Abstract

The hypomethylating agents (HMAs) azacytidine (AZA) and decitabine (DAC) are usually administered after the failure of erythropoietin-stimulating agents for lower-risk myelodysplastic syndromes (LR-MDS). However, it is unclear whether one of these HMAs has superior efficacy and safety. This was investigated in the present study by means of a meta-analysis of prospective studies published between January 1990 and July 2020 in PubMed, EMBASE, CENTRAL, and ClinicalTrials.gov databases; 19 studies with 1076 patients were included in the final analysis. The transfusion independence (TI) rate (66.7% [95% confidence interval: 41.7%-87.4%]) was higher with AZA 75 mg/m(2)/day for 7 days than with other regimens (all p<0.025). The proportion of patients with intermediate-1 risk influenced overall survival (p<0.05). There were no differences in treatment response, survival, and adverse event rates between patients treated with AZA (75 mg/m(2)/day for 5 days) and DAC (20 mg/m(2)/day for 3 days), although the latter group had a higher rate of grade 3/4 anemia (15.8% vs 0.0%; p<0.0001) and lower rate of diarrhea/constipation (6.9% vs 25.0%; p=0.002). Thus, both HMAs at high doses achieved reasonable response and TI rates with acceptable side effects, but did not prolong the overall survival in LR-MDS patients.

Abstract

Myelodysplastic syndromes (MDS) are a group of malignant hematologic diseases characterized by ineffective hematopoiesis, which may lead to chronic anemia and transfusion dependency, with up to 30% of patients progressing to acute myeloid leukemia (AML). Studies suggest transfusion dependency may impact overall survival (OS); however, there is a lack of evidence concerning the association between transfusion status (TS) and OS in patients with MDS who become transfusion independent (TI) after treatment. In addition, the holistic impact of TS on other clinical, economic, and humanistic outcomes has not been well understood. We conducted a systematic literature review (SLR) to understand this impact. Ten studies were included and showed consistent decrease in OS in transfusion dependent (TD) compared with TI patients. These findings were confirmed by a meta-analysis (MA) reporting better OS prognosis for TI patients. A second SLR was conducted to understand the association between TS and other clinical, economic, and humanistic outcomes. Twenty-eight studies were included and showed better prognosis for other outcomes, including AML progression and leukemia-free survival for TI patients. Risk of AML progression and cumulative non-leukemic death assessed by the MA showed a trend toward worse prognosis and higher risk of AML progression for TD patients. Lower healthcare resource utilization, better quality of life, and reduced non-leukemic death for TI patients were observed. Studies not eligible for MA also showed better clinical, economic and humanistic outcomes for TI patients. These findings contribute to understanding the association between transfusion dependence and OS among other outcomes in patients with MDS.

Abstract

PURPOSE Impaired response to erythropoietin underlies ineffective erythropoiesis and anemia in myelodysplastic syndromes (MDS). We investigated whether treatment with lenalidomide (LEN), which augments erythropoietin receptor signaling in vitro, can restore and improve hemoglobin response to epoetin (EPO) alfa in patients with lower-risk, non-del(5q) MDS who have anemia that is refractory to or have low probability of benefit from treatment with recombinant erythropoietin. METHODS In a phase III, US intergroup trial, we randomly assigned patients to receive either LEN and EPO alfa or LEN alone following stratification by serum erythropoietin concentration and prior erythropoietin treatment. RESULTS A total of 195 evaluable patients were randomly assigned: 99 patients to the LEN-EPO alfa cohort and 96 to LEN alone. After four cycles of treatment, the primary end point of major erythroid response (MER) was significantly higher (28.3%) with the combination compared with LEN alone (11.5%) (P = .004). Among 136 patients who completed 16 weeks of study treatment, 38.9% and 15.6% achieved MER, respectively (P = .004). Additionally, minor erythroid response was achieved in 18.2% and 20.8% of patients, for an overall erythroid response rate of 46.5% versus 32.3%. Among LEN nonresponders, 38 crossed over to the addition of EPO alfa with 10 patients (26.3%) achieving a MER. Responses to the combined treatment were highly durable with a median MER duration of 23.8 months compared with 13 months with LEN alone. CONCLUSION LEN restores sensitivity to recombinant erythropoietin in growth factor-insensitive, lower-risk, non-del(5q) MDS, to yield a significantly higher rate and duration of MER compared with LEN alone (funded by the National Cancer Institute; E2905 ClinicalTrials.gov identifier: NCT02048813).

