Nivolumab and pembrolizumab had the most reported cases of ITP in the literature. Most cases reported (53 %) included ITP-directed therapies beyond corticosteroids for the management of ICI-induced ITP. CONCLUSION: There is a significant reporting signal of ITP with several ICI agents. Clinicians should be aware of and monitor for signs of this potentially serious adverse event.

Post-Transplant Cyclophosphamide for the Prevention of Graft-vs.-Host Disease in Allogeneic Hematopoietic Cell Transplantation: A Guide to Management for the Advanced Practitioner.

Cyclophosphamide remains a critical component to haploidentical transplant conditioning regimens. Post-transplant cyclophosphamide (PTCy) emerged as an effective component of graft-vs.-host disease (GVHD) prophylaxis in the nonmyeloablative haploidentical bone marrow transplant setting. The relative ease of administration compared with ex vivo manipulations and efficacy in reducing GVHD has led to increasing PTCy use in transplant centers around the world. The role of PTCy has expanded to haploidentical transplantation with myeloablative conditioning regimens and peripheral blood progenitor cells as the donor source. Moreover, encouraging results in GVHD management have been shown with the use of PTCy alone or in combination with other immunosuppressives in the human leukocyte antigen-matched donor setting. The toxicity profile of cyclophosphamide varies extensively depending on dose, duration, overall drug exposure, and, potentially, pharmacogenetics. This review highlights the pharmacology, pharmacokinetics, and toxic effects of cyclophosphamide and offers practical guidance for clinical application in the post-transplant setting. We summarize data on the management of high-dose cyclophosphamide toxicities and provide insights into the pharmacogenetic implications on drug efficacy and safety data.

Real-world Experience of Caplacizumab for Adolescents in the First-line Setting: Case Reports.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a thrombotic microangiopathy resulting in high mortality. Caplacizumab is approved for treatment of adults with acquired thrombotic thrombocytopenic purpura that has shown faster platelet normalization, clinical improvement, and reduced risk of recurrent/refractory disease. We report 2 cases of adolescents treated off-label with caplacizumab who were able to stop before 30 days from end of plasma exchange after platelets normalized and ADAMTS13 activity recovered to >20% to 30%. Our results show similar efficacy to other reports of patients under 18 receiving caplacizumab in first line, regardless of plasma exchange strategy, and may offer insight into early cessation criteria.

Hepatitis B reactivation in patients with multiple myeloma treated with anti-CD38 monoclonal antibody-based therapies: a pharmacovigilance analysis.

BACKGROUND: Daratumumab and isatuximab are anti-CD38 monoclonal antibodies indicated for the treatment of multiple myeloma. These agents can increase the risk of infectious complications, including viral infections. Cases of hepatitis B virus (HBV) reactivation have been reported in the literature in patients receiving anti-CD38 monoclonal antibody-based therapies. AIM: The objective of this analysis was to determine if the association between anti-CD38 monoclonal antibody exposure and the development of hepatitis B reactivation had a detectable reporting signal in the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). METHOD: We conducted a post marketing pharmacovigilance analysis by querying the FAERS for reports of HBV reactivation with daratumumab or isatuximab exposure reported between 2015 and 2022. Disproportionality signal analysis was conducted by calculating reporting odds ratios (RORs). RESULTS: Sixteen cases of hepatitis B virus reactivation were reported in the FAERS database among patients receiving daratumumab or isatuximab reported between 2015 and 2022. The ROR for HBV reactivation was statistically significant for both daratumumab (ROR 4.76, 95% CI 2.76-8.22) and isatuximab (ROR 9.31, 95% CI 3.00-28.92). CONCLUSION: Overall, our analysis demonstrates a significant reporting signal for HBV reactivation with daratumumab and isatuximab.

Measuring the Impact of a Pharmacist-Driven Blood Factor Education Program: A Prospective, Single-Center Observational Study.

