Patterns of lower risk myelodysplastic syndrome progression: factors predicting progression to high-risk myelodysplastic syndrome and acute myeloid leukemia.

The patterns of low-risk myelodysplastic syndrome (MDS) progression and the clinical and molecular features of those patterns have not been well described. We divided our low-risk (LR) MDS patients (N=1,914) into 4 cohorts: 1) patients who remained LR-MDS (LR-LR; N=1,300; 68%), 2) patients who progressed from LR to high-risk (HR) MDS (LR-HR) without transformation into acute myeloid leukemia (AML) (N=317; 16.5%), 3) patients who progressed from LR to HR MDS and then AML (LR-HR-AML; N=124; 6.5%), and 4) patients who progressed from LR MDS directly to AML (LR-AML; N=173; 9%). Risk factors for progression included: male gender, low absolute neutrophil count (ANC), low platelet count, high bone marrow (BM) blasts, ferritin >1000 mcg/L, albumin <3.5 g/dL, multi-lineage dysplasia (MLD), and lack of ring sideroblasts. Among patients with marked BM fibrosis (N=49), 18% progressed directly to AML. Somatic mutations (SM) associated with an increased risk of direct or indirect AML progression included SRSF2 and NRAS. SM in IDH1, IDH2 and NPM1 were more common in patients with direct AML transformation. SM associated with progression to higher risk disease only, without AML transformation, were ASXL1, TP53, RUNX1, and CBL. SF3B1 mutation was associated with less progression. About 171 patients (13.1% of all LR-LR patients) died within two years of diagnosis of LR-MDS without disease progression. Among the 61 cases with documented cause of death, 18 patients (29.5%) died from cytopenia and MDS-related complications. Identifying patterns of disease progression of LR MDS patients and their predictive factors will be crucial to be able to tailor therapy accordingly.

Incidence of pleural effusion with dasatinib and the effect of switching therapy to a different TKI in patients with chronic phase CML.

Dasatinib is one of the second generation tyrosine kinase inhibitors (TKI) which is approved for the treatment of patients with chronic phase CML (CP-CML) both in the front line and in the second line setting. Pleural effusion (PE) is a unique toxicity associated with dasatinib use. Our aim was to study the incidence of pleural effusion in our cohort of patients who were treated with dasatinib for CP-CML and the safety upon TKI switch. A total of 390 patients were treated with dasatinib during their course of treatment for CP-CML. A total of 69 patients (17.6%) developed any grade of PE. About 33 (48%) patients developed CTCAE grade 2 PE, 34 (49%) grade 3 and only 1 patient developed grade 4 PE. Recurrence of PE was observed in 34 (49%) patients. While only 12 patients (17.3%) continued using dasatinib after development of PE, dasatinib was discontinued in the other 57 patients. Therapy was switched to bosutinib in 13 patients out of which 6 (46%) patients re-developed PE. While only 12.5% patients developed re-accumulation of pleural fluid in patients switched to imatinib, none of the patients switched to nilotinib re-developed PE. A change in TKI to bosutinib was associated with a 46% risk of recurrence of PE in patients who develop PE on dasatinib for the treatment of CP-CML. The incidence of recurrent PE was markedly lower in patient switched to imatinib or nilotinib.

Drivers of deep molecular response and long-term outcomes in patients with core binding factor acute myeloid leukemia.

A swimmer plot on clinical course of patients undergoing allogeneic stem cell transplant for core binding factor acute myeloid leukemia.

Molecular annotation of extramedullary acute myeloid leukemia identifies high prevalence of targetable mutations.

BACKGROUND: Genomic landscape of extramedullary acute myeloid leukemia (EM-AML), including myeloid sarcoma (MS) and leukemia cutis (LC), is not well characterized. The potential utility of next-generation sequencing (NGS) using EM tissue is not established. METHODS: In this multicenter retrospective study, clinical and NGS data were collected on patients with EM-AML. All statistical analyses were performed in SPSS Statistics (v 26). RESULTS: Our study included 58 patients with EM-AML. The median age at diagnosis was 62 years; 59% of patients had MS and 33% had LC. EM-AML was isolated (i.e., without blood or marrow involvement) in 31% and was first noted at relapse in 60% of patients. Median overall survival in our cohort was 18.2 months overall, with 19.1 months and 11.6 months in the newly diagnosed and the relapsed/refractory patients, respectively. At least one targetable or potentially targetable alteration was present in 52% of patients with EM-site NGS, with 26% IDH1, 21% NPM1, 11% IDH2, 6% FLT3, and 13% KMT2A-PTD. Mutations in IDH1 were significantly more prevalent on NGS from EM tissue than non-EM (blood or marrow) samples (26% vs. 3%; p = .030). Three of four patients treated with IDH inhibitors based on EM-site NGS experienced a complete response. CONCLUSIONS: Targetable mutations are frequent in EM-AML and EM-site NGS is warranted for selecting potential targeted therapies for patients with EM-AML.