Abstract

Clinically significant bleeding in patients with hematologic malignancies is a heterogeneous composite outcome currently defined as World Health Organization (WHO) bleeding Grades 2, 3, and 4. However, the clinical significance of some minor bleeds categorized as WHO Grades 1 and 2 remains controversial. We analyzed the number and frequency of individual signs and symptoms of WHO Grades 1 and 2 bleeds and explored their association with more severe incident bleeds graded as WHO Grades 3 and 4. STUDY DESIGN AND METHODS We aggregated daily bleeding assessment data from three randomized controlled trials conducted in patients with hematologic malignancies that used bleeding as an outcome. Cox proportional hazard regression analysis was used to identify signs and symptoms categorized as WHO Grades 1 and 2 bleeds that were associated with more severe bleeds (Grades 3 and 4). RESULTS We collected data from 315 patients (n = 5476 daily bleeding assessments; 3383 [61.8%] with a bleed documented). A total of 98.3% (3326/3383) were Grade 1 and 2 bleeds and 1.7% (57/3383) were Grades 3 and 4. Grade 1 and 2 bleeds were composed of 20 different bleeding signs and symptoms. Hematuria (hazard ratio, 16.1; 95% confidence interval, 4.4-59.2; P < .0001) was associated with incident Grade 3 or 4 bleeds. CONCLUSION In patients with hematologic malignancy, only hematuria (microscopic and/or macroscopic) was associated with more severe incident bleeds. This findings require validation in independent data sets.

Abstract

Background: Iron chelation therapy (ICT) in patients with lower-risk myelodysplastic syndromes (MDS) has not been evaluated in randomized studies. Objective: To evaluate event-free survival (EFS) and safety of ICT in iron-overloaded patients with low- or intermediate-1-risk MDS. Design: Multicenter, randomized, double-blind, placebo-controlled trial (TELESTO). (ClinicalTrials.gov: NCT00940602). Setting: 60 centers in 16 countries. Participants: 225 patients with serum ferritin levels greater than 2247 pmol/L; prior receipt of 15 to 75 packed red blood cell units; and no severe cardiac, liver, or renal abnormalities. Intervention: Deferasirox dispersible tablets (10 to 40 mg/kg per day) (n = 149) or matching placebo (n = 76). Measurements: The primary end point was EFS, defined as time from date of randomization to first documented nonfatal event (related to cardiac or liver dysfunction and transformation to acute myeloid leukemia) or death, whichever occurred first. Results: Median time on treatment was 1.6 years (interquartile range [IQR], 0.5 to 3.1 years) in the deferasirox group and 1.0 year (IQR, 0.6 to 2.0 years) in the placebo group. Median EFS was prolonged by approximately 1 year with deferasirox versus placebo (3.9 years [95% CI, 3.2 to 4.3 years] vs. 3.0 years [CI, 2.2 to 3.7 years], respectively; hazard ratio, 0.64 [CI, 0.42 to 0.96]). Adverse events occurred in 97.3% of deferasirox recipients and 90.8% of placebo recipients. Exposure-adjusted incidence rates of adverse events (≥15 events per 100 patient treatment-years) in deferasirox versus placebo recipients, respectively, were 24.7 versus 23.9 for diarrhea, 21.8 versus 18.7 for pyrexia, 16.7 versus 22.7 for upper respiratory tract infection, and 15.9 versus 0.9 for increased serum creatinine concentration. Limitations: The protocol was amended from a phase 3 to a phase 2 study, with a reduced target sample size from 630 to 210 participants. There was differential follow-up between treatment groups. Conclusion: The findings support ICT in iron-overloaded patients with low- to intermediate-1-risk MDS, with longer EFS compared with placebo and a clinically manageable safety profile. Therefore, ICT may be considered in these patients. Primary Funding Source: Novartis Pharma AG.

