Beyond the In-Practice CBC: The Research CBC Parameters-Driven Machine Learning Predictive Modeling for Early Differentiation among Leukemias

A targeted and timely treatment can be a beneficial tool for patients with hematological emergencies (particularly acute leukemias). The key challenges in the early diagnosis of leukemias and related hematological disorders are their symptom-sharing nature and prolonged turnaround time as well as the expertise needed in reporting confirmatory tests. The present study made use of the potential morphological and immature fraction-related parameters (research items or cell population data) generated during complete blood cell count (CBC), through artificial intelligence (AI)/machine learning (ML) predictive modeling for early (at the pre-microscopic level) differentiation of various types of leukemias: acute from chronic as well as myeloid from lymphoid. The routine CBC parameters along with research CBC items from a hematology analyzer in the diagnosis of 1577 study subjects with hematological neoplasms were collected. The statistical and data visualization tools, including heat-map and principal component analysis (PCA,) helped in the evaluation of the predictive capacity of research CBC items. Next, research CBC parameter-driven artificial neural network (ANN) predictive modeling was developed to use the hidden trend (disease’s signature) by increasing the auguring accuracy of these potential morphometric parameters in differentiation of leukemias. The classical statistics for routine and research CBC parameters showed that as a whole, all study items are significantly deviated among various types of leukemias (study groups). The CPD parameter-driven heat-map gave clustering (separation) of myeloid from lymphoid leukemias, followed by the segregation (nodding) of the acute from the chronic class of that particular lineage. Furthermore, acute promyelocytic leukemia (APML) was also well individuated from other types of acute myeloid leukemia (AML). The PCA plot guided by research CBC items at notable variance vindicated the aforementioned findings of the CPD-driven heat-map. Through training of ANN predictive modeling, the CPD parameters successfully differentiate the chronic myeloid leukemia (CML), AML, APML, acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), and other related hematological neoplasms with AUC values of 0.937, 0.905, 0.805, 0.829, 0.870, and 0.789, respectively, at an agreeably significant (10.6%) false prediction rate. Overall practical results of using our ANN model were found quite satisfactory with values of 83.1% and 89.4.7% for training and testing datasets, respectively. We proposed that research CBC parameters could potentially be used for early differentiation of leukemias in the hematology–oncology unit. The CPD-driven ANN modeling is a novel practice that substantially strengthens the predictive potential of CPD items, allowing the clinicians to be confident about the typical trend of the “disease fingerprint” shown by these automated potential morphometric items.

Effectiveness of the BNT162b2mRNA Covid-19 Vaccine in Patients with Hematological Neoplasms

Evidence regarding the effectiveness of covid-19 vaccine in patients with impaired immunity, is limited. Initial observations suggest a lower humoral response in these patients. We evaluated the relative effectiveness of the mRNA BNT162b2 vaccine in patients with hematological neoplasms compared to matched controls. Data on patients with hematological neoplasms after two vaccine doses were extracted and matched 1:1 with vaccinated controls. Subpopulation analyses focused on patients receiving therapy for the hematological neoplasm, patients without treatment who are only followed, and recipients of specific treatments. The analysis focused on covid-19 outcomes from day 7 through 43 following the second vaccine dose: Documented covid-19 infection by PCR; Symptomatic infection; Hospitalizations; Severe covid-19 disease and covid-19-related death. Of a population of 4.7 million insured people, 32,516 patients with hematological neoplasms were identified, of whom 5,017 were receiving therapy for an active disease. Vaccinated patients with hematological neoplasms, compared with vaccinated matched controls, had an increased risk of documented infections (RR 1.60, 95% confidence interval [CI] 1.12-2.37), symptomatic covid-19 (RR 1.72, 95% CI 1.05-2.85), covid-19 related hospitalizations (RR 3.13, 95% CI 1.68-7.08), severe covid-19 (RR 2.27, 95% CI 1.18-5.19) and covid-19 related death (RR 1.66, 95% CI 0.72-4.47). Limiting the analysis to patients on hematological treatments showed a higher increased risk. This analysis shows that vaccinated patients with hematological neoplasms, in particular patients on treatment, suffer from covid-19 outcomes more than vaccinated individuals with intact immune system. Ways to enhance covid-19 immunity in this patient population, such as additional doses, should be explored.

