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.

Real world outcomes in patients with Philadelphia chromosome positive acute lymphoblastic leukemia undergoing allogeneic stem cell transplantation-A single institution experience.

Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) has been associated with a worse prognosis compared to Ph negative ALL. Tyrosine kinase inhibitor (TKI) therapy has led to an improvement in response rates and survival, thus becoming a critical component of therapy. We performed a retrospective cohort study of Ph+ ALL patients treated at the University of Michigan who received TKI therapy pre- and post-allogeneic hematopoietic stem cell transplant (HSCT) from April 2007 to November 2019. The study included 40 patients with Ph+ ALL (47.5% female) with a median age of 54 (24-69) years. Median event-free survival (EFS) was not reached, with a 5-year EFS of 61%. Median overall survival (OS) was not reached, with a 5-year OS of 71%. There was no difference in 2-year EFS or OS for patients on pre-transplant imatinib or dasatinib (p = 0.16, 0.09, respectively), though definitive conclusions are challenging as post-transplant TKI therapy was variable. The incidence of any grade acute graft-versus-host disease (GVHD) was 62.5% (25/40) and any grade chronic GVHD was 77.5% (31/40). Complete molecular remission (CMR) was achieved in 57.5% of patients pre-transplant with no significant difference when stratified by induction TKI (p = 1). Achievement of CMR pre-HSCT showed a trend towards improved 2-year EFS (p=0.0198) but did not significantly change 2-year OS (p = 1). Patients receiving 1st and 2nd generation TKIs pre- and post-HSCT seem to have favorable outcomes, although type of TKI (pre-HSCT) did not significantly impact EFS or OS. In addition, attaining a CMR pre-transplant improved EFS, but did not change OS.

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.

NCCN Guidelines® Insights: Myelodysplastic Syndromes, Version 3.2022.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and management of patients with MDS based on a review of clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts meets on an annual basis to update the recommendations. These NCCN Guidelines Insights focus on some of the updates for the 2022 version of the NCCN Guidelines, which include treatment recommendations both for lower-risk and higher-risk MDS, emerging therapies, supportive care recommendations, and genetic familial high-risk assessment for hereditary myeloid malignancy predisposition syndromes.

Identification of variant APL translocations PRKAR1A-RARα and ZBTB16-RARα (PLZF-RARα) through the MI-ONCOSEQ platform.

The cornerstone of management in patients with acute promyelocytic leukemia (APL) is early diagnosis and prompt initiation of treatment with an all-trans retinoic acid (ATRA)-based regimen. Identification of the t(15;17)(PML-RARA) chromosomal translocation through conventional cytogenetics fluorescence in-situ hybridization (FISH) or detection of the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) fusion through RT-PCR represent the current standard of care for diagnosing APL. However, about 1-2% of patients with APL have a variant translocation involving other fusion partners with RARα besides PML. These patients present a unique diagnostic and clinical challenge in that conventional cytogenetics in addition to FISH and/or RT-PCR for PML-RARα may fail to identify these clinically relevant genetic lesions leading to an inappropriate diagnosis and treatment. We present two cases of patients who had APL with variant translocations whose bone marrow specimens were sent to the University of Michigan for enrollment in the MI-ONCOSEQ study (HUM00067928) after standard testing failed to identify PML-RARα or t(15;17) despite a phenotypic concern for this diagnosis. In these two patients, whole exome and transcriptome profiling via the MI-ONCOSEQ platform identified a PRKAR1A-RARα fusion in one patient and ZBTB16-RARα fusion in another patient. These cases illustrate the utility of whole exome and transcriptome profiling in diagnosing variant translocations in patients in whom there is a high clinical suspicion for APL based on hematopathology review.

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.

Novel therapeutic approaches in polycythemia vera.

Polycythemia vera (PV) is the most common Philadelphia chromosome-negative myeloproliferative neoplasm. Whereas low-risk patients are treated with aspirin and phlebotomy, high-risk patients receive cytoreductive therapy, which most commonly consists of hydroxyurea in the United States. Concerns about the long-term safety of hydroxyurea, as well as a desire for more efficacious and targeted therapy, have led to the development of novel therapies for high-risk patients with PV. Pegylated interferon (IFN) has shown promise in phase 2 studies of PV, and preliminary data from ongoing phase 3 studies suggest noninferiority as a frontline therapy. Efficient count control, tolerability, and even molecular responses as a salvage therapy have been demonstrated. Ropeginterferon-α-2b, a monopegylated IFN with a longer half-life and less frequent dose interval compared with recombinant or pegylated IFN, is an impressive agent in development. Ruxolitinib has a proven role as second-line therapy for PV, but an ongoing trial combining ruxolitinib and IFN as salvage therapy is under way. Early-phase clinical trials have also suggested that MDM2 inhibitors such as idasanutlin and histone deacetylase inhibitors should continue in their development. If these novel agents are able to modify the natural history of PV, the treatment paradigm in newly diagnosed patients will evolve from risk-adapted or reactive treatment toward early interventions.