Abstract

BACKGROUND Up to 20% of patients with acute myeloid leukemia (AML) present with hyperleukocytosis, usually defined as a white blood cell (WBC) count greater than 100 × 10(9) /L. Given the high early mortality rate, emergent cytoreduction with either leukapheresis, hydroxyurea, or chemotherapy is indicated, but the optimal strategy is unknown. STUDY DESIGN AND METHODS For this systematic review and meta-analysis we searched MEDLINE and EMBASE via Ovid, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science from inception through March 2020 for multiarm studies comparing early mortality rates of patients with AML treated with leukapheresis and those who were not. The risk ratio (RR) of early death for patients who received leukapheresis vs patients who did not was estimated using a sum of the log-ratio of individual study estimates weighted by sample size. RESULTS Among 13 two-arm, retrospective studies with 1743 patients (486 leukapheresis and 1257 nonleukapheresis patients), leukapheresis did not improve the primary outcome of early mortality compared to treatment strategies in which leukapheresis was not used (RR, 0.88; 95% confidence interval [CI], 0.69-1.13; P = .321) without statistically significant heterogeneity between studies (Cochran's Q, 18; P = .115; I(2) , 33.4%). Patients presenting with clinical leukostasis tended to be more likely to undergo leukapheresis (odds ratio, 2.01; 95% CI, 0.99-4.08; P = .052). CONCLUSION As we did not find evidence of a short-term mortality benefit and considering the associated complications and logistic burden, our results argue against the routine use of leukapheresis for hyperleukocytosis among patients with AML.

Abstract

BACKGROUND Many clinical and demographic factors can influence survival of patients with hematological malignancies who have intracranial hemorrhages. Understanding the influence of these factors on patient survival can guide treatment decisions and may inform prognostic discussions. We conducted a systematic literature review to determine survival of patients with intracranial hemorrhages and concomitant hematologic malignancy. METHODS A systematic literature review was conducted and followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Pubmed/MEDLINE, Web of Science, Ovid, SCOPUS, and Embase databases were queried with the following terms: ("intracranial hemorrhages" OR "brain hemorrhage" OR "cerebral hemorrhage" OR "subdural hematoma" OR "epidural hematoma" OR "intraparenchymal hemorrhage") AND ("Hematologic Neoplasms" OR "Myeloproliferative Disorders" OR "Myelofibrosis" OR "Essential thrombocythemia" OR "Leukemia"). Abstracts and articles were screened according to inclusion and exclusion criteria that were determined a priori. RESULTS Literature review yielded 975 abstracts from which a total of 68 full-text articles were reviewed. 12 articles capturing 634 unique patients were included in the final qualitative analysis. Median overall survival for all patients ranged from 20 days - 1.5 months while median overall survival for the subset of patients having ICH within 10 days of diagnosis of hematological malignancy was 5 days. Intraparenchymal hemorrhages, multiple foci of hemorrhage, transfusion-resistant low platelet counts, leukocytosis, low GCS scores at presentation, and ICH early in treatment course were associated with worse outcomes. CONCLUSIONS Survival for patients with hematological malignancies and concomitant ICHs remains poor. Early detection, recognition of poor prognostic and correction of hematological abnormalities appears essential to prevention and treatment of ICHs in this patient population.

Abstract

Optimal red cell transfusion support in myelodysplastic syndromes (MDS) has not been tested and established. The aim of this study was to demonstrate feasibility of recruitment and follow-up in an outpatient setting with an exploratory assessment of quality of life (QoL) outcomes (EORTC QLQ-C30 and EQ-5D-5L). We randomised MDS patients to standardised transfusion algorithms comparing current restrictive transfusion thresholds (80 g/l, to maintain haemoglobin 85-100 g/l) with liberal thresholds (105 g/l, maintaining 110-125 g/l). The primary outcomes were measures of compliance to transfusion thresholds. Altogether 38 patients were randomised (n = 20 restrictive; n = 18 liberal) from 12 participating sites in UK, Australia and New Zealand. The compliance proportion for the intention-to-treat population was 86% (95% confidence interval 75-94%) and 99% (95-100%) for restrictive and liberal arms respectively. Mean pre-transfusion haemoglobin concentrations for restrictive and liberal arms were 80 g/l (SD6) and 97 g/l (SD7). The total number of red cell units transfused on study was 82 in the restrictive and 192 in the liberal arm. In an exploratory analysis, the five main QoL domains were improved for participants in the liberal compared to restrictive arm. Our findings support the feasibility and need for a definitive trial to evaluate the effect of different red cell transfusion thresholds on patient-centred outcomes.