Coexistence of Prefibrotic Myelofibrosis with Monoclonal Gammopathy of Undetermined Significance: A Case Report

The coexistence of dual hematological neoplasms is an unusual and challenging presentation due to the different combination of etiopathology. The presentation of synchronous dual hematological malignancies can be one of the 3 types: myeloid + lymphoid or dual lymphoid or dual myeloid. Here, we are reporting a case of a 53-year-old male with simultaneous presence of JAK<i>2 V617F</i>-positive myeloproliferative neoplasm with features favoring prefibrotic phase of primary myelofibrosis (pre-PMF) in combination with monoclonal gammopathy of undetermined significance (MGUS). In such cases of simultaneous existence of dual hematological neoplasm management, it is recommended to treat the more aggressive one. Currently, our management plan is focusing on treating the pre-PMF and observation of MGUS with regular monitoring for transformation to MM.

Mutational patterns and their correlation to CHIP-related mutations and age in hematological malignancies

Acquired somatic mutations are crucial for the development of the majority of cancers. We performed a comprehensive comparative analysis of the mutational landscapes and their correlation to CHIP-related (clonal hematopoiesis of indeterminate potential) mutations and patient age of 122 genes in 3096 cases with 28 different hematological malignancies. Differences were observed regarding (i) the median number of mutations (highest, median n=4: aCML, CMML, MDS/MPN-U, s-AML; lowest, n=0, CML, MLN-eo, MGUS, PPBL), (ii) specificity of certain mutations (high frequencies in e.g. aCML (ASXL1, 86%), FL (KMT2D, 87%; CREBBP, 73%), HCL (BRAF, 100%), LPL (MYD88, 98%; CXCR4, 51%), MPN (JAK2, 68%)), (iii) distribution of mutations (broad distribution within/across the myeloid/lymphoid lineage e.g. for TET2, ASXL1, DNMT3A, TP53, BCOR, ETV6), (iv) correlation of mutations to patient age (correlated to older age across entites: e.g. TET2, DNMT3A, ASXL1, TP53, EZH2, BCOR, GATA2, IDH2; younger age: e.g. KIT, POT1, RAD21, U2AF2; WT1), (v) correlation of mutation number per patient with age (total cohort (p&lt;0.001), AML (p&lt;0.001), B-ALL (p=0.015), CLL (0.039), MDS (p&lt;0.001), MPN (p&lt;0.001), T-ALL (p=0.005)). Moreover, we observed high frequencies of mutations in RUNX1, SRSF2, IDH2, NRAS, EZH2 in cases comprising at least one DTA mutation (DNMT3A, TET2, ASXL1), while in cases without DTA mutations TP53, KRAS, WT1, SF3B1 were more frequent across entities, suggesting differences in pathophysiology. These results give further insight into the complex genetic landscape and the role of DTA mutations in hematological neoplasms and define mutation-driven entities (MDS/MPN overlap, s-AML) in comparison to entities defined by chromosomal fusions (CML, MLN-eo).

Myeloproliferative Disease: Dealing With a Diagnostic Dilemma

Myeloproliferative neoplasms (MPNs) constitute a group of hematologic clonal diseases that affect one or more myeloid lineages with abnormal proliferation. It is rare disease entity and incidence is about 1.15 to 4.99/100 000 person-years among hematological neoplasms for all subtypes of MPNs combined. Patients who present with hepatosplenomegaly, hyperleukocytosis with monocytosis should have routine tests along with bone marrow morphology possibly biopsy, quantiferon TB Gold in tube test, Dengue fever IgM, IgG, NS-1 antigen, cytogenetics t(9;22), BCR cABL fusion gene, JAK-2 V617F, MPL mutations, CALR gene test done along with karyotyping and flowcytometry to evaluate and establish diagnosis towards management.

