Myelodysplastic Neoplasms (MDS) with Ring Sideroblasts or SF3B1 Mutations: The Improved Clinical Utility of World Health Organization and International Consensus Classification 2022 Definitions, a Single-Centre Retrospective Chart Review.

Myelodysplastic neoplasms (MDS) with ring sideroblasts (RS) are diagnosed via bone marrow aspiration in the presence of either (i) ≥15% RS or (ii) 5-14% RS and an SF3B1 mutation. In the MEDALIST trial and in an interim analysis of the COMMANDS trial, lower-risk MDS-RS patients had decreased transfusion dependency with luspatercept treatment. A total of 6817 patients with suspected hematologic malignancies underwent molecular testing using a next-generation-sequencing-based genetic assay and 395 MDS patients, seen at our centre from 1 January 2018 to 31 May 2023, were reviewed. Of these, we identified 39 evaluable patients as having lower-risk MDS with SF3B1 mutations: there were 20 (51.3%) males and 19 (48.7%) females, with a median age of 77 years (range of 57 to 92). Nineteen (48.7%) patients had an isolated SF3B1 mutation with a mean variant allele frequency of 35.2% +/- 8.1%, ranging from 7.4% to 46.0%. There were 29 (74.4%) patients with ≥15% RS, 6 (15.4%) with 5 to 14% RS, one (2.6%) with 1% RS, and 3 (7.7%) with no RS. Our study suggests that a quarter of patients would be missed based on the morphologic criterion of only using RS greater than 15% and supports the revised 2022 definitions of the World Health Organization (WHO) and International Consensus Classification (ICC), which shift toward molecularly defined subtypes of MDS and appropriate testing.

Serologic Response to Vaccine for COVID-19 in Patients with Hematologic Malignancy: A Prospective Cohort Study.

BACKGROUND: Patients with hematological cancers have increased COVID-19 morbidity and mortality, and these patients show attenuated vaccine responses. This study aimed to characterize the longitudinal humoral immune responses to COVID-19 vaccination in patients with hematological malignancies. PATIENTS AND METHODS: We conducted a prospective cohort study, collecting samples from March 2021 to July 2022, from patients seen at a cancer treatment center in London, Ontario, Canada, who met the following eligibility criteria: age ≥18 years, diagnosed with a hematological malignancy, recipient of a COVID-19 vaccine during the study period, and able to provide informed consent. RESULTS: Median anti-S titers (MST) were 0.0, 64.0, and 680.5 U/mL following first (V1), second (V2), and third (V3) vaccine doses, respectively. Patients with lymphoid malignancies' response to vaccination was attenuated compared to myeloid malignancy patients after V2 and V3 (P < .001, P < .01). Active treatment was associated with lower antibody titers (MST 10) compared to treatment 12-24 months (MST 465, P = .04367) and >24 months (MST 1660.5, P = .0025) prior to vaccination. V3 significantly increased antibody titers compared to V2 for patients less than 3 months from treatment. Increasing age was associated with smaller antibody response following V2 (P < .05), but not following V3. Patients receiving anti-CD20 therapy did not demonstrate increased antibody titer levels after V3 (V2 MST 0, V3 MST 0; P > .05). CONCLUSION: We report an attenuated serologic response to COVID-19 vaccination in our study population of patients with hematological malignancy. The immune response to vaccination was affected by patient age, diagnosis, treatment, and timing of treatment exposure.

Patient and Physician Preferences for Acute Myeloid Leukemia Maintenance Treatments Following Hematopoietic Stem Cell Transplantation.