Geographic and demographic features of neuroendocrine tumors in the United States of America: A population-based study.

BACKGROUND: The incidence of neuroendocrine tumors (NETs) is rapidly rising. There are very few studies investigating the role of sociodemographic factors in NETs. This study was aimed at examining how geographic and sociodemographic characteristics shape outcomes in the NET population. METHODS: A retrospective analysis using the Surveillance, Epidemiology, and End Results database was performed, and the NET patient population from 1973 to 2015 was studied. Univariate and multivariable analyses were performed to evaluate patients' disease-specific survival (DSS) and overall survival (OS). Geographic and sociodemographic factors, including the location of residence (urban area [UA] vs rural area [RA]), sex, race, insurance status, and marital status, were included in the analysis. RESULTS: A total of 53,034 patients (5517 in RAs and 47,517 in UAs) were included in the analysis. The incidence of NETs was found to be rising in both RAs and UAs but more rapidly in RAs (with the highest incidence in 2006-2015: 5.93 per 100,000 in RAs vs 4.10 per 100,000 in UAs). Patients from RAs presented at advanced stages in comparison with patients from UAs (regional, 18% vs 16%; distant, 15% vs 13%; P < .01). In the multivariable model, RA patients had a trend toward poorer OS (hazard ratio, 1.05; P = .053) in comparison with UA patients. The multivariable analysis showed significantly worse DSS and OS for uninsured, single, and male patients in comparison with insured, married, and female patients, respectively. CONCLUSIONS: This study has identified sociodemographic disparities in NET outcomes. Access to health care could be a potential contributing factor, although differences in environmental exposure, health behavior, and tumor biology could also be responsible.

Venous thromboembolism risk in patients with hormone receptor-positive HER2-negative metastatic breast cancer treated with combined CDK 4/6 inhibitors plus endocrine therapy versus endocrine therapy alone: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Approximately 70% of patients with metastatic breast cancer (MBC) are hormone receptor (HR)-positive. Recent studies have shown that CDK4/6 inhibitors (CDKI) improve survival in combination with ET in HR-positive, HER2-negative MBC. The risk of venous thromboembolism (VTE) is 3-4 times higher in patients with breast cancer (BC) than in patients without cancer. The risk is even higher in BC patients receiving ET and chemotherapy. The aim of the study was to determine the VTE risk of CDKIs plus ET versus ET alone in patients with HR-positive, HER2-negative MBC. METHODS: We performed a systematic review and meta-analysis to demonstrate the risk of VTE in patients with HR-positive HER2-negative MBC treated with combined CDKIs and ET versus ET alone. RESULTS: Eight randomized controlled trials (RCT) with a total of 4,557 patients were eligible. The study arms comprised of palbociclib or ribociclib or abemaciclib plus ET while the control arms utilized placebo plus ET. The VTE events were 56 (2%) in the CDKIs plus ET group compared to 10 (0.5%) in the control group. Pooled relative risk (RR) for VTE was 2.62 (95% CI 1.21-5.65; P = 0.01) and the risk difference (RD) was 0.01 (95% CI 0.00-0.03; P = 0.02). Over a median follow-up of up to 36 months, RR was 3.18 (95% CI 1.22-8.24; P = 0.02) and RD was 0.03 (95% CI 0.01-0.06, P = 0.008). CONCLUSIONS: Our meta-analyses demonstrated that the addition of CDKIs to ET in patients with HR-positive HER 2-negative MBC contribute to a higher incidence of VTE. Further trials are required to define the actual relation and definitive incidence of VTE with different CDKIs.

Risk of kidney toxicity with carfilzomib in multiple myeloma: a meta-analysis of randomized controlled trials.

