The great imitator: Tuberculosis with lymphadenopathy and splenomegaly.

Tuberculosis (TB) is a leading infectious killer worldwide. Over two-thirds of new TB diagnoses in the United States occur among first-generation immigrants, especially within a year of migration. Hodgkin lymphoma (HL) accounts for a minority of lymphoma cases but presents similarly to disseminated or extrapulmonary TB. Clinical overlap between TB and HL increases patient risk of misdiagnosis. Concomitant presentation of both diseases is not uncommon but infrequently reported. We present a case of isoniazid-resistant TB with progressively worsening lymphadenopathy and splenomegaly despite appropriate TB treatment. The patient was diagnosed with HL following PET/CT and axillary lymph node biopsy.

The Coagulopathy of Acute Promyelocytic Leukemia: An Updated Review of Pathophysiology, Risk Stratification, and Clinical Management.

Acute promyelocytic leukemia (APL) has a well-established mechanism and a long-term prognosis that exceeds that of any other acute leukemia. These improving outcomes are due, in part, to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), two targeted and highly active agents in this disease. However, there remains a considerable morbidity and mortality risk in APL secondary to clinically significant hemorrhagic and/or thrombotic events. Prevention and treatment of these coagulopathic complications remain significant impediments to further progress in optimizing outcomes for patients with APL. Moreover, the relative rarity of APL hinders adequately powered randomized controlled trials for evaluating APL coagulopathy management strategies. This review draws from peer-reviewed works falling between initial descriptions of APL in 1957 and work published prior to January 2023 and provides an updated overview of the pathophysiology of hemorrhagic and thrombotic complications in APL, outlines risk stratification parameters, and compiles current clinical best practices. An improved understanding of the pathophysiologic mechanisms driving hemorrhage and thrombosis along with the completion of well-designed trials of management strategies will assist clinicians in developing interventions that mitigate these devastating complications in an otherwise largely curable disease.

Membrane bending and sphingomyelinase-associated, sulfatide-dependent hypoxic adhesion of sickle mature erythrocytes.

Abnormal erythrocyte adhesion owing to polymerization of sickle hemoglobin is central to the pathophysiology of sickle cell disease (SCD). Mature erythrocytes constitute >80% of all erythrocytes in SCD; however, the relative contributions of erythrocytes to acute and chronic vasculopathy in SCD are not well understood. Here, we showed that bending stress exerted on the erythrocyte plasma membrane by polymerization of sickle hemoglobin under hypoxia, enhances sulfatide-mediated abnormal mature erythrocyte adhesion. We hypothesized that sphingomyelinase (SMase) activity, which is upregulated by accumulated bending energy, leads to elevated membrane sulfatide availability, and thus, hypoxic mature erythrocyte adhesion. We found that mature erythrocyte adhesion to laminin in controlled microfluidic experiments is significantly greater under hypoxia than under normoxia (1856 ± 481 vs 78 ± 23, mean ± SEM), whereas sickle reticulocyte (early erythrocyte) adhesion, high to begin with, does not change (1281 ± 299 vs 1258 ± 328, mean ± SEM). We showed that greater mean accumulated bending energy of adhered mature erythrocytes was associated with higher acid SMase activity and increased mature erythrocyte adhesion (P = .022, for acid SMase activity and P = .002 for the increase in mature erythrocyte adhesion with hypoxia, N = 5). In addition, hypoxia results in sulfatide exposure of the erythrocyte membrane, and an increase in SMase, whereas anti-sulfatide inhibits enhanced adhesion of erythrocytes. These results suggest that the lipid components of the plasma membrane contribute to SCD complications. Therefore, sulfatide and the components of its upregulation pathway, particularly SMase, should be further explored as potential therapeutic targets for inhibiting sickle erythrocyte adhesion.

Reversal of life-threatening bleeding with protamine sulfate in a patient with plasma cell leukemia.

Plasma cell disorders, such as multiple myeloma, can cause numerous derangements of hemostasis. In this case report, we present a life-threatening coagulopathy in a patient with progressing multiple myeloma in which the antibody-producing heparin-like activity is a free light chain. The patient's bleeding was successfully treated using protamine sulfate, which then allowed treatment of her plasma cell leukemia. In the literature, other authors have reported similar patients who have responded to protamine sulphate either in vitro or in vivo , providing further evidence for the role of protamine sulfate in the reversal of coagulopathy and resolution of bleeding diathesis. Standard treatments of transfusion with fresh frozen plasma and cryoprecipitate are likely to be ineffective in life-threatening bleeding related to this mechanism (heparin-like effect), and it is essential that treating physicians are aware of this potential mechanism of bleeding in their patients.

Impact of diagnostic genetics on remission MRD and transplantation outcomes in older patients with AML.

