COVID-19 Severity and Survival over Time in Patients with Hematologic Malignancies: A Population-Based Registry Study.

Mortality rates for COVID-19 have declined over time in the general population, but data in patients with hematologic malignancies are contradictory. We identified independent prognostic factors for COVID-19 severity and survival in unvaccinated patients with hematologic malignancies, compared mortality rates over time and versus non-cancer inpatients, and investigated post COVID-19 condition. Data were analyzed from 1166 consecutive, eligible patients with hematologic malignancies from the population-based HEMATO-MADRID registry, Spain, with COVID-19 prior to vaccination roll-out, stratified into early (February-June 2020; n = 769 (66%)) and later (July 2020-February 2021; n = 397 (34%)) cohorts. Propensity-score matched non-cancer patients were identified from the SEMI-COVID registry. A lower proportion of patients were hospitalized in the later waves (54.2%) compared to the earlier (88.6%), OR 0.15, 95%CI 0.11-0.20. The proportion of hospitalized patients admitted to the ICU was higher in the later cohort (103/215, 47.9%) compared with the early cohort (170/681, 25.0%, 2.77; 2.01-3.82). The reduced 30-day mortality between early and later cohorts of non-cancer inpatients (29.6% vs. 12.6%, OR 0.34; 0.22-0.53) was not paralleled in inpatients with hematologic malignancies (32.3% vs. 34.8%, OR 1.12; 0.81-1.5). Among evaluable patients, 27.3% had post COVID-19 condition. These findings will help inform evidence-based preventive and therapeutic strategies for patients with hematologic malignancies and COVID-19 diagnosis.

Impact of hematologic malignancy and type of cancer therapy on COVID-19 severity and mortality: lessons from a large population-based registry study.

BACKGROUND: Patients with cancer have been shown to have a higher risk of clinical severity and mortality compared to non-cancer patients with COVID-19. Patients with hematologic malignancies typically are known to have higher levels of immunosuppression and may develop more severe respiratory viral infections than patients with solid tumors. Data on COVID-19 in patients with hematologic malignancies are limited. Here we characterize disease severity and mortality and evaluate potential prognostic factors for mortality. METHODS: In this population-based registry study, we collected de-identified data on clinical characteristics, treatment and outcomes in adult patients with hematologic malignancies and confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection within the Madrid region of Spain. Our case series included all patients admitted to 22 regional health service hospitals and 5 private healthcare centers between February 28 and May 25, 2020. The primary study outcome was all-cause mortality. We assessed the association between mortality and potential prognostic factors using Cox regression analyses adjusted for age, sex, comorbidities, hematologic malignancy and recent active cancer therapy. RESULTS: Of 833 patients reported, 697 were included in the analyses. Median age was 72 years (IQR 60-79), 413 (60%) patients were male and 479 (69%) and 218 (31%) had lymphoid and myeloid malignancies, respectively. Clinical severity of COVID-19 was severe/critical in 429 (62%) patients. At data cutoff, 230 (33%) patients had died. Age ≥ 60 years (hazard ratios 3.17-10.1 vs < 50 years), > 2 comorbidities (1.41 vs ≤ 2), acute myeloid leukemia (2.22 vs non-Hodgkin lymphoma) and active antineoplastic treatment with monoclonal antibodies (2·02) were associated with increased mortality; conventional chemotherapy showed borderline significance (1.50 vs no active therapy). Conversely, Ph-negative myeloproliferative neoplasms (0.33) and active treatment with hypomethylating agents (0.47) were associated with lower mortality. Overall, 574 (82%) patients received antiviral therapy. Mortality with severe/critical COVID-19 was higher with no therapy vs any antiviral combination therapy (2.20). CONCLUSIONS: In this series of patients with hematologic malignancies and COVID-19, mortality was associated with higher age, more comorbidities, type of hematological malignancy and type of antineoplastic therapy. Further studies and long-term follow-up are required to validate these criteria for risk stratification.

