VEXAS syndrome: A review of bone marrow aspirate and biopsies reporting myeloid and erythroid precursor vacuolation.

Myeloid and erythroid precursor vacuolation is a common dysplastic finding associated with myeloid malignancies, toxins, drug, and nutritional deficiencies. It has been described as a core morphologic feature in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. We sought to determine the number of cases attributable to VEXAS syndrome in bone marrow biopsies and aspirates (BAMB) reporting myeloid precursor vacuolation. We reviewed 1318 individual BAMB reports from January 2020 to July 2021 where "vacuole(s)," "vacuolation," or "vacuolated" was reported. Bone marrow biopsies with vacuolation confined to blasts or those completed as routine workup prior to stem cell transplant or post induction chemotherapy for AML (acute myeloid leukemia) were excluded. Myeloid and erythroid precursor vacuolation was noted in 219 reports representing 210 patients. The most common etiology was myelodysplastic syndrome (MDS) (38.6%), AML (16.7%), lymphoproliferative disorders and multiple myeloma (7.6%), drug or toxin exposure (5.2%) myeloproliferative neoplasm (MPN) or MPN/MDS overlap syndrome (4.3%). VEXAS syndrome was determined to be the etiology in 2.9% of patients. Two additional cases of VEXAS syndrome with bone marrow biopsies reported in the specified time frame did not explicitly report myeloid or erythroid precursor vacuolation but were identified based on clinical suspicion and repeat BAMB review. Myeloid and erythroid precursor vacuolation is a dysplastic feature attributable to VEXAS syndrome in at least 2.9% of cases. Standardized reporting of vacuolization, triaging of molecular sequencing and optimal treatment of this disorder are critical issues facing those seeing patients with suspected VEXAS syndrome.

A young woman with persistent sore throat, Epstein-Barr virus, lymphadenopathy, and aberrant CD4 + CD7- T-cells.

A young woman with persistent EBV viremia and lymphocytosis had an abnormal CD4- T cell population with aberrant loss of CD7. She had a diagnosis of chronic active EBV (CAEBV), a lymphoproliferative disorder for which she ultimately required allogeneic hematopoietic stem cell transplantation.

High transferrin saturation predicts inferior clinical outcomes in patients with myelodysplastic syndromes.

Iron overload (IO) reflected by elevated ferritin is associated with increased mortality in myelodysplastic syndromes (MDS), however, ferritin is an imperfect metric. Elevated labile plasma iron correlates with clinical outcomes and transferrin saturation (TSAT) >80%, but is not readily measurable. The trajectory of TSAT, and its association with clinical outcomes remain undefined. Canadian MDS registry patients were evaluated. Mean TSAT, mean ferritin and transfusion dose density (TDD) were determined. Survival was evaluated by TSAT and ferritin (<50%, 50-80%, >80%), (≤500 µg/L, 501-800 µg/L, >800 µg/L). In 718 patients, median age was 74 years; 12%, 31%, 29%, 15% and 13% were IPSS-R very low, low, intermediate, high and very high. TSAT and ferritin were moderately correlated (r=0.63, P<0.0001). TSAT increased over time in transfusion- dependent patients (P=0.006). Higher TSAT and ferritin were associated with inferior 5-year overall (OS), progression- free (PFS), and leukemia-free survival (LFS) (P≤0.008) and higher TDD with inferior 5-year OS. TSAT >80% trended with inferior cardiac death-free survival (P=0.053). In univariate analysis, age, IPSS-R, blast percentage by Eastern Cooperative Oncology Group Performance Status, frailty, Charlson Comorbidity Index, iron chelation (Y/N), TDD, TSAT and ferritin were significantly associated with inferior OS. By multivariable analysis, TSAT >80% (P=0.007) remained significant for OS (R2 30.3%). In MDS, TSAT >80% and ferritin >800 µg/L portended inferior OS, PFS and LFS. TSAT may indicate the presence of oxidative stress, and is readily measurable in a clinical setting. The relationship between TSAT and cardiac death-free survival warrants further study.

