Real-world outcomes with immunosuppressive therapy for aplastic anemia in patients treated at the University of Michigan.

Aplastic anemia (AA) is a rare bone marrow failure disorder that is treated with either allogeneic stem cell transplant or immunosuppressive therapy (IST) consisting of antithymocyte globulin (ATG), cyclosporine (CSA), and eltrombopag. While outcomes are favorable in younger patients, older patients (>60) have significantly worse long-term survival. The dose of ATG is often reduced in older patients and those with multiple comorbidities given concerns for tolerability. The efficacy and safety of dose-attenuated IST in this population is largely undescribed. We performed a retrospective review of patients with AA treated with IST. Our analysis was confounded by changes in practice patterns and the introduction of eltrombopag. We identified 53 patients >60 years old, of which, 20 received dose-attenuated IST, with no statistically significant difference in overall survival between full and attenuated dose cohorts. Overall response rates in both cohorts were similar at 6 months at 71% and 68%. There were more documented infectious complications in the full dose cohort (13 vs. 3). This supports the consideration of dose-attenuated IST in older patients with concerns about tolerance of IST. Lastly, our data confirmed favorable outcomes of younger patients receiving IST, especially in combination with eltrombopag.

Evaluating the efficacy and toxicity of dose adjusted pegylated L-asparaginase in combination with therapeutic drug monitoring.

The incorporation of pediatric-inspired regimens in the adolescent-young-adult (AYA) and adult populations have resulted improved survival outcomes (Stock et al. Blood 133(14):1548-1559 2019; Dunsmore et al. J Clin Oncol 38(28):3282-3293 2020; DeAngelo et al. Leukemia 29(3):526-534 2015). Nonetheless incorporation of such regimens is limited by increased toxicity to asparaginase. Dosing strategies that reduce the weight-based dose of pegylated-L-asparaginase (PEG-asparaginase) utilizing activity monitoring have been shown to result in better tolerability of these regimens. The purpose of this study was to analyze the efficacy and safety of treating adults with Philadelphia chromosome negative (Ph-) ALL with pediatric-inspired regimens that incorporate PEG-asparaginase dose adjustments and asparaginase activity level monitoring. Patients aged 18-65 years initiated on pediatric-inspired regimens utilizing dose-reduced PEG-asparaginase with therapeutic drug monitoring-guided adjustments were included. The screening of 122 patients treated between 2015 and 2021 resulted in the inclusion of 54 patients. The median age of the cohort was 35 years (16-65 years), and median body mass index (BMI) was 30 kg/m2 (18.3-53.4 kg/m2). The 36-month survival estimate was 62.1% (95% CI 48.1-77.7%), and the median overall survival (OS) was 62.2 months (95% CI 35.1-89.3 months). In the AYA cohort, the 36-month survival was 71.2% (95% CI 55.8-91%) and the median overall survival was not reached. Survival was not significantly affected by immunophenotype or BMI. Discontinuation due to toxicity or hypersensitivity reactions was low at 11% and 9% respectively. The encouraging survival outcomes and favorable tolerability of this older population in the real-world setting support the use of individualized PEG-asparaginase dosing with PharmD-guided therapeutic drug monitoring.

Oncology stewardship in acute myeloid leukemia.

In recent years, an explosion of novel agents has shifted the treatment paradigm for patients with acute myeloid leukemia. The optimal place in therapy for many of these novel agents remains unknown due to limited guidance from national guidelines and the way these agents were studied prior to entering the market. A critical evaluation of the literature and incorporation of oncology stewardship principles can be helpful in determining an optimal place for these agents while being mindful of the overall cost that is associated with therapies. The purpose of this review is to critically evaluate the efficacy and safety data for five controversial agents and provide examples of the use of stewardship practices in determining their place in the treatment of acute myeloid leukemia.

Early Antibiotic Discontinuation or De-escalation in High-Risk Patients With AML With Febrile Neutropenia and Prolonged Neutropenia.