The incidence and relative risk of kidney toxicity with carfilzomib in multiple myeloma (MM) has been incompletely characterized. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing carfilzomib-based with non-carfilzomib-based regimens in MM to investigate the risk of kidney toxicity. Point estimates were pooled in the form of risk ratios (RR) with 95% confidence intervals (CI) using the random-effects model. We identified four RCTs with 2954 patients. The median duration of treatment ranged from 16.3 to 88 weeks in carfilzomib arms. The cumulative rate of kidney toxicities in the carfilzomib arms was 21.3% for all grades and 8.3% for grades 3-5 toxicities, with acute kidney injury being the predominantly reported event. Patients receiving a carfilzomib-based regimen had a significantly higher risk of total kidney toxicity compared with those in the control arms, with pooled RR of 1.79 (95% CI, 1.43-2.23, p < 0.001) and 2.29 (95% CI, 1.59-3.30; p < 0.001), for all grades and grades 3-5 toxicities, respectively. Despite adjustment for the duration of exposure in treatment arms, pooled incidence rate ratios (IRR) for kidney toxicity was significantly increased in the carfilzomib arm compared with control (pooled IRR of 1.28 for all grades and 1.66 for grades 3-5 toxicity). Subgroup analysis based on carfilzomib dose, infusion length, and treatment setting did not identify any significant subgroup effect. Kidney toxicity is an important adverse effect of carfilzomib-based regimens. Prospective studies should investigate patient-, disease-, and treatment-related risk factors for severe kidney toxicities and impact on long-term outcome.

Breast cancer chemoprevention: An update on current practice and opportunities for primary care physicians.

Several risk assessment models have been validated for the estimation of risk of breast cancer in women. Chemoprevention through hormonal therapy is an effective way to reduce the incidence of breast cancer in women with high risk. Selective estrogen receptor modulators, tamoxifen and raloxifene, are approved for this indication by the United States Food and Drug Administration, and aromatase inhibitors have also shown promise in recent studies. These medications are generally well tolerated, except for reported increased rates of fractures and venous thromboembolic events. Despite strong recommendations from several regulatory bodies, advocacy for chemoprevention has been inadequate in practice, more so among the primary care physicians. Studies have identified several barriers in physicians, patients, and the system, contributing to this problem. Lack of knowledge about risk assessment models and chemoprevention options preclude physicians from prescribing these medications with confidence. Fear of potential adverse events, confusion regarding the purpose of the therapy, and need for continued adherence for five years are among the principal reasons for reduced chemoprevention uptake and early discontinuation among patients. Multifaceted interventions directed at education and training of health care professionals, proper counseling of women at high risk, and promotion of the development of improved medications might help ensure better chemoprevention uptake in the target population.

Pain Severity and Adequacy of Pain Management in Terminally Ill Patients with Cancer: An Experience from North Palestine.

AIM: Chronic pain is common in terminally ill patients with cancer and affects their quality of life. In this study, we wanted to evaluate pain severity and the adequacy of prescribed analgesics in terminally ill patients with cancer in North Palestine. METHODS: We conducted a cross-sectional descriptive study in North Palestine on 77 terminally ill patients with cancer. Pain experience was evaluated with Brief Pain Inventory-Short Form (BPI-SF). Pain management index (PMI) was calculated to determine the adequacy of interventions. The relationships between adequacy of pain management and socioeconomic and clinical factors were analyzed by the covariance method. Statistical analyses were performed using Statistical Package for the Social Sciences (SPSS version 15.0 [SPSS Inc., Chicago, USA]). RESULTS: Fifty-nine patients (76.6%) reported moderate-to-severe pain. According to the PMI, only 64.9% of the patients received adequate pain management. Thirty-five patients (45%) wanted additional treatment or an increase in the dose of pain medications. Although men and women reported similar pain severities, women were more likely to be inadequately treated (P = 0.027). Pain severity was significantly less in patients who received health-care services at least once in the last month before the interview, compared to those without recent access to health care (P = 0.024). CONCLUSION: There is substantial inadequacy in pain management in patients with cancer. The BPI-SF should be routinely used to evaluate pain severity, and analgesics should be prescribed equitably without discrimination with regard to gender and socioeconomic status of patients.

Thrombosis in Philadelphia negative classical myeloproliferative neoplasms: a narrative review on epidemiology, risk assessment, and pathophysiologic mechanisms.

