Supportive Care for Patients With Myelodysplastic Syndromes.

ABSTRACT: Myelodysplastic syndromes are a heterogeneous group of bone marrow disorders characterized by ineffective hematopoiesis, progressive cytopenias, and an innate capability of progressing to acute myeloid leukemia. The most common causes of morbidity and mortality are complications related to myelodysplastic syndromes rather than progression to acute myeloid leukemia. Although supportive care measures are applicable to all patients with myelodysplastic syndromes, they are especially essential in patients with lower-risk disease who have a better prognosis compared with their higher-risk counterparts and require longer-term monitoring of disease and treatment-related complications. In this review, we will address the most frequent complications and supportive care interventions used in patients with myelodysplastic syndromes, including transfusion support, management of iron overload, antimicrobial prophylaxis, important considerations in the era of COVID-19 (coronavirus infectious disease 2019), role of routine immunizations, and palliative care in the myelodysplastic syndrome population.

Blood cancer in children infected with COVID-19: A comprehensive systematic review (preprint)

Background: Blood cancer is the most common type of cancer and the leading cause of death by disease past infancy among children. Children with blood cancer are vulnerable population to viral infections such as coronavirus disease 2019 (COVID-19). Objectives: To estimate the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in blood cancer children and analyse the demographic parameters, clinical characteristics and treatment outcomes in blood cancer children with COVID-19 illness. Methods: For this systematic review, we searched ProQuest, Medline, Embase, PubMed, CINAHL, Wiley online library, Scopus and Nature through the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guideline for studies on the development of COVID-19 in children with blood cancer, published from December 1, 2019 to April 30, 2023, with English language restriction. Results: Of the 3077 papers that were identified, 155 articles were included in the systematic review (83 case report, 54 cohort and 18 case-series studies). Studies involving 1289 blood cancer children with confirmed COVID-19 were analysed. Leukaemias (1141 cases) were the most frequent types of blood cancer observed in children who developed COVID-19, followed by non-Hodgkin’s lymphomas (59 cases), Hodgkin’s lymphomas (36 cases), Langerhans cell histiocytosis (7 cases), myelodysplastic syndrome (7 cases) and myeloid neoplasm (1 case). Among all 1289 blood cancer paediatric cases who transmitted SARS-CoV-2, some children were documented to be admitted to the intensive care unit (ICU) (n = 175, 13.6%), intubated and placed on mechanical ventilation (n = 111, 8.6%), suffered acute respiratory distress syndrome (n = 144, 11.2%) or died (n = 111, 8.6%). Overall, COVID-19 in children with different types of blood cancer resulted in no or low severity of disease in more than 78.6% of all included cases (COVID-19 severity: asymptomatic = 239, mild = 603, or moderate = 171). Treatment for COVID-19 was not necessary in a high number of blood cancer children (n = 94, 7.3%). Fatality in blood cancer children with COVID-19 was reported in any of the included blood cancer categories for leukaemias (n = 99, 8.7%), non-Hodgkin’s lymphomas (n = 7, 11.9%), Hodgkin’s lymphomas (n = 2, 5.5%), myelodysplastic syndrome (n = 1, 14.3%) or myeloid neoplasm (n = 1, 100%). Fatality rate in blood cancer children infected with SARS-CoV-2 was the highest in patients with Hispanic ethnicity (n = 44/111, 39.6%) and COVID-19–related fatality was highest in male patients (76.5% of deceased patients). Most studies reported to alter the intensity and regimen of anticancer treatment in blood cancer children during course of SARS-CoV-2 infection, however, many studies have reported to successfully treat COVID-19 without any changes to the anticancer treatment. Conclusion: Globally, leukaemias were the most prevalent and myeloid neoplasms were the least prevalent blood cancer types in children who developed SARS-CoV-2 infection. Children with blood cancer tend to have milder COVID-19 symptoms and are less likely to be hospitalized and have better prognosis when compared to adults. Continuation of anticancer treatment in individual paediatric blood cancer patients with COVID-19 seems to be possible.

Three doses of BNT162b2 COVID-19 mRNA vaccine establish long-lasting CD8+ T cell immunity in CLL and MDS patients.

Patients with hematological malignancies are prioritized for COVID-19 vaccine due to their high risk for severe SARS-CoV-2 infection-related disease and mortality. To understand T cell immunity, its long-term persistence, and its correlation with antibody response, we evaluated the BNT162b2 COVID-19 mRNA vaccine-specific immune response in chronic lymphocytic leukemia (CLL) and myeloid dysplastic syndrome (MDS) patients. Longitudinal analysis of CD8+ T cells using DNA-barcoded peptide-MHC multimers covering the full SARS-CoV-2 Spike-protein (415 peptides) showed vaccine-specific T cell activation and persistence of memory T cells up to six months post-vaccination. Surprisingly, a higher frequency of vaccine-induced antigen-specific CD8+ T cells was observed in the patient group compared to a healthy donor group. Furthermore, and importantly, immunization with the second booster dose significantly increased the frequency of antigen-specific CD8+ T cells as well as the total number of T cell specificities. Altogether 59 BNT162b2 mRNA vaccine-derived immunogenic responses were identified, of which 23 established long-term CD8+ T cell memory response with a strong immunodominance for NYNYLYRLF (HLA-A24:02) and YLQPRTFLL (HLA-A02:01) epitopes. In summary, we mapped the vaccine-induced antigen-specific CD8+ T cells and showed a booster-specific activation and enrichment of memory T cells that could be important for long-term disease protection in this patient group.