Contemporary Use of Interferon Therapy in the Myeloproliferative Neoplasms.

PURPOSE OF REVIEW: The purpose of this article is to review the current evidence behind interferon therapy in patients with myeloproliferative neoplasms. RECENT FINDINGS: Preliminary analysis suggests that interferon may be non-inferior to hydroxyurea in patients with polycythemia vera and essential thrombocytosis. Responses have been observed regardless of JAK2 mutational status, but the presence of non-JAK2 somatic mutations may negatively influence response rates. Pegylated interferon has proven efficacy for patients with myeloproliferative neoplasms. Both newly diagnosed and previously treated patients with polycythemia vera and essential thrombocytosis exhibit high hematologic response rates, and some of these patients achieve molecular responses as well. Interferon therapy leads to lower rates of hematologic response in MF patients, but patients earlier on in their disease course have a better chance of responding. There are ongoing trials comparing pegylated interferon to hydroxyurea in essential thrombocytosis (ET) and polycythemia vera (PV), and early analysis suggests non-inferiority. However, longer follow-up is needed before drawing any conclusions. Future research is needed to better define characteristics of the best responders and to determine whether novel forms of interferon therapy or combination therapy with interferon can enhance efficacy and tolerability.

Left Atrial and Left Atrial Appendage 4D Blood Flow Dynamics in Atrial Fibrillation.

BACKGROUND: Atrial 4D flow magnetic resonance imaging was used for the characterization of left atrial (LA) and left atrial appendage (LAA) flow dynamics in patients with atrial fibrillation (AF). METHODS AND RESULTS: 4D flow magnetic resonance imaging measured in vivo 3D blood flow velocities in 60 AF patients and 15 controls. Anatomic maps of LA and LAA stasis and velocity were calculated to quantify atrial peak velocity, mean velocity, and stasis (velocities <0.1 m/s). In a substudy with 30 AF patients, 4D flow metrics were compared with Doppler transesophageal echocardiography. For all 15 controls, LAA mean and peak velocities were consistently lower (by 21%/12%; P<0.001) while LAA stasis was higher (by 58%; P<0.001) compared with the LA. In contrast, lower LAA velocity and increased LAA stasis were only found in a fraction (38 of 60) of AF patients. In AF patients, increased CHA2DS2-VASc score was associated with significantly (P<0.043) reduced LA velocities and elevated stasis. There was a heterogeneous expression of atrial flow dynamics, and 25% to 68% of AF patients demonstrated flow in the normal range: 25%/68% for LA/LAA stasis and 38%/60% for LA/LAA peak velocities. Transesophageal echocardiography velocities modestly but significantly (P<0.05) correlated with 4D flow-based LA velocities (r=0.41) and stasis (r=-0.39). CONCLUSIONS: AF resulted in overall impaired but individually variable flow dynamics in both the LA and LAA. AF patients demonstrated atrial flow in the normal range, despite elevated CHA2DS2-VASc score.

Path toward economic resilience for family caregivers: mitigating household deprivation and the health care talent shortage at the same time.

Rising costs and a workforce talent shortage are two of the health care industry's most pressing challenges. In particular, serious illnesses often impose significant costs on individuals and their families, which can place families at an increased risk for multigenerational economic deprivation or even an illness-poverty trap. At the same time, family caregivers often acquire a wide variety of health care skills that neither these caregivers nor the health care industry typically use. As these skills are marketable and could be paired with many existing medical certifications, this article describes a possible "path toward economic resilience" (PER) through a program whereby family caregivers could find meaningful employment using their new skills. The proposed program would identify ideal program candidates, assess and supplement their competencies, and connect them to the health care industry. We provide a set of practical steps and recommended tools for implementation, discuss pilot data on the program's appeal and feasibility, and raise several considerations for program development and future research. Our analysis suggests that this PER program could appeal to family caregivers and the health care industry alike, possibly helping to address two of our health care system's most pressing challenges with one solution.

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Aurora kinases are overexpressed in many cancers and are targets for anticancer drugs. The yeast homolog of Aurora B kinase, IPL1, was found to be a ploidy-specific lethality gene. Given that polyploidization is a common feature of many cancers, we hypothesized polyploidization also sensitizes mammalian cells to inhibition of Aurora kinases. Using two models of apparent diploid vs. tetraploid cell lines (one based on the hepatocellular carcinoma cell line Hep3B and another on untransformed mouse fibroblasts), we found that tetraploid cells were more sensitive to Aurora B inhibition than their diploid counterparts. Apoptosis could be induced in tetraploid cells by two different Aurora B inhibitors. Furthermore, tetraploid cells were sensitive to Aurora B inhibition but were not affected by Aurora A inhibition. Interestingly, the underlying mechanism was due to mitotic slippage and the subsequent excessive genome reduplication. In support of this, abolition of cytokinesis with dihydrocytochalasin B resulted in similar effects on tetraploid cells as Aurora B inhibition. These results indicate that inhibition of Aurora B or cytokinesis can promote apoptosis effectively in polyploid cancer cells.