Incidence and socioeconomic factors in older adults with acute myeloid leukaemia: Real-world outcomes from a population-based cohort.

OBJECTIVES: Acute myeloid leukaemia (AML) is a disease of older adults, who are vulnerable to socio-economic factors. We determined AML incidence in older adults and the impact of socio-economic factors on outcomes. METHODS: We included 3024 AML patients (1996-2016) identified from a population-based registry. RESULTS: AML incidence in patients ≥60 years increased from 11.01 (2001-2005) to 12.76 (2011-2016) per 100 000 population. Among 879 patients ≥60 years in recent eras (2010-2016), rural residents (<100 000 population) were less likely to be assessed by a leukaemia specialist (39% rural, 47% urban, p = .032); no difference was seen for lower (43%, quintile 1-3) vs. higher (47%, quintile 4-5) incomes (p = .235). Similar numbers received induction chemotherapy between residence (16% rural, 18% urban, p = .578) and incomes (17% lower, 17% high, p = 1.0). Differences between incomes were seen for hypomethylating agent treatment (14% low, 20% high, p = .041); this was not seen for residence (13% rural, 18% urban, p = .092). Among non-adverse karyotype patients ≥70 years, 2-year overall survival was worse for rural (5% rural, 12% urban, p = .006) and lower income (6% low, 15% high, p = .017) patients. CONCLUSIONS: AML incidence in older adults is increasing, and outcomes are worse for older rural and low-income residents; these patients face treatment barriers.

Iron overload in myelodysplastic syndromes: Evidence based guidelines from the Canadian consortium on MDS.

In 2008 the first evidence-based Canadian consensus guideline addressing the diagnosis, monitoring and management of transfusional iron overload in patients with myelodysplastic syndromes (MDS) was published. The Canadian Consortium on MDS, comprised of hematologists from across Canada with a clinical and academic interest in MDS, reconvened to update these guidelines. A literature search was updated in 2017; topics reviewed include mechanisms of iron overload induced cellular damage, evidence for clinical endpoints impacted by iron overload including organ dysfunction, infections, marrow failure, overall survival, acute myeloid leukemia progression, and endpoints around hematopoietic stem-cell transplant. Evidence for an impact of iron reduction on the same endpoints is discussed, guidelines are updated, and areas identified where evidence is suboptimal. The guidelines address common questions around the diagnosis, workup and management of iron overload in clinical practice, and take the approach of who, when, why and how to treat iron overload in MDS. Practical recommendations for treatment and monitoring are made. Evidence levels and grading of recommendations are provided for all clinical endpoints examined.

Outcomes of Intermediate Risk Karyotype Acute Myeloid Leukemia in First Remission Undergoing Autologous Stem Cell Transplantation Compared With Allogeneic Stem Cell Transplantation and Chemotherapy Consolidation: A Retrospective, Propensity-score Adjusted Analysis.

INTRODUCTION: Optimal post-remission therapy (PRT) for intermediate risk acute myeloid leukemia remains an area of ongoing research. We aimed to retrospectively compare outcomes following autologous stem cell transplantation (autoSCT) with allogeneic SCT (alloSCT) and consolidation chemotherapy (CMT) in patients with intermediate-risk karyotype AML in first complete remission. PATIENTS AND METHODS: We compared overall survival (OS) and leukemia-free survival (LFS) using propensity score (PS)-adjusted analysis of patients receiving PRT with autoSCT, matched sibling (MSD) alloSCT, unrelated/mismatch (UD/MM) alloSCT, and CMT. We included patients diagnosed between 1984 and 2003 (period of autoSCT at our center) in CR1 following induction CMT and received at least 2 consolidative cycles. RESULTS: We identified 190 patients (62 MSD-alloSCT, 18 UD/MM-alloSCT, 30 autoSCT, and 80 CMT). Baseline characteristics were used for PS calculation and were well-balanced after weight adjustment. The median follow-up for patients surviving beyond 1 year was 8.7 years. We excluded 55 patients based on PS calculation. Adjusted multivariate hazard ratio (HR), 95% confidence interval (CI) and P-value for OS, considering CMT as reference, were: MSD-alloSCT (HR, 0.4; 95% CI, 0.2-0.8; P = .009), UD/MM-alloSCT (HR, 1.5; 95% CI, 0.6-3.9; P = .363), and autoSCT (HR, 1.2; 95% CI, 0.5-3.1; P = .666), respectively. Adjusted multivariate HR, 95% CI and P-value for LFS were MSD-alloSCT (HR, 0.3; 95% CI, 0.2-0.6; P < .001), UD/MM-alloSCT (HR, 1.1; 95% CI, 0.4-2.7; P = .854), and autoSCT (HR, 0.8; 95% CI, 0.3-2.2; P = .697), respectively. CONCLUSION: Patients with intermediate risk-karyotype acute myeloid leukemia who underwent MSD-alloSCT in first complete remission had the best outcomes. There were no survival differences between autoSCT, UD/MM-alloSCT, and CMT. Further study incorporating molecular changes and minimal residual disease status is warranted to select appropriate patients for autoSCT.