BACKGROUND: There is minimal data evaluating the safety of antibiotic de-escalation in patients with acute myeloid leukemia (AML) with fever and ongoing neutropenia. Therefore, this study evaluated antibiotic prescribing, infection-related outcomes, and patient outcomes of an antibiotic de-escalation initiative. PATIENTS AND METHODS: This pre-post quasiexperimental study included adult patients with AML hospitalized with febrile neutropenia. An antibiotic de-escalation guideline was implemented in January 2017, which promoted de-escalation or discontinuation of intravenous antipseudomonal ß-lactams. The primary outcome assessment was the incidence of bacterial infection in a historical control group before guideline implementation compared with an intervention group after guideline implementation. RESULTS: A total of 93 patients were included. Antibiotic de-escalation occurred more frequently in the intervention group (71.7% vs 7.5%; P<.001), which resulted in fewer days of therapy for intravenous antipseudomonal ß-lactams (14 vs 25 days; P<.001). Thirty-day all-cause mortality and length of hospitalization were not different between groups. However, the intervention group had significantly fewer episodes of Clostridioides difficile colitis (5.7% vs 27.5%; P=.007). CONCLUSIONS: Implementation of an antibiotic de-escalation guideline resulted in decreased use of intravenous antipseudomonal ß-lactams and fewer episodes of C difficile colitis, without adversely impacting patient outcomes. Additional studies are needed, preferably in the form of randomized controlled trials, to confirm these results.

Real world use of FLT3 inhibitors for treatment of FLT3+ acute myeloid leukemia (AML): A single center, propensity-score matched, retrospective cohort study.

BACKGROUND: Patients diagnosed with acute myeloid leukemia with a FLT3 mutation (FLT3+ AML) have historically had poor outcomes. While the addition of the FLT3 inhibitors to induction therapy has been shown to improve survival outcomes in FLT3+ AML, interactions and overlapping toxicities between FLT3 inhibitors and standard of care medications used during induction therapy (e.g. azole antifungals, anthracyclines) and logistical barriers have complicated their use. To avoid these concerns, our institution has opted to defer initiation of midostaurin until after completion of induction therapy. However, to our knowledge no study confirming the effectiveness of this strategy for real world FLT3 inhibitor use has been published. METHODS: We performed a single center, propensity-score matched, retrospective cohort study characterizing efficacy and safety of our strategy for use of FLT3 inhibitors in the treatment of FLT3+ AML. The primary outcome was median event-free survival (EFS), while secondary endpoints included median overall survival (OS), overall response rate (ORR), 30-day mortality, duration of neutropenia, duration of thrombocytopenia, consolidation cycle delays, documented infections, and all-cause hospital readmission. RESULTS: A total of 83 FLT3+ AML patients treated with intensive induction therapy were included in the study, of whom 48 were propensity-score matched and analyzed. Baseline characteristics were similar between the patients who received a FLT3 inhibitor after induction therapy and the historical control arm. Median EFS was not significantly different but compared favorably between the FLT3 inhibitor cohort and historical controls (not reached vs 8 months, p = 0.343) with 18-month EFS of 54% and 43% for the two cohorts, respectively. Similarly, no significant differences were noted with regard to median OS (not reached vs 28.7 months, p = 0.752), ORR (79.2% vs 79.2%), or safety outcomes between groups. CONCLUSION: Compared to historical controls, addition of a FLT3 inhibitor to intensive chemotherapy post-induction may improve EFS or OS in a real world patient cohort with longer follow-up and a larger sample size. The omission of midostaurin in induction allowed for the use of an azole antifungal and the intensification of anthracycline dose may have contributed to high remission rates in both groups.

Clinical Availability of ATRA for Patients With Suspected Acute Promyelocytic Leukemia: Why Guidelines May Not Be Followed.