Introduction: Patients with bleeding disorders are best served by multidisciplinary teams. Pharmacists can play a critical role in the optimal management of patients with bleeding disorders through blood factor stewardship strategies and programs. An educational program was developed and implemented wherein a hematology pharmacist provided brief recorded lectures to an entire department of pharmacists in a multi-site health-system with the goal to improve the knowledge base and confidence among this population of general practitioners. Methods: The primary objective of this study was to evaluate the educational outcomes of a blood factor education program for pharmacists. The impact of the educational program was determined by measuring the difference in mean test scores between the pre- and post-program surveys. Results: The final analysis included 214 participants. The primary endpoint of mean competency test score was significantly improved in the post-test compared to pre-test (78.33% vs 52.83%; P < .0001). Any degree of test score improvement was observed in 99% (n = 212) of participants. Pharmacist confidence was significantly improved in all 20 domains of bleeding disorders and blood factor product verification and management. Conclusion: This program identified that most pharmacists in a large multi-site health-system were not familiar with bleeding disorders to a satisfactory degree, commonly because of the relative rare encounters with bleeding disorder-related orders, and that despite systems-based support there was an opportunity to improve practice through education. Such educational programming could be beneficial for the development of pharmacist-provided care and is a measure that could be implemented as part of blood factor stewardship initiatives.

Avatrombopag for the Treatment of Immune Thrombocytopenia and Periprocedural Thrombocytopenia Associated With Chronic Liver Disease.

Objective: To review the pharmacology, pharmacokinetics, clinical efficacy, safety, dosing and administration, and place in therapy of avatrombopag for the treatment of immune thrombocytopenia and chronic liver disease-associated thrombocytopenia. Summary: Avatrombopag is an orally administered thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenia and is the first oral thrombopoietin receptor agonist approved for the treatment of perioperative thrombocytopenia associated with chronic liver disease in adults. The efficacy and safety of avatrombopag has been demonstrated in a multicenter, randomized, double blind, placebo-controlled phase III study in the setting of immune thrombocytopenia and in 2 identically designed, multicenter, randomized, double blind, placebo-controlled phase III trials in the setting of thrombocytopenia associated with chronic liver disease. The most common adverse events reported in the clinical trials were headache, fatigue, and gastrointestinal toxicities. The incidence of bleeding events was comparable between the avatrombopag and placebo treatment groups in each study. Avatrombopag has not been shown to be associated with hepatoxicity and does not require food restriction like the other oral thrombopoietin receptor agonist for immune thrombocytopenia, eltrombopag. Also, unlike eltrombopag for immune thrombocytopenia, it can be dosed less frequently than once daily. Conclusion: Avatrombopag offers another safe and effective oral option for the treatment of immune thrombocytopenia without food restrictions and an alternative, transfusion-sparing option for thrombocytopenia associated with chronic liver disease patients undergoing surgery.

Acquired thrombotic thrombocytopenic purpura associated with immune checkpoint inhibitors: A real-world study of the FDA adverse event reporting system.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are used for a variety of cancers and are associated with a risk of developing immune-related adverse events, most commonly colitis, dermatitis, hepatitis, and thyroiditis. Rare autoimmune hematologic toxicities have been reported but are less well-described in the literature. Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening autoimmune condition that has been reported with ICIs but has been limited to case reports. METHODS: We performed a retrospective observational analysis of the United States Food and Drug Administration Adverse Event Reporting System (FAERS) data. We searched for cases of TTP reported with exposure to ICIs from initial FDA approval for each agent to December 31, 2021. Disproportionality signal analysis was done by calculating the reporting odds ratio (ROR). RESULTS: There were 35 reports of TTP with ICIs in the FAERS database, including atezolizumab (n = 7), durvalumab (n = 2), nivolumab (n = 18), and pembrolizumab (n = 8). The ROR was significant for atezolizumab (ROR 6.22, 95% CI 2.96-13.09), nivolumab (ROR 3.16, 95% CI 1.99-5.03), and pembrolizumab (ROR 2.56, 95% CI 1.28-5.12). CONCLUSIONS: There is a significant reporting signal of TTP with several ICI agents. Clinicians should be aware of and monitor for signs of this potentially serious adverse event.

Daratumumab for the Treatment of Multiple Myeloma: A Review of Clinical Applicability and Operational Considerations.