Multiparametric Flow Cytometry for MRD Monitoring in Hematologic Malignancies: Clinical Applications and New Challenges

Along with the evolution of immunophenotypic and molecular diagnostics, the assessment of Minimal Residual Disease (MRD) has progressively become a keystone in the clinical management of hematologic malignancies, enabling valuable post-therapy risk stratifications and guiding risk-adapted therapeutic approaches. However, specific prognostic values of MRD in different hematological settings, as well as its appropriate clinical uses (basically, when to measure it and how to deal with different MRD levels), still need further investigations, aiming to improve standardization and harmonization of MRD monitoring protocols and MRD-driven therapeutic strategies. Currently, MRD measurement in hematological neoplasms with bone marrow involvement is based on advanced highly sensitive methods, able to detect either specific genetic abnormalities (by PCR-based techniques and next-generation sequencing) or tumor-associated immunophenotypic profiles (by multiparametric flow cytometry, MFC). In this review, we focus on the growing clinical role for MFC-MRD diagnostics in hematological malignancies—from acute myeloid and lymphoblastic leukemias (AML, B-ALL and T-ALL), to chronic lymphocytic leukemia (CLL) and multiple myeloma (MM)—providing a comparative overview on technical aspects, clinical implications, advantages and pitfalls of MFC-MRD monitoring in different clinical settings.

Factors associated with non-invasive ventilation failure and mortality in oncologic patients outside the intensive care unit

Introduction: New treatments have been introduced with the objective to increase the survival rate of oncologic patients. As a result of these approaches, there was an increase in the number of cases of toxicity and complications, which can lead to acute respiratory failure (ARF). One of the most frequent ways to treat ARF is non-invasive ventilation (NIV). Despite the proven benefits in several clinical conditions, NIV results in cancer patients are controversial. Objective: To evaluate risk factors associated with NIV failure and hospital mortality in oncologic patients. Methods: Retrospective cohort study including patients with solid tumors and hematological neoplasms admitted for hospitalization at National Cancer Institute between January 1, 2017 and December 31, 2019, who underwent NIV. The association between the variables of exposure and the outcome was performed by gross and adjusted logistic regression. The Kaplan-Meier method was used to analyze the length of hospital stay. Results: Sixty-three patients who underwent NIV in hospitalization were evaluated, and 26 failed NIV. The patients had a mean age of 58.5 years (±15.6), most were male (57.1%), under 60 years old (58.7%) and had comorbidities (55.5%). The patients with pulmonary infection (OR 6.53; 95% CI 1.21-35.12; p=0.02) had a higher risk of failure in NIV. In relation to hospital mortality, patients older than 60 years (OR 6.90; 95% CI, 2.12-22.45; p=0.001) had a higher risk. Conclusion: Patients who presented pulmonary infection were more likely to fail in NIV. Higher hospital mortality was observed among elderly patients.

Concurrent diagnosis of acute myeloid leukemia and symptomatic COVID-19 infection: a case report successfully treated with Azacitidine-Venetoclax combination

SARS-COV2 pandemic has caused profound challenges in health care systems worldwide. Patients affected by hematological neoplasms appear to be particularly at risk of developing COVID-19 complications, with unfavorable outcomes. Here, we present the case of a 57-years-old woman diagnosed with severe COVID-19 pneumonia and concurrent acute myeloid leukemia (AML). At the time of diagnosis, it was decided to postpone leukemia therapy to enable adequate COVID-19 pneumonia treatment. When her conditions related to pneumonia improved, the combination of Azacitidine-Venetoclax was used as first-line treatment, instead of conventional intensive chemotherapy. At the end of the first two cycles, the patient showed complete remission, and a post-remission consolidation with allogeneic hematopoietic stem cell transplantation has been planned. This case suggests that Azacytidine-Venetoclax induction may represent a valid and safe alternative to intensive chemotherapy in the challenging setting of patients with a concomitant diagnosis of AML and severe COVID-19 infection.