BACKGROUND: All-trans retinoic acid (ATRA) serves as the backbone of the management of patients with acute promyelocytic leukemia (APL), with guidelines recommending the initiation of ATRA as soon as APL is suspected. As a regional referral center for patients with acute leukemia, those who are suspected of having APL are often transferred to our facility. However, many referring centers are unable to initiate treatment using ATRA. We conducted an exploratory analysis of the clinical availability of ATRA and the factors limiting access to this critical drug. PATIENTS AND METHODS: The United States was divided into 6 geographic regions: Northwest, Southwest, Central, Southeast, Northeast, and the Great Lakes. Twenty hospitals were randomly selected from states within each of these regions and were surveyed as to whether they typically treated patients with acute leukemia, the availability of ATRA at their institution, and reported reasons for not stocking ATRA (if not available). RESULTS: Less than one-third of hospitals queried (31%) had ATRA in stock. Neither the size of the hospital nor the hospital's status as academic versus nonacademic (53% vs 31%; P=.08) influenced ATRA availability. Of the hospitals that referred patients with APL, only 14% (7/49) had ATRA readily available. Hospitals that treated patients with APL were more likely to have ATRA available than referring centers (58% vs 14%; P=.000002). CONCLUSIONS: Nearly two-thirds of the hospitals surveyed that cared for patients with acute leukemia do not have ATRA immediately available. Moreover, the vast majority of hospitals that refer patients to other centers do not have ATRA. These findings should spur investigation into the impact of immediate ATRA availability on the morbidity and mortality of patients with APL. A call by hematologists nationwide to their formulary committees is warranted to ensure that this lifesaving medication is available to patients suspected of having APL.

Utility of methicillin-resistant Staphylococcus aureus (MRSA) nasal screening in patients with acute myeloid leukemia (AML).

BACKGROUND: Current literature has demonstrated the utility of the MRSA nasal screen as a de-escalation tool to decrease unnecessary anti-MRSA antibiotic therapy. However, data on the applicability of this test in patients with hematologic malignancy is lacking. METHODS: This is a single-center, retrospective cohort study of patients with acute myeloid leukemia (AML) with or without a history of hematopoietic cell transplant (HCT), with pneumonia and MRSA nasal screening with respiratory cultures obtained. The primary outcome was to determine the negative predictive value (NPV) of the MRSA nasal screen for MRSA pneumonia. Secondary outcomes included sensitivity, specificity, positive predictive value (PPV) of the MRSA nasal screen and prevalence of MRSA pneumonia. RESULTS: Of 98 patients with AML and pneumonia, the prevalence of MRSA pneumonia was 4.1% with confirmed positive MRSA respiratory cultures observed in 4 patient cases. In patients with confirmed MRSA pneumonia, 3 had positive MRSA nasal screens while 1 had a false negative result, possibly due to a long lag time (21 days) between MRSA nasal screen and pneumonia diagnosis. Overall, the MRSA nasal screen demonstrated 75% sensitivity and 100% specificity, with a PPV of 100% and a NPV of 98.9%. CONCLUSIONS: Given the low prevalence, empiric use of anti-MRSA therapy in those AML and HCT patients with pneumonia may not be warranted in clinically stable patients. For patients in whom empiric anti-MRSA antibiotics are initiated, nasal screening for MRSA may be utilized to de-escalate anti-MRSA antibiotics in patients with AML with or without HCT.

Correction to: Targeting and Therapeutic Monitoring of H3K27M-Mutant Glioma.

The original version of this review article unfortunately contained a mistake in the author group section.

Targeting and Therapeutic Monitoring of H3K27M-Mutant Glioma.