OBJECTIVE: To review the available data for the efficacy and safety of daratumumab in the treatment of multiple myeloma (MM), both in the newly diagnosed and relapsed/refractory settings, as well as provide additional guidance to clinicians on operational, safety, and supportive care considerations. DATA SOURCES: A literature search of PubMed (1966 to October 2021) was conducted using the keywords daratumumab, Darzalex, and myeloma. Data were also obtained from prescribing information and unpublished abstracts from meetings. STUDY SELECTION AND DATA EXTRACTION: All relevant published articles, prescribing information, and unpublished meeting abstracts on daratumumab for the treatment of MM were reviewed. DATA SYNTHESIS: Daratumumab is an anti-CD38 monoclonal antibody indicated for the treatment of MM. The addition of daratumumab to proteasome inhibitor and immunomodulatory drug-based regimens has led to a consistent improvement in progression-free survival and response rates in relapsed/refractory MM as per the POLLUX, CASTOR, APOLLO, and CANDOR trials. The ALCYONE and MAIA phase III trials have demonstrated an overall survival benefit when adding daratumumab to frontline regimens for transplant-ineligible patients with newly diagnosed MM. In transplant-eligible patients, daratumumab-based quadruplet regimens have improved depth of response in the CASSIOPIEA and GRIFFIN trials. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Operational and safety considerations that clinicians need to account for do exist, including different administration and infusion strategies, infusion-related reactions, increased risk for infectious complications, and interference with blood transfusion management. CONCLUSIONS: Daratumumab has led to a shift in the treatment paradigm of both newly diagnosed and relapsed/refractory MM, leading to improvements in outcomes such as response rates, depth of response, and progression-free survival.

Retrospective Analysis of Clinical Outcomes Associated With the Use of Pegfilgrastim On-body Injector in Patients Receiving Chemotherapy Requiring Granulocyte Colony-Stimulating Factor Support.

Objectives: Pegfilgrastim is a granulocyte colony-stimulating factor (G-CSF) used as primary prophylaxis in patients receiving myelosuppressive chemotherapy regimens that have greater than 20% risk of developing febrile neutropenia (FN). Historically, pegfilgrastim has been administered 24 to 72 hours after chemotherapy, necessitating a return to clinic to receive the provider-administered injection. An alternative option is the pegfilgrastim on-body injector (OBI). With the OBI device, patients have their pegfilgrastim administered 27 hours after receiving chemotherapy while remaining at home, avoiding an additional clinic appointment. Concerns with pegfilgrastim OBI include lack of experience with the device in both the patient and provider, device-related failures, and the success of delivery. This study evaluates pegfilgrastim OBI failure rates through associated patient outcomes among cancer patients receiving chemotherapy requiring G-CSF. Methods: A retrospective electronic chart review was conducted of adult patients with cancer who received chemotherapy and pegfilgrastim OBI from July 1, 2016, to July 31, 2018. The primary objective of this study was the incidence of FN in patients receiving pegfilgrastim OBI. Results: There were no reported cases of hospitalization due to FN in patients who received pegfilgrastim OBI. Dose delays and dosage modifications were not observed in our review. The OBI device failure rate was found to be low (1.92%). Conclusion: The low device failure rate from this study suggests that the OBI is a viable option for administration of pegfilgrastim in patients receiving chemotherapy requiring G-CSF.

Publication rates of hematology/oncology abstracts presented at major pharmacy association meetings.

INTRODUCTION: Professional conferences are where research findings are initially presented. Studies suggest many research ideas presented at conferences are never published. Previous studies have demonstrated that the full publication rate of abstracts presented at pharmacy meetings is approximately 20%. The objective of this study was to determine the full publication rate of hematology/oncology abstracts presented at major pharmacy organization annual meetings. METHODS: A systematic search of PubMed and Google Scholar was performed. Publication status was evaluated for hematology/oncology abstracts presented at annual meetings for the following organizations: American College of Clinical Pharmacy Annual Meeting, American Society of Health-System Pharmacists Midyear Clinical Meeting, Hematology/Oncology Pharmacy Association Annual Meeting, and International Society of Oncology Pharmacy Practitioners Annual Meeting. Data collected included the meeting of abstract presentation, number of authors, abstract study type, country of origin, journal of publication, and type of publication. Abstracts presented as trainee research were excluded. RESULTS: Of 451 oncology abstracts evaluated, the most common topic categories included pharmacotherapy (n = 244; 54.1%), clinical pharmacy practice (n = 84; 18.6%), and operational/compounding (n = 69; 15.3%). The overall publication rate was 17.5% (n = 79). Abstracts were published as full manuscripts over a spread of 48 different journals. Factors associated with full publication included abstracts with more than 5 authors (OR 3.86, 95% CI 2.32-6.43; p < 0.0001) and abstracts presented at oncology-focused pharmacy meetings (OR 2.92, 95% CI 1.49-5.72; p = 0.0018). CONCLUSION: This study showed an overall publication rate of 17.5% for abstracts presented at pharmacy meetings, consistent with prior studies.