Excellent real-world outcomes of adults with Burkitt lymphoma treated with CODOX-M/IVAC plus or minus rituximab.

Treatment of Burkitt lymphoma (BL) with intensive, multi-agent chemotherapy with aggressive central nervous system (CNS) prophylaxis results in high cure rates, although no regimen is standard of care. We examined population-based survival outcomes of adults with BL treated with a modified combination of cyclophosphamide, vincristine, doxorubicin, prednisone and systemic high-dose methotrexate (MTX) (CODOX-M) with IVAC (ifosfamide, mesna, etoposide, cytarabine and intrathecal MTX) (CODOX-M/IVAC) ± rituximab over a 15-year period in British Columbia. For the 81 patients identified (including 8 with CNS involvement and 18 with human immunodeficiency virus-associated BL), 5-year progression-free survival (PFS) and overall survival (OS) were 75% [95% confidence interval (CI): 63-83%] and 77% (95% CI: 66-85%), respectively, with no treatment-related deaths. Those who completed the regimen per protocol (n = 38) had significantly improved 5-year PFS 86% (P = 0·04) and OS 92% (P = 0·008), as did those under 60 years with 5-year PFS 82% (P = 0·005) and OS 86% (P = 0·002), which remained significant in multivariate analysis [PFS: hazard ratio (HR) 3·36, P = 0·018; OS HR 4·03, P = 0·012]. Incorporation of high-dose systemic methotrexate also significantly affected multivariate survival outcomes (OS HR 0·28, P = 0·025). Stem cell transplant in first remission had no effect on OS or PFS. This large, real-world analysis of BL patients treated with CODOX-M/IVAC ± rituximab demonstrates excellent survival outcomes comparable to clinical trials. These results help to serve as a benchmark when comparing curative therapies for BL patients as novel regimens are incorporated into clinical practice.

A predictive model of response to erythropoietin stimulating agents in myelodysplastic syndrome: from the Canadian MDS patient registry.

Prediction of response to erythropoietin stimulating agents (ESAs) in anemic MDS patients is often based on the Nordic score. We wished to validate the Nordic score (IWG 2006 response criteria) in a larger cohort and determine if other variables such as IPSS/IPSS-R, ferritin, LDH, and a novel European ESA response score (Santini 2013) were of prognostic importance. We analyzed 208 ESA-treated MDS patients (WHO 2008 criteria) from a prospective registry. Ninety-four and 93% had lower risk scores by IPSS (low/int - 1) and IPSS-R (low/very low), respectively. Erythroid response was achieved in 94 patients (47%); responses were similar with erythropoietin (50%) and darbepoetin (39%; p = 0.2). The Nordic and European scores were both validated on univariate analysis. Variables independently predictive of response in multivariate analysis were low-risk IPSS score (OR 0.1, p = 0.0016) and serum EPO level < 100 mIU/mL (OR 8.7, p < 0.0001). We propose a new ESA response score, consisting of (a) IPSS low score (1 point) and (b) serum EPO levels < 100 mIU/ml (2 points), yielding scores ranging from 0 to 3, with response rates varying from 17 to 81%. The Nordic score has validity but we observed lower than the expected response rates in the best risk group. Our proposed scoring system appears more discriminating but needs validation.