Older patients with acute myeloid leukemia (AML) have high relapse risk and poor survival after allogeneic hematopoietic cell transplantation (HCT). Younger patients may receive myeloablative conditioning to mitigate relapse risk associated with high-risk genetics or measurable residual disease (MRD), but older adults typically receive reduced-intensity conditioning (RIC) to limit toxicity. To identify factors that drive HCT outcomes in older patients, we performed targeted mutational analysis (variant allele fraction ≥2%) on diagnostic samples from 295 patients with AML aged ≥60 years who underwent HCT in first complete remission, 91% of whom received RIC, and targeted duplex sequencing at remission in a subset comprising 192 patients. In a multivariable model for leukemia-free survival (LFS) including baseline genetic and clinical variables, we defined patients with low (3-year LFS, 85%), intermediate (55%), high (35%), and very high (7%) risk. Before HCT, 79.7% of patients had persistent baseline mutations, including 18.3% with only DNMT3A or TET2 (DT) mutations and 61.4% with other mutations (MRD positive). In univariable analysis, MRD positivity was associated with increased relapse and inferior LFS, compared with DT and MRD-negative mutations. However, in a multivariable model accounting for baseline risk, MRD positivity had no independent impact on LFS, most likely because of its significant association with diagnostic genetic characteristics, including MDS-associated gene mutations, TP53 mutations, and high-risk karyotype. In summary, molecular associations with MRD positivity and transplant outcomes in older patients with AML are driven primarily by baseline genetics, not by mutations present in remission. In this group of patients, where high-intensity conditioning carries substantial risk of toxicity, alternative approaches to mitigating MRD-associated relapse risk are needed.

Arsenic trioxide dose capping to decrease toxicity in the treatment of acute promyelocytic leukemia.

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination therapy yields high complete remission and disease-free survival rates in acute promyelocytic leukemia (APL). ATO is dosed on actual body weight and high ATO doses in overweight patients may contribute to increased toxicity. We performed a retrospective, two-center study comparing toxicities in patients who received the Lo-Coco et al ATRA/ATO regimen with capped ATO, ≤10 mg/dose, and non-capped ATO, >10 mg/dose. A total of 44 patients were included; 15 received doses ≤10 mg and 29 received >10 mg. During induction, there was no difference in the incidence of grade ≥3 hepatotoxicity, grade ≥3 QTc prolongation, neurotoxicity, and cardiac toxicity between groups. In consolidation, patients receiving >10 mg/dose experienced a greater incidence of neurotoxicity (66.7% vs 22.2%; p = 0.046). Capping doses saved $24634.37/patient and reduced waste of partially-used vials. At a median follow-up of 27 months, no disease relapses occurred in either group. This represents an opportunity to improve the safety profile of this highly effective regimen.

Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation.

PURPOSE: Clonal hematopoiesis (CH) can be transmitted from a donor to a recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain. PATIENTS AND METHODS: We performed targeted error-corrected sequencing on samples from 1,727 donors age 40 years or older and assessed the effect of donor CH on recipient clinical outcomes. We measured long-term engraftment of 102 donor clones and cytokine levels in 256 recipients at 3 and 12 months after transplant. RESULTS: CH was present in 22.5% of donors, with DNMT3A (14.6%) and TET2 (5.2%) mutations being most common; 85% of donor clones showed long-term engraftment in recipients after transplantation, including clones with a variant allele fraction < 0.01. DNMT3A-CH with a variant allele fraction ≥ 0.01, but not smaller clones, was associated with improved recipient overall (hazard ratio [HR], 0.79; P = .042) and progression-free survival (HR, 0.72; P = .003) after adjustment for significant clinical variables. In patients who received calcineurin-based graft-versus-host disease prophylaxis, donor DNMT3A-CH was associated with reduced relapse (subdistribution HR, 0.59; P = .014), increased chronic graft-versus-host disease (subdistribution HR, 1.36; P = .042), and higher interleukin-12p70 levels in recipients. No recipient of sole DNMT3A or TET2-CH developed donor cell leukemia (DCL). In seven of eight cases, DCL evolved from donor CH with rare TP53 or splicing factor mutations or from donors carrying germline DDX41 mutations. CONCLUSION: Donor CH is closely associated with clinical outcomes in transplant recipients, with differential impact on graft alloimmune function and potential for leukemic transformation related to mutated gene and somatic clonal abundance. Donor DNMT3A-CH is associated with improved recipient survival because of reduced relapse risk and with an augmented network of inflammatory cytokines in recipients. Risk of DCL in allogeneic hematopoietic cell transplantation is driven by somatic myelodysplastic syndrome-associated mutations or germline predisposition in donors.

Coagulopathy in Acute Promyelocytic Leukemia: Can We Go Beyond Supportive Care?