Ibrutinib treatment via alternative administration in a patient with chronic lymphocytic leukemia and dysphagia.

INTRODUCTION: Ibrutinib is a small molecule inhibitor of Bruton's tyrosine kinase indicated for the treatment of a variety of B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, and Waldenstrom's macroglobulinemia. These indolent hematologic malignancies are considered diseases of the elderly, a population that may have dysphagia leading to difficulty swallowing tablets and capsules. Ibrutinib is currently not available in a liquid oral dosage form. We report the utilization and clinical outcomes associated with alternative administration of ibrutinib capsules in a patient with chronic lymphocytic leukemia and significant dysphagia. CASE REPORT: An 86-year old female requiring chronic lymphocytic leukemia-directed therapy due to a rising absolute lymphocyte count and worsening, transfusion-dependent anemia with a past medical history of dementia and dysphagia, was initiated on ibrutinib. MANAGEMENT & OUTCOME: Due to the patient's significant inability to swallow, ibrutinib capsules were administered via an alternative method by opening them and sprinkling onto soft food or applesauce. With ibrutinib therapy, the patient has had a significant clinical response in her chronic lymphocytic leukemia as evidenced by her decreased absolute lymphocyte count and achieving transfusion independence with improvements in hemoglobin. DISCUSSION: Ibrutinib administration via this alternative method resulted in an initial clinical response in the treatment of our patient's chronic lymphocytic leukemia as evidenced by a decreasing absolute lymphocyte count and improved anemia that achieved transfusion independence. The patient has maintained this response to therapy after approximately 1 year at the time of manuscript preparation.

Evaluation of Montelukast for the Prevention of Infusion-related Reactions With Daratumumab.

BACKGROUND: Daratumumab is an anti-CD38 monoclonal antibody indicated for the treatment of multiple myeloma. Infusion-related reactions (IRRs) are among the most common adverse events associated with daratumumab. IRRs are most common with the first infusion of daratumumab. Recommended premedications to be given prior to the daratumumab dose include acetaminophen, diphenhydramine, and a corticosteroid. There is emerging data to suggest that the addition of montelukast to this premedication regimen can lower the incidence of daratumumab-related IRRs. PATIENTS AND METHODS: This was a single-center, retrospective chart review conducted at a large, multistate health system with several different hematology/oncology practice sites. Eligible patients included those with a primary diagnosis of a plasma cell disorder who received at least 1 dose of daratumumab. The primary outcome was the incidence of IRRs with the first daratumumab infusion. RESULTS: A total of 141 patients receiving daratumumab-based therapy were included in this study. All patients received acetaminophen, diphenhydramine, and a corticosteroid as premedications prior to the first infusion of daratumumab. Overall, 46 (33%) patients experienced an IRR with the first infusion of daratumumab. The incidence of IRR was lower in patients that received montelukast as a premedication compared with those that did not (montelukast, n = 25 [27%]; no montelukast, n = 21 [45%]; P = .0371). Patients in each arm experienced similar rates of overall, composite pulmonary, gastrointestinal, and systemic IRR manifestations. CONCLUSION: The use of montelukast prior to the first daratumumab infusion led to a reduction in the incidence of IRRs in our experience.

Safety and Cost Benefits of the Rapid Daratumumab Infusion Protocol.

INTRODUCTION: Daratumumab is approved for the treatment of multiple myeloma in both frontline and relapsed/refractory settings. Its major limitation is the long infusion time, especially with the first dose. Recent data demonstrated the feasibility of infusing daratumumab at an accelerated rate of 90 minutes starting from cycle 1 on day 15. Herein, we report the safety profile and cost associated with rapid daratumumab infusion protocol. PATIENTS AND METHODS: A chart review was performed to identify patients who completed at least 1 cycle of daratumumab (single agent or in combination) from April 2016 to October 2018. Patients were divided into 2 cohorts: cohort 1 received rapid daratumumab infusion after its implementation in March 2018, whereas cohort 2 included patients treated with daratumumab administered at the standard rate. The primary endpoint was to compare differences in rates of infusion-related reactions (IRRs). An Excel (Microsoft)-based model was developed to estimate cost and productivity. RESULTS: A total of 100 patients with relapsed/refractory disease were included in this study (53 in cohort 1 and 47 in cohort 2). Of the 53 patients in cohort 1, 18 (34%) received rapid daratumumab infusion starting with cycle 1. Overall, there was no statistically significant difference in rates of IRRs between cohort 1 and 2 (1.9% vs. 4.3%, P = .59); 1 patient in cohort 1 developed an IRR. The total costs estimated for a 52-week regimen of daratumumab infused at standard and rapid rates were $137,200 and $122,200 (P < .001), respectively. CONCLUSION: Our findings indicate that rapid daratumumab infusion is safe and tolerable and provides cost savings for patients with relapsed/refractory disease.