Abstract

BACKGROUND The risk of venous thromboembolism is increased in adults and enhanced by asparaginase-based chemotherapy, and venous thromboembolism introduces a secondary risk of treatment delay and premature discontinuation of key anti-leukaemic agents, potentially compromising survival. Yet, the trade-off between benefits and harms of primary thromboprophylaxis in adults with acute lymphoblastic leukaemia (ALL) treated according to asparaginase-based regimens is uncertain. OBJECTIVES The primary objectives were to assess the benefits and harms of primary thromboprophylaxis for first-time symptomatic venous thromboembolism in adults with ALL receiving asparaginase-based therapy compared with placebo or no thromboprophylaxis. The secondary objectives were to compare the benefits and harms of different groups of primary systemic thromboprophylaxis by stratifying the main results per type of drug (heparins, vitamin K antagonists, synthetic pentasaccharides, parenteral direct thrombin inhibitors, direct oral anticoagulants, and blood-derived products for antithrombin substitution). SEARCH METHODS We conducted a comprehensive literature search on 02 June 2020, with no language restrictions, including (1) electronic searches of Pubmed/MEDLINE; Embase/Ovid; Scopus/Elsevier; Web of Science Core Collection/Clarivate Analytics; and Cochrane Central Register of Controlled Trials (CENTRAL) and (2) handsearches of (i) reference lists of identified studies and related reviews; (ii) clinical trials registries (ClinicalTrials.gov registry; the International Standard Randomized Controlled Trial Number (ISRCTN) registry; the World Health Organisation's International Clinical Trials Registry Platform (ICTRP); and pharmaceutical manufacturers of asparaginase including Servier, Takeda, Jazz Pharmaceuticals, Ohara Pharmaceuticals, and Kyowa Pharmaceuticals), and (iii) conference proceedings (from the annual meetings of the American Society of Hematology (ASH); the European Haematology Association (EHA); the American Society of Clinical Oncology (ASCO); and the International Society on Thrombosis and Haemostasis (ISTH)). We conducted all searches from 1970 (the time of introduction of asparaginase in ALL treatment). We contacted the authors of relevant studies to identify any unpublished material, missing data, or information regarding ongoing studies. SELECTION CRITERIA Randomised controlled trials (RCTs); including quasi-randomised, controlled clinical, cross-over, and cluster-randomised trial designs) comparing any parenteral/oral preemptive anticoagulant or mechanical intervention with placebo or no thromboprophylaxis, or comparing two different pre-emptive anticoagulant interventions in adults aged at least 18 years with ALL treated according to asparaginase-based chemotherapy regimens. For the description of harms, non-randomised observational studies with a control group were eligible for inclusion. DATA COLLECTION AND ANALYSIS Using a standardised data collection form, two review authors independently screened and selected studies, extracted data, assessed risk of bias for each outcome using standardised tools (RoB 2.0 tool for RCTs and ROBINS-I tool for non-randomised studies) and the certainty of evidence for each outcome using the GRADE approach. Primary outcomes included first-time symptomatic venous thromboembolism, all-cause mortality, and major bleeding. Secondary outcomes included asymptomatic venous thromboembolism, venous thromboembolism-related mortality, adverse events (i.e. clinically relevant non-major bleeding and heparin-induced thrombocytopenia for trials using heparins), and quality of life. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. For non-randomised studies, we evaluated all studies (including studies judged to be at critical risk of bias in at least one of the ROBINS-I domains) in a sensitivity analysis exploring confounding. MAIN RESULTS We identified 23 non-randomised studies that met the inclusion criteria of this review, of which 10 studies provided no outcome data for adults with ALL. We included the remaining 13 studies in the 'Risk of bias' assessment, in which we identified invalid control group definition in two studies and judged outcomes of nine studies to be at critical risk of bias in at least one of the ROBINS-I domains and outcomes of two studies at serious risk of bias. We did not assess the benefits of thromboprophylaxis, as no RCTs were included. In the main descriptive analysis of harms, we included two retrospective non-randomised studies with outcomes judged to be at serious risk of bias. One study evaluated antithrombin concentrates compared to no antithrombin concentrates. We are uncertain whether antithrombin concentrates have an effect on all-cause mortality (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.26 to 1.19 (intention-to-treat analysis); one study, 40 participants; very low certainty of evidence). We are uncertain whether antithrombin concentrates have an effect on venous thromboembolism-related mortality (RR 0.10, 95% CI 0.01 to 1.94 (intention-to-treat analysis); one study, 40 participants; very low certainty of evidence). We do not know whether antithrombin concentrates have an effect on major bleeding, clinically relevant non-major bleeding, and quality of life in adults with ALL treated with asparaginase-based chemotherapy, as data were insufficient. The remaining study (224 participants) evaluated prophylaxis with low-molecular-weight heparin versus no prophylaxis. However, this study reported insufficient data regarding harms including all-cause mortality, major bleeding, venous thromboembolism-related mortality, clinically relevant non-major bleeding, heparin-induced thrombocytopenia, and quality of life. In the sensitivity analysis of harms, exploring the effect of confounding, we also included nine non-randomised studies with outcomes judged to be at critical risk of bias primarily due to uncontrolled confounding. Three studies (179 participants) evaluated the effect of antithrombin concentrates and six studies (1224 participants) evaluated the effect of prophylaxis with different types of heparins. When analysing all-cause mortality; venous thromboembolism-related mortality; and major bleeding (studies of heparin only) including all studies with extractable outcomes for each comparison (antithrombin and low-molecular-weight heparin), we observed small study sizes; few events; wide CIs crossing the line of no effect; and substantial heterogeneity by visual inspection of the forest plots. Although the observed heterogeneity could arise through the inclusion of a small number of studies with differences in participants; interventions; and outcome assessments, the likelihood that bias due to uncontrolled confounding was the cause of heterogeneity is inevitable. Subgroup analyses were not possible due to insufficient data. AUTHORS' CONCLUSIONS We do not know from the currently available evidence, if thromboprophylaxis used for adults with ALL treated according to asparaginase-based regimens is associated with clinically appreciable benefits and acceptable harms. The existing research on this question is solely of non-randomised design, seriously to critically confounded, and underpowered with substantial imprecision. Any estimates of effect based on the existing insufficient evidence is very uncertain and is likely to change with future research.