PURPOSE OF REVIEW: H3K27M is a frequent histone mutation within diffuse midline gliomas and is associated with a dismal prognosis, so much so that the 2016 CNS WHO classification system created a specific category of "Diffuse Midline Glioma, H3K27M-mutant". Here we outline the latest pre-clinical data and ongoing current clinical trials that target H3K27M, as well as explore diagnosis and treatment monitoring by serial liquid biopsy. RECENT FINDINGS: Multiple epigenetic compounds have demonstrated efficacy and on-target effects in pre-clinical models. The imipridone ONC201 and the IDO1 inhibitor indoximod have demonstrated early clinical activity against H3K27M-mutant gliomas. Liquid biopsy of cerebrospinal fluid has shown promise for clinical use in H3K27M-mutant tumors for diagnosis and monitoring treatment response. While H3K27M has elicited a widespread platform of pre-clinical therapies with promise, much progress still needs to be made to improve outcomes for diffuse midline glioma patients. We present current treatment and monitoring techniques as well as novel approaches in identifying and targeting H3K27M-mutant gliomas.

Successful use of blinatumomab in a patient with acute lymphoblastic leukemia and severe hepatic dysfunction.

Relapsed/refractory acute lymphoblastic leukemia poses a significant clinical challenge due to its poor prognosis, with survival rates of less than a year, even with novel therapies. Patients frequently experience toxicities from induction chemotherapy such as hepatotoxicity, which can limit therapeutic options upon relapse. Blinatumomab, a novel immunotherapy, has demonstrated excellent efficacy in relapsed/refractory acute lymphoblastic leukemia; however, there are limited data on use of this agent in patients with significant organ dysfunction. In this report, we describe the safe and effective use of blinatumomab in an adult patient with refractory Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia in the setting of severe hepatic dysfunction. Blinatumomab may represent a viable option to treat relapsed/refractory acute lymphoblastic leukemia in patients with significant hepatic dysfunction.

Role of caplacizumab in the treatment of acquired thrombotic thrombocytopenic purpura.

Acquired thrombotic thrombocytopenic purpura is a rare blood disorder with a high early mortality rate, if untreated. Standard of care plasma exchange and glucocorticoids have dramatically improved survival. However, additional advancements are necessary to further decrease mortality. Caplacizumab-yhdp (Cablivi®) is the first Food and Drug Administration-approved treatment indicated for adult patients with acquired thrombotic thrombocytopenic purpura, in combination with plasma exchange and immunosuppressive therapy. However, there are considerable risks associated with the use of caplacizumab and they must be weighed against the benefits of the medication.

The leukemia strikes back: a review of pathogenesis and treatment of secondary AML.

Secondary AML is associated with a disproportionately poor prognosis, consistently shown to exhibit inferior response rates, event-free survival, and overall survival in comparison with de novo AML. Secondary AML may arise from the evolution of an antecedent hematologic disorder, or it may arise as a complication of prior cytotoxic chemotherapy or radiation therapy in the case of therapy-related AML. Because of the high frequency of poor-risk cytogenetics and high-risk molecular features, such as alterations in TP53, leukemic clones are often inherently chemoresistant. Standard of care induction had long remained conventional 7 + 3 until its reformulation as CPX-351, recently FDA approved specifically for secondary AML. However, recent data also suggests relatively favorable outcomes with regimens based on high-dose cytarabine or hypomethylating agents. With several investigational agents being studied, the therapeutic landscape becomes even more complex, and the treatment approach involves patient-specific, disease-specific, and therapy-specific considerations.

Managing liver dysfunction in haematology patients: Switch antifungals, or use the tincture of time?

Liver function test (LFT) abnormalities are a common occurrence in haematology patients receiving antifungal therapies. The cause of elevated LFTs is often multifactorial. Posaconazole is associated with elevated LFTs in approximately 5%-10% of patients. Recently, DiPippo, et al demonstrated that switching to isavuconazole in such cases leads to a reduction in LFTs in the majority of patients. However, the LFTs in such patients may have declined with time while continuing on posaconazole therapy. We retrospectively assessed LFT kinetics in 157 AML patients receiving posaconazole for antifungal prophylaxis and found that in 27 patients who developed grade 2 or higher CTCAE hepatotoxicity, 85% (23/27) had lower LFTs at the end of posaconazole therapy, despite continuation in the setting of hepatotoxicity, and this change from maximum LFTs was statistically significant (P < 0.0001). Thus, the development of LFT abnormalities while on posaconazole therapy may not warrant a switch to an alternative, potentially less effective antifungal, as hepatotoxicity is often multifactorial and generally resolves with time in the majority of patients.