Purpose: This study assessed and compared preferences for treatment attributes of maintenance therapies post-hematopoietic stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML) and in physicians who treat these patients. Patients and Methods: Patients with AML post HSCT and physicians from the United States, United Kingdom, Canada, and Australia (physicians only) completed a web-based discrete choice experiment (DCE). The DCE used inputs identified via a targeted literature review and qualitative interviews to ascertain relevant treatment attributes and associated levels. Six treatment attributes were selected (chance of 2-year relapse-free survival, quality of life [QoL], risk of serious infections, risk of nausea, chance of achieving transfusion independence, and duration of hospitalization annually), each with three or four levels. The experimental design included 36 choice tasks that presented a pair of hypothetical treatment profiles with varying attribute levels; participants chose a preferred treatment for each choice task. Choice tasks were divided into three blocks of 12 tasks each in the patient survey and 4 blocks of 9 tasks each in the physician survey; survey participants were randomly assigned to one of the blocks. Random parameter logit regression models were used to assess the impact of stated attributes on preferences for maintenance treatment post HSCT. Results: Surveys from 84 patients and 149 physicians were assessed. For patients, QoL was the most important attribute, followed by duration of hospitalization and chance of 2-year relapse-free survival. For physicians, chance of 2-year relapse-free survival was the most important attribute, followed by QoL and risk of serious infections. Conclusion: Differences in how patients and physicians valued post-HSCT maintenance treatment attributes were identified. These differences suggest that patient-centered decision-making may help physicians choose maintenance treatments for patients with AML post HSCT that better meet their treatment needs and improve their treatment satisfaction.

Design of the VIALE-M phase III trial of venetoclax and oral azacitidine maintenance therapy in acute myeloid leukemia.

Prevention of relapse is a major therapeutic challenge and an unmet need for patients with acute myeloid leukemia (AML). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in AML cells. When combined with azacitidine, it leads to prolonged overall survival and rapid, durable remissions in treatment-naive AML patients ineligible for intensive chemotherapy. VIALE-M is a randomized, double-blind, two-arm study to evaluate the safety and efficacy of venetoclax in combination with oral azacitidine (CC-486) as maintenance therapy in patients in complete remission with incomplete blood count recovery after intensive induction and consolidation therapies. The primary end point is relapse-free survival. Secondary outcomes include overall survival, minimal residual disease conversion and improvement in quality-of-life. Trial Registration Number: NCT04102020 (ClinicalTrials.gov).

Medical image fusion by sparse-based modified fusion framework using block total least-square update dictionary learning algorithm.

Purpose: The technique of fusing or integrating medical images collected from single and various modalities is known as medical image fusion. This is done to improve the quality of the images and combine information from several medical images. The whole procedure aids medical practitioners in gaining correct information from single images. Image fusion is one of the fastest-growing research topics in the medical imaging field. Sparse modeling is a popular signal representation technique used for image fusion with different dictionary learning approaches. We propose a medical image fusion with sparse representation (SR) and block total least-square (BLOTLESS) update dictionary learning. Approach: The domain of dictionary learning is the most significant research domain related to SR. An efficient dictionary increases the effectiveness of sparse modeling. Due to SR being an ongoing interesting research area, the medical image fusion process is done with a modified image fusion framework with recently developed BLOTLESS update dictionary learning. Results: The experimental results are compared for the image fusion process using other state-of-the-art dictionary learning algorithms, such as simultaneous codeword optimization, method of optimal directions, and K-singular value decomposition. The effectiveness of the algorithm is evaluated based on image fusion quantitative parameters. Results show that the BLOTLESS update dictionary algorithm is a promising modification for the sparse-based image fusion with its applicability in the fusion of images related to different diseases. Conclusions: The experiments and results show that the dictionary learning algorithm plays an important role in the sparse-based image fusion general framework. The fusion results also show that the proposed improved image fusion framework for medical images is promising compared with frameworks with other dictionary learning algorithms. As an application, it is also used as a tool for the fusion of different modularities of images related to brain tumor and glioma.

Clinical value of next-generation sequencing compared to cytogenetics in patients with suspected myelodysplastic syndrome.

Next-generation sequencing (NGS) increasingly influences diagnosis, prognosis and management of myelodysplastic syndrome (MDS). In addition to marrow morphology and flow cytometry, our institution performs cytogenetics (CG) and NGS-based testing routinely in patients with suspected MDS. We evaluated the relative value of NGS in the assessment of patients with suspected MDS. We initially compared the diagnostic and prognostic information derived from CG and NGS in 134 patients. NGS enhanced the diagnostic yield compared to CG for clonal myeloid disorders (sensitivity 77% vs. 42·2%; specificity 90·2% vs. 78%; positive predictive value 92·8% vs. 76%; and negative predictive value 70·8% vs. 45·5%). The identification of poor prognosis mutations by NGS altered risk category in 27/39 (69·2%) patients with MDS with good/intermediate risk CG. Subsequently, we prospectively evaluated 70 patients with suspected MDS using an 'NGS-first approach' with CG restricted to samples with morphological abnormalities. We rarely identified mutations or CG abnormalities in patients without dysplastic features. NGS has a superior diagnostic performance compared to CG in patients with suspected MDS. We estimate that by using an 'NGS-first approach' we could reduce karyotyping by approximately 30%.