Abstract

BACKGROUND Preoperative chemotherapy is important in the management of women with breast cancer, with the ability to downstage the breast primary tumor and axillary lymph nodes. Long-term studies are needed to identify late toxicities, recurrence patterns, and equivalency with postoperative chemotherapy for recurrence-free survival (RFS) and overall survival (OS). PATIENTS AND METHODS We conducted a single-institution prospective randomized control trial comparing preoperative or postoperative fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamides/granulocyte colony-stimulating factor chemotherapy for women with untreated clinical stage II (T1N1, T2N0, and T2N1) breast cancer. Long-term follow-up was conducted to define toxicities, recurrence patterns and RFS and OS. RESULTS Fifty-three women with clinical stage II breast cancer were randomized, 26 patients to receive preoperative chemotherapy and 27 to receive postoperative chemotherapy. Long-term follow-up, with a median of 25.3 years, was obtained. Local or systemic recurrence occurred in 8 women in the preoperative group and in 10 women in the postoperative group, and recurrences were predominantly within 10 years of treatment. Late toxicities included local upper extremity paresthesia's, upper extremity edema and congestive heart failure in 1 patient each. Analysis revealed no difference in RFS (20-year RFS probabilities; preoperative: 61.3%, postoperative: 54.7%, P=0.42), or in OS between the 2 treatment groups (20-year probabilities, preoperative: 64.6%, postoperative: 62.2%, P=0.44). Twenty-five of 53 patients (47%) were alive and without disease at this follow-up. CONCLUSION Twenty-five-year follow-up for this prospective randomized trial confirms the equivalency of preoperative versus postoperative chemotherapy with fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamides/granulocyte colony-stimulating factor for stage II breast cancer for both RFS and OS.