ITACA: A new validated international erythropoietic stimulating agent-response score that further refines the predictive power of previous scoring systems.

BACKGROUND: In 'real-life', the Nordic score guides Erythropoietic stimulating agent (ESA) use in lower-risk myelodysplastic syndrome (MDS) with predicted response rates of 25% or 74%. As new treatments emerge, a more discriminating score is needed. OBJECTIVES: To validate existing ESA predictive scores and develop a new score that identifies non-responders. METHODS: ESA-treated patients were identified in 3 MDS registries in Italy and Canada (FISM 555, GROM 233, and MDS-CAN 208). Clinical and disease-related variables were captured. Nordic, MDS-CAN, and IPSS-R-based ESA scores were calculated and documented ESA responses compared. RESULTS: 996 ESA-treated patients were identified. Overall response rate (ORR) was 59%. The database was randomly divided into balanced derivation (n = 463) and validation (n = 462) cohorts. By multivariate analysis, transfusion independence, erythropoietin (EPO) level <100 IU/L, and IPSS low-risk were independently predictive of response. Assigning a score of 1 to each resulted in a scoring system of 0-3 with response rates of 23%, 43%, 67%, and 85%. ORR was concordant in the validation cohort. The 'ITACA' score had the highest discriminating power of response. CONCLUSION: ITACA is an internally-validated predictive SS of ESA response in real-life 'good risk' MDS patients derived from a large international dataset that surpasses others. The incorporation of biologic markers to better identify non-responders is still needed.

Overall survival in lower IPSS risk MDS by receipt of iron chelation therapy, adjusting for patient-related factors and measuring from time of first red blood cell transfusion dependence: an MDS-CAN analysis.

Analyses suggest iron overload in red blood cell (RBC) transfusion-dependent (TD) patients with myleodysplastic syndrome (MDS) portends inferior overall survival (OS) that is attenuated by iron chelation therapy (ICT) but may be biassed by unbalanced patient-related factors. The Canadian MDS Registry prospectively measures frailty, comorbidity and disability. We analysed OS by receipt of ICT, adjusting for these patient-related factors. TD International Prognostic Scoring System (IPSS) low and intermediate-1 risk MDS, at RBC TD, were included. Predictive factors for OS were determined. A matched pair analysis considering age, revised IPSS, TD severity, time from MDS diagnosis to TD, and receipt of disease-modifying agents was conducted. Of 239 patients, 83 received ICT; frailty, comorbidity and disability did not differ from non-ICT patients. Median OS from TD was superior in ICT patients (5·2 vs. 2·1 years; P < 0·0001). By multivariate analysis, not receiving ICT independently predicted inferior OS, (hazard ratio for death 2·0, P = 0·03). In matched pair analysis, OS remained superior for ICT patients (P = 0·02). In this prospective, non-randomized analysis, receiving ICT was associated with superior OS in lower IPSS risk MDS, adjusting for age, frailty, comorbidity, disability, revised IPSS, TD severity, time to TD and receiving disease-modifying agents. This provides additional evidence that ICT may confer clinical benefit.

Patient-related factors independently impact overall survival in patients with myelodysplastic syndromes: an MDS-CAN prospective study.