Outcomes of patients with relapsed or refractory acute myeloid leukemia: a population-based real-world study.

With standard therapies for patients with acute myeloid leukemia (AML), many patients either do not achieve complete response (CR) or relapse after CR. There are a scarcity of real-world data on outcomes of unselected patients with relapsed/refractory acute myeloid leukemia (RR-AML). We retrospectively evaluated treatment patterns and survival outcomes of unselected patients aged ≥18 years diagnosed with RR-AML identified from the Alberta Cancer Registry, Alberta, Canada, between January 2013 and December 2016. We included 199 patients who met predefined criteria for RR-AML. Following RR-AML diagnosis, 23% of patients received intensive therapy (IT), 33% non-intensive therapy (NIT), and 44% best supportive care (BSC). The unadjusted median overall survival (OS) of the study cohort was 5.3 months from the time of RR-AML diagnosis, with a 5-year OS rate of 12.6% (95% confidence interval 7.5-21.1). According to treatment intensity after RR-AML, the median OS outcomes were 13.6, 9.4, and 2.0 months for IT, NIT, and BSC groups, respectively (P<0.001). Patients who received treatment (IT or NIT) had better survival than those who received only BSC. This study emphasizes the need for newer therapy options for patients with RR-AML.

Day 14 Bone Marrow Evaluation During Acute Myeloid Leukemia Induction in a Real-world Canadian Cohort.

INTRODUCTION: The 2017 National Comprehensive Cancer Network guidelines for acute myeloid leukemia have recommended performing bone marrow (BM) aspiration and BM trephine biopsy (BMTB) 14 to 21 days after starting induction therapy (commonly referred to as "day 14 [D14] marrow"). Those who do not achieve a hypoplastic marrow, with cellularity < 20% and blasts < 5%, are recommended to undergo 2-cycle induction (2CI). We performed a retrospective analysis to determine the impact of D14 BM characteristics in predicting for remission, association with overall survival (OS), and the effect of 2CI according to the D14 BM results. PATIENTS AND METHODS: Patients aged 18 to 70 years undergoing induction therapy with standard "7 + 3" regimens were included. D14 cellularity was determined from BMTB samples and the blast percentage was assessed by morphology on BM aspiration and BMTB samples. The outcomes evaluated included the rates of complete remission (CR) and OS. RESULTS: A total of 486 patients with results from D14 BM evaluation were included in the present study. On multivariate analysis, cytogenetic risk and D14 blasts < 5% were predictive of CR/CR with incomplete count recovery (P < .001). Cytogenetic risk (P < .001), age < 60 years (P = .001), and D14 blasts < 5% (P = .045) predicted for OS. 2CI was performed in 131 patients (27%). Patients with hypocellular D14 BM but residual blasts (n = 106) underwent 2CI in 46% of cases, with improved remission rates (43.9% vs. 72.0%; P = .004) but no difference in OS. CONCLUSIONS: The results from D14 BM evaluations are predictive of subsequent remission and OS. Our findings did not show a survival benefit with D14 BM-driven 2CI.

Muscle aches and pains: do I have leukemia?

We describe a 65-year-old man who presented with 'aches and pains' localized to the lower extremities, and was diagnosed with acute myeloid leukemia (AML). We hypothesize that this case represents an atypical presentation of AML with an immune-mediated necrotizing-like myopathy as a possible paraneoplastic manifestation of the disease, which improved after initiating chemotherapy. Our patient received a full course of 7 + 3 chemotherapy with cytarabine and daunorubicin. Proximal leg weakness and pain improved markedly following this treatment, establishing a temporal relationship between the possible paraneoplastic manifestation and treatment of underlying disease. Associations between malignancy and myopathies such as polymyositis and dermatomyositis have been well established in the literature. However, paraneoplastic IMNM is still a rare clinical phenomenon and has infrequently been associated with AML. This case may suggest myopathy and associated muscle 'aches and pains' as possible presenting symptoms of underlying AML, highlighting the heterogeneity of the clinical manifestations of this disease.

