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.

Impact of Chemotherapy Educational Videos for Patients with Acute Myeloid Leukemia.

Patient education in acute myeloid leukemia (AML) has become increasingly complex with the introduction of new treatments and chemotherapy regimens. Video education presents an opportunity to supplement traditional patient education and address some of the gaps associated with standard methods. This single-center study sought to assess the potential impact of supplemental video education on patients receiving induction chemotherapy for AML. Participants were consented to be randomized to receive their education with or without a supplemental video designed for their treatment regimen. We then provided a survey to each participant to assess knowledge retention, anxiety, and overall satisfaction with their care. Patients that received video education were found to have significantly improved knowledge retention compared to those that did not. There were no differences detected in anxiety or patient satisfaction. Video education appears to be an effective supplemental method for patient education in AML. Limitations include the single-center nature of the study at an urban academic medical center with a relatively well-educated, primarily Caucasian, younger population. Future research is warranted to assess the video in a diverse set of languages and to explore its broader benefits.

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.

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.

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.

A review of CD19-targeted immunotherapies for relapsed or refractory acute lymphoblastic leukemia.

Aim Novel immunotherapies have generated high response rates and unique adverse effects among patients with relapsed or refractory acute lymphoblastic leukemia. Therapies engaging endogenous T-cells against acute lymphoblastic leukemia are emerging for children and adults with various poor prognostic factors, thus accurate knowledge of immunotherapies is necessary for their effective implementation in the future. In this review, we evaluate clinical trial data regarding chimeric antigen receptor T-cells and blinatumomab, for the treatment of relapsed or refractory acute lymphoblastic leukemia. Summary In the relapsed or refractory setting, response rates rapidly diminish after subsequent lines of chemotherapy and cumulative toxicities may cause significant patient harm. Immunotherapies provide an approach to improve response rates and minimize traditional toxicities via novel mechanisms of action. Two therapies targeting CD19 antigens expressed on B-cell acute lymphoblastic leukemia lineages, chimeric antigen receptor T-cells, and blinatumomab have induced complete remissions among high-risk patient populations, especially those refractory to multiple therapies. Adverse effects such as cytokine release syndrome and neurologic sequelae remain serious precautions of each therapy. Conclusion Knowledge of immunotherapy mechanisms and clinical outcomes associated with immunotherapies is critical for the optimization of treating patients with relapsed or refractory acute lymphoblastic leukemia. Future use of chimeric antigen receptor T-cells and blinatumomab demands proper assessment of a patient's disease and treatment history in addition to unique monitoring and supportive care interventions.

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.

Rational use of rasburicase for the treatment and management of tumor lysis syndrome.

Purpose There is a lack of high-level evidence identifying meaningful outcomes and the optimal place in therapy of rasburicase in patients with, or at high risk for tumor lysis syndrome. The primary objective of this study was to evaluate and characterize outcomes resulting from an institution-specific guideline emphasizing supportive care, xanthine oxidase inhibitors, and lower doses of rasburicase. Methods In this retrospective chart review, we compared conservative rasburicase dosing, in accordance with newly developed UMHS tumor lysis syndrome guidelines, with aggressive rasburicase in adult patients (≥ 18 years of age) with hematological or solid tumor malignancies, and a uric acid level between 8 and 15 mg/dL. The primary efficacy outcome assessed the difference in the proportion of patients achieving a uric acid level <8 mg/dL within 48 h using a one-sided noninferiority test. The principle safety outcomes analyzed included incidence of acute kidney injury and hemodialysis requirement. Results One hundred sixty-one patients met inclusion criteria and were included in the study. Within 48 h of an elevated uric acid level, treatment was successful in 97.03% of patients in the conservative group, as compared with 98.33% in the aggressive group (difference, 1.3 percentage points; 95% confidence interval [CI], -3.33 to 5.93). Furthermore, there was no difference in the proportion of patients requiring hemodialysis (2.97% vs. 10.0%, p-value 0.079), or incidence of acute kidney injury (4.0% vs. 12.5%, p-value 1.00) between the treatment group and control group, respectively. Conclusions Conservative rasburicase use was noninferior to aggressive rasburicase use in patients with or at high risk for tumor lysis syndrome.

Risk factors and impact of Clostridium difficile recurrence on haematology patients.

Objectives: The incidence of Clostridium difficile infection (CDI) in adults with malignancy is 7%-14% compared with 1%-2% in the general hospitalized population. Despite the increased incidence of CDI in this population, a major concern is the propensity of CDI to recur, leading to delays in therapy impacting outcomes. We conducted a retrospective case-control study to identify risk factors for recurrent CDI (rCDI) and to determine the impact of rCDI on adult patients with a haematological malignancy. Methods: Adult haematology patients with CDI from June 2010 to December 2014 were divided into two groups: rCDI and non-rCDI. Multivariable models using logistic regression were constructed to identify risk factors for rCDI. Results: A total of 100 patients in our study yielded a 41% recurrence rate. CDI impacted chemotherapy significantly more in the rCDI group (53.7% versus 11.9%, P <0.001), primarily due to interruptions in established treatment plans (46.3% versus 10.3%, P <0.001). Risk factors for rCDI identified at index included salvage lymphoma chemotherapy (OR 9.64, 95% CI 1.02-91.15, P = 0.048) and severe CDI (OR 4.82, 95% CI 1.31-17.66, P = 0.018). Longitudinal risk factors included exposure to fluoroquinolones (OR 3.96, 95% CI 1.04-15.15, P = 0.044), ceftriaxone (OR 18.93, 95% CI 1.27-281.95, P = 0.033) and piperacillin/tazobactam (OR 10.4, 95% CI 1.81-59.64, P = 0.009). Conclusions: Haematology patients exhibit a higher rate of rCDI than general hospitalized patients. Utilization of this multivariable model to guide index CDI therapy at index may help to decrease the rCDI and prevent delays or interruptions in chemotherapy.

Risk factors for subtherapeutic levels of posaconazole tablet.

Background: Posaconazole is the prophylactic antifungal of choice for patients with haematological malignancies at high risk of invasive fungal infections (IFIs). Studies have demonstrated that subtherapeutic concentrations of posaconazole are associated with breakthrough fungal infections and specific risk factors for subtherapeutic troughs associated with the suspension formulation have been identified. However, these risk factors have not been evaluated in a large patient population with the recently approved tablet formulation. Objectives: To determine the risk factors for subtherapeutic posaconazole troughs associated with the tablet formulation in patients receiving posaconazole as IFI prophylaxis. Patients and methods: From 1 February 2013 to 31 March 2015 all posaconazole serum trough concentrations were evaluated. A total of 157 patients receiving posaconazole tablet for prophylaxis during induction therapy for haematological malignancies and allogeneic stem cell transplant recipients with graft-versus-host disease were included for analysis. Results: Overall, 28 patients (18%) had subtherapeutic troughs (<700 ng/mL). Patients were more likely to have subtherapeutic troughs if they had diarrhoea (n = 24; 83%) (P < 0.001), were receiving a proton pump inhibitor (n = 27; 93%) (P = 0.016) and weighed >90 kg (n = 14; 48%) (P = 0.047). Conclusions: While the posaconazole tablet has provided more consistent therapeutic concentrations when compared with the suspension there may still be a role for therapeutic drug monitoring (TDM). These results may guide us to a specific population in which TDM is necessary to identify subtherapeutic troughs.