Thrombosis is common in cancer patients and is associated with increased morbidity and mortality. Myeloproliferative neoplasms (MPN) are common malignancies in elderly individuals and are known for a high incidence of thrombotic complications. Different risk factors have been identified in studies, and risk models have been developed to identify patients with MPN at higher risk for thrombosis. Several pathophysiological mechanisms help explain the increased likelihood of thrombosis in these patients. Factors, such as leukocyte and platelet activation leading to the formation of leukocyte-platelet aggregates, activation of the coagulation cascade by microparticles, high levels of inflammatory cytokines, and endothelial dysfunction have a crucial role in thrombosis in MPN patients. Recent studies have demonstrated a significant association between the allele burden of specific genetic mutations (mainly JAK2V617F) associated with MPN and the incidence of thrombotic events, thus suggesting a possible role for these mutations in thrombogenesis.

Characteristic OCT Pattern in Waldenstrom Macroglobulinemia.

PURPOSE: To report characteristic optical coherence tomography (OCT) patterns as a guide in diagnosis of Waldenstrom macroglobulinemia in a patient presenting with bilateral vision loss. CASE REPORT: A 60-year-old male patient presented with bilateral sudden-onset vision loss and low-grade fever. The patient had bilateral exudative retinal detachment involving the macula. Spectral domain OCT revealed neurosensory detachment along with a very regular and harmonious cystoid change in the outer retina as well as deposits around photoreceptors. The patient had lymphadenopathy and hepatosplenomegaly. Serum protein electrophoresis showed the presence of M band in the gamma globulin region, which, on immune fixation, showed a monoclonal band at the "IgM and K" region. Infiltration by lymphoplasmacytic proliferative cells with secondary myelofibrosis was seen in the bone marrow biopsy specimen. The immunophenotype scattergram of lymphoplasmacytic proliferative cells of bone marrow showed no light-chain expression, and the cells were brightly positive for CD19, CD5, and CD20. Quantitative assay of immunoglobulin M was 10,057 mg/dL. CONCLUSIONS: Spectral domain OCT showing a harmonious and regular cystoid pattern and deposits around photoreceptors was a guide in our diagnosis of this case of Waldenstrom macroglobulinemia presenting with retinal detachment and retinal deposits.

Triple-Negative Myelofibrosis: Disease Features, Response to Treatment and Outcomes.

BACKGROUND: Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms. About 90% of cases are driven by constitutive activation of 1 of 3 genes impacting the JAK/STAT pathway: JAK2, CALR, and MPL. Triple-negative myelofibrosis (TN-MF) accounts for only 5%-10% of cases and carries the worst outcomes. Little has been described about this subset of disease. Given the marked heterogeneity surrounding disease biology, clonal architecture, clinical presentation, and poor outcomes in TN-MF, identification of features of interest and assessment of treatment response are areas in need of further investigation. PATIENTS AND METHODS: We collected and evaluated baseline clinical and molecular parameters from 626 patients with a diagnosis of myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa (Florida, US) between 2003 and 2021 and compared them based on presence or absence of the three classical phenotypic driver mutations. RESULTS: A small proportion of patients (6%) harbored TN-MF which correlated with inferior outcomes, marked by a 4-year reduction in overall survival time compared to the non-TN cohort (mOS 37.4 months vs. 85.7 months; P = .009) and higher rates of leukemic transformation. More pronounced thrombocytopenia and anemia, lower LDH, EPO levels, as well as lower percentage of marrow blasts at baseline were more commonly seen in TN-MF (P < .05). Similarly, patients with TN-MF had higher risk disease per DIPSS+ and GIPSS. Mutations impacting RNA splicing, epigenetic modification and signaling, specifically SRSF2, SETBP1, IDH2, CBL, and GNAS, were more commonly seen among those lacking a classical phenotypic driver. The prevalence of co-mutant ASXL1/SRSF2 clones was significantly higher in TN-MF as was trisomy 8. TN patients had fewer responses (46.2% vs. 63.4%) and shorter duration of response to ruxolitinib. CONCLUSION: TN-MF is invariably associated with significantly decreased survival and more aggressive clinical behavior with higher rates of leukemic transformation and shorter duration of response to ruxolitinib. Mutations impacting RNA splicing, epigenetic modification and signaling (SRSF2, SETBP1, IDH2, CBL, and GNAS) are more common in TN-MF, which likely drive its aggressive course and may account for suboptimal responses to JAK inhibition.