Clinical Validation of a Myeloid Next-Generation Sequencing Panel for Single-Nucleotide Variants, Insertions/Deletions, and Fusion Genes.

Myeloid neoplasms are a heterogeneous group of neoplasms including acute myeloid leukemia (AML), myeloproliferative neoplasms, myelodysplastic syndrome, and myeloproliferative neoplasms/myelodysplastic syndrome. Genetic abnormalities are used as diagnostic, prognostic, and predictive biomarkers in patients with these diseases. Herein, we describe the clinical validation of the Oncomine Myeloid Research (OMR) next-generation sequencing panel that interrogates for 40 genes and 29 fusion genes commonly seen in myeloid neoplasms. Our validation set of 77 DNA samples included acute and chronic myeloid neoplasms, with 91 single-nucleotide variants and small insertions/deletions. The 71 RNA samples from patients with AML included most of the AML-defining translocations. The OMR on the Ion Torrent S5 platform shows good performance in terms of depth of coverage, on-target reads, and uniformity. The panel achieved 91.3% and 100% concordance with reference DNA and RNA samples, respectively, with a clinical sensitivity and specificity of 96.7% and 100% for DNA and 99.8% and 100% for RNA, respectively. Precision and reproducibility were 100%, and the lower limit of detection was generally 5% variant allele fraction for DNA and 2-log reduction from initial value for RNA fusion genes. In conclusion, the OMR panel is a highly accurate and reproducible next-generation sequencing panel for the detection of common genetic alterations in myeloid neoplasms.

A strategy of Day14 bone marrows and early intervention is not superior to a strategy of noDay14 bone marrows and delayed intervention in patients with acute myeloid leukemia.

We conducted a retrospective study of 364 acute myeloid leukemia patients treated using a Day14 or a noDay14 strategy. Under the Day14 strategy, patients received an interim marrow at 7-10 days following chemotherapy and, in case of residual disease, received immediate reinduction chemotherapy. Under the noDay14 strategy patients were only evaluated at end-of-induction (EOI). Overall induction mortality was higher in the Day14 cohort (8.3 vs. 3.6%, p = .12) but rates of remission (75.4 vs. 83%, p = .13) and refractory disease (14.3 vs. 13.4%, p = .87) at EOI were similar in the Day14 and noDay14 cohorts as were relapse rates (37.9% vs. 34.3%, p = .616), median relapse-free survival (14.8 vs. 15 months, p = .658) and median overall survival (25.3 vs. 37.2 months, p = .264). In multivariate analysis, the use of a Day14 strategy did not impact outcomes suggesting that a Day14 strategy is not superior to a noDay14 strategy.

Randomized study of continuous high-dose lenalidomide, sequential azacitidine and lenalidomide, or azacitidine in persons 65 years and over with newly-diagnosed acute myeloid leukemia.

Therapy of acute myeloid leukemia in older persons is associated with poor outcomes because of intolerance to intensive therapy, resistant disease and co-morbidities. This multi-center, randomized, open-label, phase II trial compared safety and efficacy of three therapeutic strategies in patients 65 years or over with newly-diagnosed acute myeloid leukemia: 1) continuous high-dose lenalidomide (n=15); 2) sequential azacitidine and lenalidomide (n=39); and 3) azacitidine only (n=34). The efficacy end point was 1-year survival. Median age was 76 years (range 66-87 years). Thirteen subjects (15%) had prior myelodysplastic syndrome and 41 (47%) had adverse cytogenetics. One-year survival was 21% [95% confidence interval (CI): 0, 43%] with high-dose lenalidomide, 44% (95%CI: 28, 60%) with sequential azacitidine and lenalidomide, and 52% (95%CI: 35, 70%) with azacitidine only. Lenalidomide at a continuous high-dose schedule was poorly-tolerated resulting in a high rate of early therapy discontinuations. Hazard of death in the first four months was greatest in subjects receiving continuous high-dose lenalidomide; hazards of death thereafter were similar. These data do not favor use of continuous high-dose lenalidomide or sequential azacitidine and lenalidomide over the conventional dose and schedule of azacitidine only in patients aged 65 years or over with newly-diagnosed acute myeloid leukemia. (clinicaltrials.gov identifier: 01358734).