UNLABELLED: Little is known about the effects of frailty, disability and physical functioning on the clinical outcomes for myelodysplastic syndromes (MDS). We investigated the predictive value of these factors on overall survival (OS) in 445 consecutive patients with MDS and chronic monomyelocytic leukaemia (CMML) enrolled in a multi-centre prospective national registry. Frailty, comorbidity, instrumental activities of daily living, disability, quality of life, fatigue and physical performance measures were evaluated at baseline and were added as covariates to conventional MDS-related factors as predictors of OS in Cox proportional hazards models. The median age was 73 years, and 79% had revised International Prognostic Scoring System (IPSS-R) risk scores of intermediate or lower. Frailty correlated only modestly with comorbidity. OS was significantly shorter for patients with higher frailty and comorbidity scores, any disability, impaired grip strength and timed chair stand tests. By multivariate analysis, the age-adjusted IPSS-R, frailty (Hazard ratio 2·7 (95% confidence interval [CI] 1·7-4·2), P < 0·0001) and Charlson comorbidity score (Hazard ratio 1·8 (95% CI 1·1-2·8), P = 0·01) were independently prognostic of OS. Incorporation of frailty and comorbidity scores improved risk stratification of the IPSS-R by 30% and 5%, respectively. These data demonstrate for the first time, the importance of considering frailty in prognostic models and a potential target for therapeutic intervention in optimizing clinical outcomes in older MDS patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02537990.

Heterogeneity of chronic graft-versus-host disease biomarkers: association with CXCL10 and CXCR3+ NK cells.

Chronic graft-versus-host disease (cGVHD) remains one of the most significant long-term complications after allogeneic blood and marrow transplantation. Diagnostic biomarkers for cGVHD are needed for early diagnosis and may guide identification of prognostic markers. No cGVHD biomarker has yet been validated for use in clinical practice. We evaluated both previously known markers and performed discovery-based analysis for cGVHD biomarkers in a 2 independent test sets (total of 36 cases ≤1 month from diagnosis and 31 time-matched controls with no cGVHD). On the basis of these results, 11 markers were selected and evaluated in 2 independent replication cohorts (total of 134 cGVHD cases and 154 controls). cGVHD cases and controls were evaluated for several clinical covariates, and their impact on biomarkers was identified by univariate analysis. The 2 replications sets were relatively disparate in the biomarkers they replicated. Only sBAFF and, most consistently, CXCL10 were identified as significant in both replication sets. Other markers identified as significant in only 1 replication set included intercellular adhesion molecule 1 (ICAM-1), anti-LG3, aminopeptidase N, CXCL9, endothelin-1, and gelsolin. Multivariate analysis found that all covariates evaluated affected interpretation of the biomarkers. CXCL10 had an increased significance in combination with anti-LG3 and CXCL9, or inversely with CXCR3(+)CD56(bright) natural killer (NK) cells. There was significant heterogeneity of cGVHD biomarkers in a large comprehensive evaluation of cGVHD biomarkers impacted by several covariates. Only CXCL10 strongly correlated in both replication sets. Future analyses for plasma cGVHD biomarkers will need to be performed on very large patient groups with consideration of multiple covariates.

Allogeneic Hematopoietic Stem Cell Transplantation Is an Effective Salvage Therapy for Patients with Chronic Myeloid Leukemia Presenting with Advanced Disease or Failing Treatment with Tyrosine Kinase Inhibitors.

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only known curative therapy for chronic myeloid leukemia (CML); however, it is rarely utilized given the excellent long-term results with tyrosine kinase inhibitor (TKI) treatment. The purpose of this study is to examine HSCT outcomes for patients with CML who failed TKI therapy or presented in advanced phase and to identify predictors of survival, relapse, and nonrelapse mortality (NRM). Fifty-one patients with CML underwent HSCT for advanced disease at diagnosis (n = 15), TKI resistance as defined by the European LeukemiaNet guidelines (n = 30), TKI intolerance (n = 2), or physician preference (n = 4). At a median follow-up of 71.9 months, the 8-year overall survival (OS), event-free survival (EFS), relapse, and NRM were 68%, 46%, 41%, and 23%, respectively. In univariate analysis, predictors of OS included first chronic phase (CP1) disease status at HSCT (P = .0005), European Society for Blood and Marrow Transplantation score 1 to 4 (P = .04), and complete molecular response (CMR) to HSCT (P < .0001). Donor (female) to patient (male) gender combination (P = .02) and CMR to HSCT (P < .0001) predicted lower relapse. In multivariate analysis, CMR to HSCT remained an independent predictor of OS (odds ratio [OR], 43), EFS (OR, 56) and relapse (OR, 29). This report indicates that the outlook is excellent for those patients who remain in CP1 at the time of HSCT and achieve a CMR after HSCT. However, only approximately 50% of those in advanced phase at HSCT are long-term survivors. This highlights the ongoing need to try to identify patients earlier, before disease progression, who are destined to fail this treatment to optimize transplantation outcomes.