Use of eltrombopag for secondary immune thrombocytopenia in clinical practice.

Eltrombopag is a second-line treatment in primary immune thrombocytopenia (ITP). However, its role in secondary ITP is unknown. We evaluated the efficacy and safety of eltrombopag in secondary ITP in daily clinical practice. Eighty-seven secondary ITP patients (46 with ITP secondary to autoimmune syndromes, 23 with ITP secondary to a neoplastic disease subtype: lymphoproliferative disorders [LPDs] and 18 with ITP secondary to viral infections) who had been treated with eltrombopag were retrospectively evaluated. Forty-four patients (38%) had a platelet response, including 40 (35%) with complete responses. Median time to platelet response was 15 days (95% confidence interval, 7-28 days), and was longer in the LPD-ITP group. Platelet response rate was significantly lower in the LPD-ITP than in other groups. However, having achieved response, there were no significant differences between the durable response of the groups. Forty-three patients (49·4%) experienced adverse events (mainly grade 1-2), the commonest being hepatobiliary laboratory abnormalities. There were 10 deaths in this case series, all of which were related to pre-existing medical conditions. In routine clinical practice, eltrombopag is effective and well-tolerated in unselected patients with ITP secondary to both immune and infectious disorders. However, the response rate in LPD-ITP is low.

Identification, introgression, and validation of fruit volatile QTLs from a red-fruited wild tomato species.

Volatile organic compounds (VOCs) are major determinants of fruit flavor, a primary objective in tomato breeding. A recombinant inbred line (RIL) population consisting of 169 lines derived from a cross between Solanum lycopersicum and a red-fruited wild tomato species Solanum pimpinellifolium accession (SP) was characterized for VOCs in three different seasons. Correlation and hierarchical cluster analyses were performed on the 52 VOCs identified, providing a tool for the putative assignation of individual compounds to metabolic pathways. Quantitative trait locus (QTL) analysis, based on a genetic linkage map comprising 297 single nucleotide polymorphisms (SNPs), revealed 102 QTLs (75% not described previously) corresponding to 39 different VOCs. The SP alleles exerted a positive effect on most of the underlying apocarotenoid volatile QTLs-regarded as desirable for liking tomato-indicating that alleles inherited from SP are a valuable resource for flavor breeding. An introgression line (IL) population developed from the same parental genotypes provided 12 ILs carrying a single SP introgression and covering 85 VOC QTLs, which were characterized at three locations. The results showed that almost half of the QTLs previously identified in the RILs maintained their effect in an IL form, reinforcing the value of these QTLs for flavor/aroma breeding in cultivated tomato.

Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia.

Eltrombopag is effective and safe in immune thrombocytopenia (ITP). Some patients may sustain their platelet response when treatment is withdrawn but the frequency of this phenomenon is unknown. We retrospectively evaluated 260 adult primary ITP patients (165 women and 95 men; median age, 62 years) treated with eltrombopag after a median time from diagnosis of 24 months. Among the 201 patients who achieved a complete remission (platelet count >100 × 10(9) /l), eltrombopag was discontinued in 80 patients. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n = 33), platelet count >400 × 10(9) /l (n = 29), patient's request (n = 5), elevated aspartate aminotransferase (n = 3), diarrhea (n = 3), thrombosis (n = 3), and other reasons (n = 4). Of the 49 evaluable patients, 26 patients showed sustained response after discontinuing eltrombopag without additional ITP therapy, with a median follow-up of 9 (range, 6-25) months. These patients were characterized by a median time since ITP diagnosis of 46.5 months, with 4/26 having ITP < 1 year. Eleven patients were male and their median age was 59 years. They received a median of 4 previous treatment lines and 42% were splenectomized. No predictive factors of sustained response after eltrombopag withdrawal were identified. Platelet response following eltrombopag cessation may be sustained in an important percentage of adult primary ITP patients who achieved CR with eltrombopag. However, reliable markers for predicting which patients will have this response are needed.