Acute promyelocytic leukemia (APL) is characterized by frequent complications due to a distinct coagulopathy. While advances in treatments have improved long-term survival, hemorrhagic and thrombotic complications remain the most common causes of death and morbidity. Improved understanding of the mechanisms of the coagulopathy associated with APL may lead to therapeutic interventions to mitigate the risk of hemorrhage and thrombosis.

Rhizopus microsporus typhlitis in a patient with acute myelogenous leukemia.

While patients undergoing treatment for hematologic malignancies are at risk for a variety of infections, gastrointestinal mucormycosis is a rare and feared complication. Diagnosis requires a high index of suspicion and timely evaluation. Prompt treatment improves patient outcomes.

Systems controls are needed to reduce mistaken tests for hemophagocytic lymphohistiocytosis, results of a prospective quality-improvement cohort study.

ABSTRACT: Medical diagnosis and therapy often rely on laboratory testing. We observed mistaken testing in evaluations for hemophagocytic lymphohistiocytosis (HLH) that led to delays and adverse outcomes. Physicians were mistakenly ordering interleukin-2 and quantitative natural killer cell flow cytometry, rather than soluble interleukin 2 receptor (sIL2R) or qualitative natural killer functional tests in the evaluation of patients suspected to have HLH.We initiated a prospective quality improvement project to reduce mistaken testing, reduce delays in correct testing due to mistaken ordering, and improve HLH evaluations. This consisted of provider education, developing an evaluation algorithm, and ultimately required systems interventions such as pop-ups and removal of the mistaken tests from the electronic ordering catalog.Active education reduced mistaken testing significantly in HLH evaluations from baseline (73.3% vs 33.3%, P = .003, relative risk reduction (RRR) 54.5%), but failed to meet the pre-specified RRR cutoff for success (70%). Education alone did not significantly reduce the proportion of HLH evaluations with delays in sIL2R testing (23.3% vs 7.4%, P = .096). Mistaken testing increased after the active intervention ended (33.3% vs 43.5%, P = .390, with RRR 40.7% from baseline. Mistaken test removal was successful: mistaken testing dropped to 0% (P < .001, RRR 100%), saved $14,235 yearly, eliminated delays in sIL2R testing from mistaken testing (23.3% vs 0%, P = .008), and expedited sIL2R testing after admission for HLH symptoms (14.6 days vs 3.8 days, P = .0012). These data show systems controls are highly effective in quality improvement while education has moderate efficacy.

Deep learning for diagnosis of acute promyelocytic leukemia via recognition of genomically imprinted morphologic features.

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML), classified by a translocation between chromosomes 15 and 17 [t(15;17)], that is considered a true oncologic emergency though appropriate therapy is considered curative. Therapy is often initiated on clinical suspicion, informed by both clinical presentation as well as direct visualization of the peripheral smear. We hypothesized that genomic imprinting of morphologic features learned by deep learning pattern recognition would have greater discriminatory power and consistency compared to humans, thereby facilitating identification of t(15;17) positive APL. By applying both cell-level and patient-level classification linked to t(15;17) PML/RARA ground-truth, we demonstrate that deep learning is capable of distinguishing APL in both discovery and prospective independent cohort of patients. Furthermore, we extract learned information from the trained network to identify previously undescribed morphological features of APL. The deep learning method we describe herein potentially allows a rapid, explainable, and accurate physician-aid for diagnosing APL at the time of presentation in any resource-poor or -rich medical setting given the universally available peripheral smear.

FLT3-ITD Allelic Burden and Acute Promyelocytic Leukemia Risk Stratification.

The significance of FLT3-ITD in acute promyelocytic leukemia (APL) is not well-established. We performed a bi-center retrospective study of 138 APL patients, 59 (42.8%) of whom had FLT3-ITD. APL patients with FLT3-ITD had higher baseline white blood cell counts (WBCs) (p < 0.001), higher hemoglobin, (p = 0.03), higher aspartate aminotransferase (p = 0.001), lower platelets (p = 0.004), lower fibrinogen (p = 0.003), and higher incidences of disseminated intravascular coagulation (p = 0.005), M3v variant morphology (p < 0.001), and the bcr3 isoform (p < 0.001). FLT3-ITD was associated with inferior post-consolidation complete remission (CR) (p = 0.02) and 5-year overall survival (OS) of 79.7%, compared to 94.4% for FLT3-WT (wild-type) (p = 0.02). FLT3-ITD was strongly associated with baseline WBCs ≥ 25 × 109/L (odds ratio (OR): 54.4; 95% CI: 10.4-286.1; p < 0.001). High FLT3-ITD allelic burdens correlated with high-risk (HR) Sanz scores and high WBCs, with every 1% increase in allelic burden corresponding to a 0.6 × 109/L increase in WBC. HR APL was associated with a 38.5% increase in allelic burden compared with low-risk (LR) APL (95% CI: 19.8-57.2; p < 0.001). Our results provide additional evidence that FLT3-ITD APL is a distinct subtype of APL that warrants further study to delineate potential differences in therapeutic approach.