Outcome of Patients With Non-Hodgkin Lymphomas With Concurrent MYC and BCL2 Rearrangements Treated With CODOX-M/IVAC With Rituximab Followed by Hematopoietic Stem Cell Transplantation.

BACKGROUND: Double-hit lymphoma is characterized by the presence of concurrent MYC (myelocytomatosis oncogene) and BCL2 (B-cell lymphoma 2) gene rearrangements. Prognosis is poor with standard chemoimmunotherapy. Since 2003, the British Columbia Cancer Agency has used CODOX-M/IVAC+R (cyclophosphamide, vincristine, doxorubicin, methotrexate, cytarabine, ifosfamide, and etoposide, combined with rituximab) followed by consolidative hematopoietic cell transplantation as definitive treatment for double-hit lymphoma. PATIENTS AND METHODS: A retrospective review of the survival outcomes of patients with double-hit lymphoma treated at our institution was conducted. Thirty-two patients diagnosed with non-Hodgkin lymphoma with concurrent MYC and BCL2 translocations from 2003 to 2013 were identified. Cases with MYC or BCL2 amplification and those with overexpression in immunohistochemistry analysis were excluded. RESULTS: Median age at diagnosis was 53.0 years (range, 35.5-70.9 years), 23 (72%) were male, and 30 (94%) had stage III to IV disease. CODOX-M/IVAC+R was administered in 25 (78%) patients and 20 (80%) achieved a partial remission or better, of which 9 (36%) had a complete remission. Nineteen of the 32 (59%) patients underwent upfront hematopoietic cell transplantation. At a median follow-up of living patients of 26.4 months, 14 (44%) were alive in remission, 15 (47%) died, and 3 (9%) were alive in relapse. The 2-year progression-free survival (PFS) and overall survival (OS) of all patients were 41% and 53%, respectively. The sixteen patients treated with CODOX-M/IVAC+R followed by hematopoietic cell transplantation had a 2-year PFS of 60% and 2-year OS of 82%. CONCLUSION: Patients with double-hit lymphoma treated with CODOX-M/IVAC+R followed by hematopoietic cell transplantation can achieve durable remissions, although disease progression before transplantation remains a significant problem.

Normal karyotype CALLA-positive adult pre-B ALL: dismal outcome with chemotherapy for patients with loss/gain of ABL1 and/or BCR FISH signals.

BACKGROUND: Diagnostic karyotype and molecular studies represent the most powerful prognostic indicators in acute myeloid leukemia and provide the framework for risk stratification. Risk stratification in ALL has also a vital role in predicting outcome and identifying patients at higher risk of relapse with multiagent chemotherapy, but the role of diagnostic karyotype and molecular markers in adult ALL is limited to few well recognized cytogenetic abnormalities. PATIENTS AND METHODS: We report a case series of 6 adult ALL patients with a characteristic molecular abnormality that have done poorly with chemotherapy. Between April 2004 and November 2009, 72 adult ALL patients (Pre-B-cell 61; T-cell 11) were referred to and treated at the Leukemia/BMT Program of BC in Vancouver, Canada. FISH for BCR-ABL fusion was positive in 12 of 61 Pre-B cell ALL patients. An additional 6 patients were negative for this typical fusion but had FISH abnormalities related to BCR and/or ABL1. RESULTS: In this report, we describe the clinical and hematopathologic characteristics of these 6 patients and their poor outcome. We review the literature where only 2 similar cases with normal karyotype Pre-B ALL and associated FISH BCR/ABL1 numerical abnormalities were found. CONCLUSION: We recommend screening all adult pre-B ALL patients with normal karyotype for this clonal abnormality and suggest classifying these ALL patients into the high-risk category.