Persistent cytogenetic abnormalities in patients undergoing intensive chemotherapy for acute myeloid leukemia.

We evaluated the impact of bone marrow sample characteristics on the detection of persistent cytogenetic abnormalities (PCA) following induction chemotherapy for acute myeloid leukemia (AML). PCA's were identified in 20.4% of patients and were more common with complete remission without count recovery (CRi) vs. those with count recovery (CR, 45.8 vs. 13.5%, p = .001), with >2% blasts vs. ≤2% blasts (42 vs. 12%, p = .001) and with hypocellular trephine biopsies relative to those with normo/hypercellular biopsies (42.1 vs. 17.3%, p = .03), although in a multivariate analysis only CRi and blast count >2% were independently associated with a PCA. PCA's were not observed in patients with favorable risk karyotype. Amongst patients with intermediate and unfavorable risk karyotypes PCA were not associated with differences in overall or, amongst non-transplanted patients, relapse free survival. Thus, although PCAs are common post-induction it is unclear whether they provide any independent prognostic information beyond the diagnostic karyotype.

New Treatment Strategies for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

PURPOSE OF REVIEW: To review recent studies that address important questions regarding the treatment of Philadelphia chromosome-positive ALL. RECENT FINDINGS: Less intensive non-myelosuppressive induction approaches can produce comparable anti-leukemic responses with less toxicity. Second-generation tyrosine kinase inhibitors (TKIs) are not clearly associated with superior outcomes compared to imatinib. Ponatinib is associated with lower early relapse rates, but has additional vascular risks. Patients achieving complete molecular response (CMR) appear to have comparable survivals with chemotherapy + TKI alone as compared with allogeneic stem cell transplant (alloSCT). In contrast, those not achieving CMR have superior outcomes with alloSCT. There is no clear evidence of benefit for post-transplant TKI therapy. Patients resistant to chemotherapy + TKIs may respond to blinatumomab or inotuzumab; these agents may also convert some patients to CMR. Future studies should further explore the potential of ponatinib and antibody-based therapies to more precisely define optimal molecular responses.

Incremental value of the bone marrow trephine biopsy in detecting residual leukemia following treatment for Acute Myeloid Leukemia.

Most guidelines suggest that only the bone marrow aspirate (BMA) is necessary to assess residual disease following intensive chemotherapy for Acute Myeloid Leukemia (AML) with the bone marrow trephine biopsy (BMTB) recommended in cases of a poor quality BMA. We performed a retrospective study evaluating this in a cohort of patients receiving intensive chemotherapy for AML. Residual disease was assessed by morphological examination of the BMA and BMTB±immunohistochemistry. Of the 647 marrows 32.6% were interim marrows performed prior to peripheral count recovery, 41.7% were end of induction (EOI) marrows and the remaining were 'other marrows'. The BMA and BMTB findings were concordant in 92.8% of cases. The BMTB led to a change in diagnosis from 'no leukemia' to 'residual leukemia' in 5.2% of interim, 3.7% of EOI and 2.4% of 'other' marrows. The BMA alone had a sensitivity of 86.8% in detecting residual leukemia and of 82.3%, 82.5% and 94.2% for interim, EOI and 'other marrows', respectively. Despite the high concordance between the BMA and the BMTB the poor sensitivity of the BMA in detecting residual leukemia, particularly at EOI, may lead to an overestimation of the complete remission rates which may have therapeutic and clinical trial implications.

The fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) chemotherapy regimen is an alternative to anthracycline-based therapy for the treatment of acute myeloid leukemia for patients with pre-existing cardiac disease.