Increased body mass index is a risk factor for acute promyelocytic leukemia.

Introduction: Obesity has become increasingly prevalent worldwide and is a risk factor for many malignancies. We studied the correlation between body mass index (BMI) and the incidence of acute promyelocytic leukemia (APL), non-APL acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and control hospitalized patients without leukemia in the same community. Methods: Multi-center, retrospective analysis of 71,196 patients: APL (n=200), AML (n=437), ALL (n=103), non-leukemia hospitalized (n=70,456) admitted to University of Maryland and Johns Hopkins Cancer Centers, and University of Maryland Medical Center. Results: Patients with APL had a significantly higher unadjusted mean and median BMI (32.5 kg/m2 and 30.3 kg/m2) than those with AML (28.3 kg/m2 and 27.1 kg/m2), ALL (29.3 kg/m2 and 27.7 kg/m2), and others (29.3 kg/m2 and 27.7 kg/m2) (p<0.001). Log-transformed BMI multivariable models demonstrated that APL patients had a significantly higher adjusted mean BMI by 3.7 kg/m2 (p<0.001) or approximately 10% (p<0.01) compared to the other groups, when controlled for sex, race, and age. Conclusions: This study confirms that when controlled for sex, age, and race there is an independent association of higher BMI among patients with APL compared to patients with ALL, AML, and hospitalized individuals without leukemia in the same community.

Payment incentives and the use of higher-cost drugs: a retrospective cohort analysis of intravenous iron in the Medicare population.

OBJECTIVES: Medicare Part B payment methods incentivize the use of more expensive injectable and infused drugs. We examined prescribing patterns in the context of intravenous (IV) iron, for which multiple similarly safe and efficacious formulations exist, with wide variations in price. STUDY DESIGN: We conducted a retrospective cohort analysis of IV iron utilization and payment in the Medicare population between 2015 and 2017. METHODS: This analysis used a national, random 20% sample of Medicare fee-for-service beneficiaries with Part B claims for IV iron between January 2015 and December 2017-a period before, during, and after a national shortage of iron dextran. This sample included 66,710 Medicare fee-for-service beneficiaries with at least 1 Part B claim for IV iron. RESULTS: The greatest increase in utilization occurred in the most expensive iron formulation, ferric carboxymaltose; its market share rose from 27.4% of use in 2015 to 47.7% in 2017. The use of a less expensive formulation, iron dextran, decreased from 26.7% to 18.7% over the same period. An alternative payment model in Maryland hospitals was associated with markedly less utilization of ferric carboxymaltose, accounting for 4.7% of IV iron utilization in Maryland hospitals. CONCLUSIONS: There was an increase in the dispensing of a higher-priced IV iron formulation associated with a shortage of a less expensive drug that persisted once the shortage ended. These findings in IV iron have broader implications for Part B drug payment policy because the price of the drug determines the physician and health system payment.

One-unit compared to two-unit platelet transfusions for adult oncology outpatients.

BACKGROUND AND OBJECTIVES: Platelet dosing has been studied in adult oncology inpatients, but there is almost no published evidence to guide platelet dosing for adult outpatients. We evaluated transfusion indices after 1 unit and 2 unit apheresis platelet transfusions at our hospital to determine whether a benefit to 2-unit transfusions could be detected. MATERIALS AND METHODS: A retrospective chart review was conducted of all adult oncology patients who received an outpatient platelet transfusion over a 16-month period (July 2016-November 2017). Pre- and post-transfusion platelet count, and chronology of subsequent platelet transfusions were compared. RESULTS: A total of 8467 platelet transfusions were administered to 602 patients during the study period. 59·8% of patients (n = 360) were transfused interchangeably with one or two platelets throughout the study period. The primary study population were comprised of these patients. On average, a 2-unit platelet transfusions resulted in a higher immediate post-transfusion platelet count (43 vs. 37 x 103 /µl, P < 0·001) and a lower corrected count increment (9707 vs. 14 060, P < 0·001). Transfusion with 2 platelets did not increase the number of days between outpatient transfusions (median; 4 vs. 4, P = 0·959) or the platelet count at the time of next transfusion (11 vs. 11 x 103 /µl, P = 0·147). CONCLUSION: Among adult, oncology outpatients that were transfused interchangeably with one or two units of platelets, transfusion with two platelets did not offer a durable improvement in platelet count or impact the subsequent transfusion schedule.