A Review of Growth Factor Support in Bloodless Autologous Hematopoietic Stem Cell Transplant.

Bloodless autologous hematopoietic cell transplantation is associated with risks of severe bleeding and profound anemia. RBC or platelet transfusions are often used to prevent these hematologic complications. However, in patients such as Jehovah's Witnesses who refuse major blood components, the lack of transfusion support is not an absolute contraindication to an autologous hematopoietic cell transplant. Pennsylvania Hospital performed the world's first bloodless hematopoietic cell transplant more than 15 years ago and has gradually improved its technique with a sizable patient population. Erythropoiesis-stimulating agents were successfully employed as part of their pretransplant regimen to prevent severe anemia. Thrombopoietin agonists' potential role in bloodless transplant is also currently being explored. Although there is limited literature, available reports in combination with physiologic reasoning may support the use of these growth factors to promote transplant success. These agents offer potential benefit and may be of utility in minimizing complications of a bloodless transplant. In this review, we summarize the available literature and offer insight into how we may incorporate growth factors to allow bloodless autologous hematopoietic cell transplantation to be an available option to patients who may otherwise be denied.

Ibrutinib for the treatment of Bing-Neel syndrome, a complication of Waldenström macroglobulinemia: Patient case report.

Bing-Neel syndrome is a rare complication of Waldenström macroglobulinemia, characterized by infiltration of lymphoplasmacytic cells to the central nervous system. Multiple treatment modalities exist including purine analogs, bendamustine, high-dose methotrexate, or high-dose cytarabine. Of interest, ibrutinib, a Bruton tyrosine kinase inhibitor has also displayed efficacy in Bing-Neel syndrome. Current literature is limited for the treatment of Bing-Neel syndrome considering its rarity, and while ibrutinib is indicated for the treatment of Waldenström macroglobulinemia, it is utilized off-label for treatment of Bing-Neel syndrome. Additionally, debate exists regarding the recommended dosing strategy for ibrutinib for this indication with disease remission demonstrated at 560 mg and 420 mg. We present a case report that provides additional evidence for this debate with a patient who received 560 mg of ibrutinib initially and maintained disease control despite a dose reduction to 420 mg for tolerability. Ultimately, more data are needed to develop standardized Bing-Neel syndrome treatment strategies with specific consideration to the use of ibrutinib in this condition.

A clinical pharmacy pilot within a Precision Medicine Program for cancer patients and review of related pharmacist clinical practice.

PURPOSE: The implementation, benefits, and challenges of clinical pharmacist services within a Precision Medicine Program for cancer patients are described. By relating the practice model that was developed, this report may further encourage pharmacists at cancer centers nationally to be involved and lead precision-based care in the oncology setting. SUMMARY: A clinical pharmacist was integrated into a Precision Medicine Program for oncology patients using somatic testing to identify actionable mutations and apply targeted therapy to malignancies. This pharmacist served as a drug resource for the program's molecular tumor board and oncologists seeking precision-based oncologic strategies. The pharmacist was a facilitator of drug assistance and dispensing in collaboration with the specialty pharmacy and provided care to 14 oncology patients receiving precision-based therapies. The clinical pharmacist was readily accepted as an addition to the team by both oncologists and patients and the experience served as an important learning opportunity. CONCLUSION: The success of integrating this precision medicine pharmacist into a newly formed Precision Medicine Program and the model it can serve as may be considered for other cancer centers that may or may not have easily accessible pharmacogenomic experts and resources. This service highlights the importance of pharmacist care in such a program and the various opportunities for integration. Oncology clinical pharmacists should seek to integrate into Precision Medicine Programs and systems directing this care and develop their knowledge and understanding of genomics to continue providing the highest level of cancer care as a pivotal member of the cancer care team.