We conducted a retrospective study assessing FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) as first-line treatment in 56 newly diagnosed acute myeloid leukemia patients considered ineligible for anthracycline-based treatment due to advanced age, significant comorbidities, or pre-existing cardiac disease. The median age was 69 (21-80); 46% received FLAG for pre-existing cardiac disease and others due to age (32%), non-cardiac comorbidities (20%), or previous anthracycline exposure (2%). The induction mortality was 16% and, among evaluable patients, 48% achieved a complete remission after the first induction course with an additional patient achieving a remission after a second course for a total complete remission rate of 50%. Four patients proceeded to an allogeneic stem cell transplant including two with pre-existing cardiac disease. Among non-transplanted patients, the relapse rate (RR) was 47%. When censored at time of stem cell transplant, the median relapse-free survival was 14.7 months. The median overall survival was 9.3 months with 1- and 2-yr survivals of 44% and 22%, respectively. There was no difference in clinical outcomes between patients treated with FLAG for cardiac reasons vs. other reasons. In conclusion, FLAG is a useful alternative to anthracycline-based induction for Acute myeloid leukemia in those with significant comorbidities including pre-existing cardiac disease.

Serum voriconazole level variability in patients with hematological malignancies receiving voriconazole therapy.

INTRODUCTION: Voriconazole plasma concentrations have been correlated with oral dosing in healthy subjects, but have been poorly characterized in ill patients with hematological malignancies receiving intensive chemotherapy. METHODS: The relationship between orally administered voriconazole, plasma concentrations and liver toxicity was examined in a cohort of 69 primarily acute leukemia patients undergoing intensive chemotherapy. RESULTS: Oral administration of voriconazole was associated with significant interpatient variability, with voriconazole steady-state concentrations ranging from 0 µg/mL to 16.6 µg/mL. Approximately 20% of patients achieved steady-state concentrations <1 µg/mL. When adjusted for weight, patients receiving higher voriconazole doses tended toward higher plasma concentrations; however, there was no significant relationship between the plasma concentration and genotype, age, sex or use of concomitant proton pump inhibitors. Voriconazole concentrations were correlated with higher serum alkaline phosphatase levels at day 6 to 8, and with higher bilirubin and aspartate aminotransferase levels at day 14 to 16, but not with other liver enzyme levels. CONCLUSION: In ill patients with acute leukemia and related disorders undergoing treatment with oral voriconazole, there is a poor correlation between the voriconazole dose and plasma concentrations, and many patients achieve levels that are considered to be subtherapeutic. The findings support the routine use of therapeutic drug monitoring in these patients.

INTRODUCTION: Les concentrations plasmatiques de voriconazole sont corrélées avec les doses orales chez les sujets en santé, mais sont mal caractérisées chez les patients malades atteints d'une hémopathie maligne sous chimiothérapie intensive. MÉTHODOLOGIE: Les chercheurs ont examiné le lien entre le voriconazole administré par voie orale et la toxicité hépatique dans une cohorte de 69 patients atteints surtout de leucémie aiguë sous chimiothérapie intensive. RÉSULTATS: L'administration de voriconazole par voie orale s'associait à une importante variabilité interpatient, les concentrations à l'état stable oscillant entre 0 µg/mL et 16,6 µg/mL. Environ 20 % des patients ont obtenu des concentrations à l'état stable de moins de 1 µg/mL. Après rajustement selon le poids, les patients qui receviaent des doses plus élevées de voriconazole avaient tendance à présenter des concentrations plasmatiques plus élevées. Cependant, on ne constatait aucun lien significatif entre la concentration plasmatique et le géno-type, l'âge, le sexe ou l'utilisation concomitante d'inhibiteurs de la pompe à protons. Les concentrations de voriconazole étaient corrélées avec des taux de phosphatase alcaline sérique plus élevés les jours 6 à 8 et à des taux de bilirubine et d'aspartate aminotransférase plus élevés les jours 14 à 16, mais pas à d'autres taux d'enzymes hépatiques. CONCLUSION: Chez les patients malades atteints d'une leucémie aiguë et de troubles connexes qui suivent un traitement au voriconazole par voie orale, la corrélation entre la dose de voriconazole et les concentrations plasmatiques est faible, et de nombreux patients obtiennent des taux considérés comme subthérapeutiques. Les observations soutiennent une pharmacovigilance systématique chez ces patients.