Sustained response after discontinuation of short-and medium-term treatment with eltrombopag in patients with immune thrombocytopenia.

Eltrombopag is effective and safe in chronic immune thrombocytopenia (ITP) patients not responding to previous therapy. However, when eltrombopag is discontinued, platelet counts usually return to baseline within 2 weeks. Here, we describe the clinical characteristics of the, to the best of our knowledge, largest case series of patients with ITP, who presented sustained responses after discontinuing eltrombopag (n = 12). The median time from diagnosis to eltrombopag initiation was 24 months (range, 1-480). The median number of prior therapies was 5 (range, 1-7), and the median duration of eltrombopag treatment was 5 months (range, 1-13). Three patients received eltrombopag for only 1 month. The treatment was well-tolerated. The median (range) follow-up of this case series was of 7 months (6-20), during which all patients maintained a safe platelet count without the need for anti-ITP treatment. The communication of such cases may support the conduction of new studies to investigate which predictive factors could identify ITP patients with sustained responses after discontinuing eltrombopag without additional therapy. The need of long-term use of eltrombopag should be re-examined.

Pharmacological profiles of acute myeloid leukemia treatments in patient samples by automated flow cytometry: a bridge to individualized medicine.

BACKGROUND: We have evaluated the ex vivo pharmacology of single drugs and drug combinations in malignant cells of bone marrow samples from 125 patients with acute myeloid leukemia using a novel automated flow cytometry-based platform (ExviTech). We have improved previous ex vivo drug testing with 4 innovations: identifying individual leukemic cells, using intact whole blood during the incubation, using an automated platform that escalates reliably data, and performing analyses pharmacodynamic population models. PATIENTS AND METHODS: Samples were sent from 24 hospitals to a central laboratory and incubated for 48 hours in whole blood, after which drug activity was measured in terms of depletion of leukemic cells. RESULTS: The sensitivity of single drugs is assessed for standard efficacy (EMAX) and potency (EC50) variables, ranked as percentiles within the population. The sensitivity of drug-combination treatments is assessed for the synergism achieved in each patient sample. We found a large variability among patient samples in the dose-response curves to a single drug or combination treatment. CONCLUSION: We hypothesize that the use of the individual patient ex vivo pharmacological profiles may help to guide a personalized treatment selection.

Allogeneic hematopoietic stem cell transplantation in patients 50 years of age and older.

BACKGROUND AND OBJECTIVES: The population of elderly patients with hematologic malignancies is increasing and so will the activity of stem cell transplantation (SCT) in this population. The aim of this study was to analyze the toxicity and survival of allogeneic SCT in patients 50 years and older (elderly group), and compare the results with a standard adult population (young group). DESIGN AND METHODS: Thirty-two elderly patients (median age 52.5, range 50-59 years) and 97 young patients (median 32, range 20-40) received a myeloablative, allogeneic SCT from HLA-identical siblings at a single institution, and formed the basis of this retrospective study. The majority of transplants in both groups were performed with non-T-cell-depleted bone marrow, conditioned with busulfan + cyclophosphamide and received cyclosporine + methotrexate as graft-versus-host disease (GVHD) prophylaxis. The percentage of high-risk patients was nearly double in the elderly group (41% vs. 23%, p = 0.06). RESULTS: We observed a low incidence of toxicities in the elderly group, including veno-occlusive disease, acute and chronic GVHD, transplant-related mortality, time to engraftment, and relapse incidence, without significant differences compared within the young group. The 3-year survival rates were not statistically different between the elderly and young groups: 51% vs. 55% for all patients; 87% vs. 69% in chronic myeloid leukemia; 79% vs. 62% in standard risk patients and 13% vs. 31% in high risk ones. In multivariate analyses no significant difference in overall survival was found between age groups. INTERPRETATION AND CONCLUSIONS: According to our experience, age alone (between 50-59), should not be considered a contraindication to a conventional HLA identical sibling transplant.