Investigation of Serum Albumin as a Dynamic Treatment-Specific Surrogate for Outcomes in Patients With Myelofibrosis Treated With Ruxolitinib.

PURPOSE: Ruxolitinib improves splenomegaly and disease-related symptoms in most patients with myelofibrosis (MF), and it has been associated with a survival benefit in higher-risk patients with splenomegaly. Spleen volume reduction has been associated with a survival benefit in ruxolitinib-treated patients; however, its use as a surrogate is limited. We hypothesized that an anti-inflammatory response to ruxolitinib would correlate with improved patient outcomes. METHODS: We interrogated serum albumin, an acute phase reactant and marker of nutritional status in 590 patients with MF and analyzed differential trajectories of albumin on the basis of ruxolitinib treatment. Additionally, we assessed the prognostic role of baseline albumin and change in albumin. RESULTS: We found that serum albumin levels tend to decrease in patients with MF; however, this tendency is abrogated by ruxolitinib treatment. To that end, baseline serum albumin level correlates with overall survival (OS) in patients with MF, independent of the variables that comprise the dynamic international prognostic scoring system; however, this correlation is limited to ruxolitinib-naïve patients. In ruxolitinib-treated patients, the change in serum albumin after ruxolitinib treatment, rather than the baseline value, is associated with improved OS, a finding not seen in ruxolitinib-naïve patients. CONCLUSION: These findings suggest that serum albumin, a ubiquitously available laboratory value, has specific relevance in patients with MF and reflects therapeutic response to ruxolitinib.

Mutations highly specific for secondary AML are associated with poor outcomes in ELN favorable risk NPM1-mutated AML.

ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous malignancy with outcomes largely predicted by genetic abnormalities. Mutations of NPM1 are common in AML, occurring in ∼30% of cases, and generally considered a favorable risk factor. Mutations highly specific for secondary AML (sMut) have been shown to confer poor prognosis, but the overall impact of these mutations in the setting of favorable-risk AML defined by mutant NPM1 remains unclear. In this multicenter study of patients with AML (n = 233) with NPM1 mutation at diagnosis, we observed that patients with sMut had worse overall survival (OS) than those without sMut (15.3 vs 43.7 months; P = .002). Importantly, this finding persisted in the European LeukemiaNet (ELN) 2017-defined favorable risk subset (14.7 months vs not reached; P < .0001). Among patients who achieved NPM1 measurable residual disease (MRD) negativity, longer OS was observed in the entire cohort (P = .015) as well as in both the sMut subset (MRD negative: median OS (mOS) 73.9 months vs MRD positive: 12.3 months; P = .0170) and sMut ELN 2017-favorable subset (MRD negative: mOS 27.3 vs MRD positive: 10.5 months; P = .009). Co-occurrence of sMut and mutant NPM1 confers a poor prognosis in AML.

Clinical and Genomic-Based Decision Support System to Define the Optimal Timing of Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes.

PURPOSE: Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop and validate a decision support system to define the optimal timing of HSCT for patients with MDS on the basis of clinical and genomic information as provided by the Molecular International Prognostic Scoring System (IPSS-M). PATIENTS AND METHODS: We studied a retrospective population of 7,118 patients, stratified into training and validation cohorts. A decision strategy was built to estimate the average survival over an 8-year time horizon (restricted mean survival time [RMST]) for each combination of clinical and genomic covariates and to determine the optimal transplantation policy by comparing different strategies. RESULTS: Under an IPSS-M based policy, patients with either low and moderate-low risk benefited from a delayed transplantation policy, whereas in those belonging to moderately high-, high- and very high-risk categories, immediate transplantation was associated with a prolonged life expectancy (RMST). Modeling decision analysis on IPSS-M versus conventional Revised IPSS (IPSS-R) changed the transplantation policy in a significant proportion of patients (15% of patient candidate to be immediately transplanted under an IPSS-R-based policy would benefit from a delayed strategy by IPSS-M, whereas 19% of candidates to delayed transplantation by IPSS-R would benefit from immediate HSCT by IPSS-M), resulting in a significant gain-in-life expectancy under an IPSS-M-based policy (P = .001). CONCLUSION: These results provide evidence for the clinical relevance of including genomic features into the transplantation decision making process, allowing personalizing the hazards and effectiveness of HSCT in patients with MDS.