Successful use of cytarabine and bendamustine in a patient with mantle cell lymphoma and acute renal failure using intermittent hemodialysis: A case report.

Mantle cell lymphoma is a mature B-cell non-Hodgkin lymphoma characterized by the hallmark (11;14) chromosomal translocation, which often presents with lymphadenopathy and extra-nodal involvement. Young, fit patients are generally treated with chemotherapy approaches that incorporate high-dose cytarabine (e.g. the Nordic regimen) followed by autologous hematopoietic cell transplantation. Because of the significant activity of cytarabine in mantle cell lymphoma, increasingly, high- and intermediate-dose cytarabine are being used in the treatment of elderly mantle cell lymphoma patients. In practice, many patients present with significant organ dysfunction and there is limited data on the use of high- to intermediate-dose cytarabine and bendamustine in this setting. Here, we report a case of a critically ill, elderly patient with mantle cell lymphoma and concomitant acute kidney injury and oliguria who was successfully treated with a cycle of cytarabine (Ara-C) and bendamustine accompanied by intermittent hemodialysis.

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.

Development of the CNS TAP tool for the selection of precision medicine therapies in neuro-oncology.

The number of targeted therapies utilized in precision medicine are rapidly increasing. Neuro-oncology offers a unique challenge due to the varying blood brain barrier (BBB) penetration of each agent. Neuro-oncologists face a difficult task weighing the growing number of potential targeted therapies and their likelihood of BBB penetration. We developed the CNS TAP Working Group and performed an extensive literature review for the evidence-based creation of the CNS TAP tool, which was retrospectively validated by analyzing brain tumor patients who underwent therapy targeted based on genomic results from an academic sequencing study (MiOncoseq, n = 17) or private molecular profiling (Foundation One, n = 7). The CNS TAP tool scores relevant targeted agents by applying multiple variables (i.e., pre-clinical data, clinical data, BBB permeability) to patient specific genomic information and clinical trial availability. In the Michigan cohort, the CNS TAP tool predicted the selected agent 85.7% of the time. The CNS TAP tool predicted the agent independently selected by pediatric neuro-oncologists in the Colorado cohort 50% of the time. Patients with recurrent brain tumors treated with agents predicted by the CNS TAP tool demonstrated a median progression-free survival of 4 months and four patients with recurrent high-grade glioma maintained ongoing partial responses of at least 6 months. The CNS TAP tool is a formalized algorithm to assist clinicians select the optimal targeted therapy for neuro-oncology patients. The CNS TAP tool has relatively high concordance with selected therapies and clinical outcomes in patients receiving targeted therapy in this heterogeneous retrospective cohort were promising.

Successful reintroduction of blinatumomab in a patient with relapsed/refractory acute lymphoblastic leukemia following grade 4 cytokine release syndrome.

Relapsed/refractory acute lymphoblastic leukemia poses a clinical challenge due to its poor prognosis and lack of effective treatment. Blinatumomab, a novel immunotherapy, has demonstrated excellent efficacy in relapsed/refractory acute lymphoblastic leukemia; however, life-threatening toxicities such as cytokine release syndrome have been reported in pivotal clinical trials. In this report, we describe the safe reintroduction of blinatumomab in an adult patient with relapsed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia after experiencing grade 4 blinatumomab-induced cytokine release syndrome using a unique dosing strategy and a very diligent monitoring approach. As blinatumomab often represents a last-line therapeutic option for many patients, such a step-wise dosing approach and diligent monitoring plan may be useful in an attempt to retrial blinatumomab in patients who require reintroduction of therapy.