SOCS1 Haploinsufficiency Presenting as Severe Enthesitis, Bone Marrow Hypocellularity, and Refractory Thrombocytopenia in a Pediatric Patient with Subsequent Response to JAK Inhibition.

Haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1) is a recently discovered autoinflammatory disorder with significant rheumatologic, immunologic, and hematologic manifestations. Here we report a case of SOCS1 haploinsufficiency in a 5-year-old child with profound arthralgias and immune-mediated thrombocytopenia unmasked by SARS-CoV-2 infection. Her clinical manifestations were accompanied by excessive B cell activity, eosinophilia, and elevated IgE levels. Uniquely, this is the first report of SOCS1 haploinsufficiency in the setting of a chromosomal deletion resulting in complete loss of a single SOCS1 gene with additional clinical findings of bone marrow hypocellularity and radiologic evidence of severe enthesitis. Immunologic profiling showed a prominent interferon signature in the patient's peripheral blood mononuclear cells, which were also hypersensitive to stimulation by type I and type II interferons. The patient showed excellent clinical and functional laboratory response to tofacitinib, a Janus kinase inhibitor that disrupts interferon signaling. Our case highlights the need to utilize a multidisciplinary diagnostic approach and consider a comprehensive genetic evaluation for inborn errors of immunity in patients with an atypical immune-mediated thrombocytopenia phenotype.

Three-doses of BNT162b2 COVID-19 mRNA vaccine establishes long-lasting CD8+ T cell immunity in CLL and MDS patients (preprint)

Patients with hematological malignancies are prioritized for COVID-19 vaccine due to their high risk for severe SARS-CoV-2 infection related disease and mortality. To understand T cell immunity, its long-term persistence, and correlation with antibody response, we evaluated the BNT162b2 COVID 19 mRNA vaccine-specific immune response in chronic lymphocytic leukemia (CLL) and myeloid dysplastic syndrome (MDS) patients. Longitudinal analysis of CD8+ T cells using DNA-barcoded peptide-MHC multimers covering the full SARS-CoV-2 Spike-protein (415 peptides) showed vaccine-specific T cell activation and persistence of memory T cells up to six months post-vaccination. Surprisingly, a higher frequency of vaccine-induced antigen-specific CD8+ T cell was observed in the patient group compared to a healthy donor group. Furthermore, and importantly, immunization with the second booster dose significantly increased the frequency of antigen-specific CD8+ T cells as well as the total number of T cell specificities. Altogether 59 BNT162b2 vaccine-derived immunogenic epitopes were identified, of which 23 established long-term CD8+ T cell memory response with a strong immunodominance for NYNYLYRLF (HLA-A24:02) and YLQPRTFLL (HLA-A02:01) epitopes. In summary, we mapped the vaccine-induced antigen-specific CD8+ T cells and showed a booster-specific activation and enrichment of memory T cells that could be important for long-term disease protection in this patient group.

Antibody responses to SARS-CoV-2 vaccination in patients with acute leukaemia and high risk MDS on active anti-cancer therapies (preprint)

Patients with haematological malignancies, such as acute leukaemia and high-risk MDS (HR-MDS), have significantly increased mortality and morbidity from COVID-19. However vaccine efficacy in these patients and the impact of systemic anti-cancer therapy (SACT) on vaccine response remains to be fully established. SARS-CoV-2 antibody responses in 53 patients with ALL, AML or HR-MDS receiving SACT were characterised following two doses of either BNT162b2 or ChAdOx1nCoV-19. All patients were tested for anti-S antibodies after 2 doses, 60% after the first dose and anti-N antibody testing was performed on 46 patients (87%). Seropositivity rates after 2 vaccine doses were 95% in AML/HR-MDS patients and 79% in ALL. After stratification by prior SARS-CoV-2 infection, naive patients with AML/HR-MDS had higher seroconversion rates and median anti-S antibody titres compared to ALL (median 291U/mL versus 5.06U/mL), and significant increases in anti-S titres with consecutive vaccine doses, not seen in ALL. No difference was seen in serological response between patients receiving intensive chemotherapy or non-intensive therapies (HMA) but significantly reduced titres were present in AML/HR-MDS patients who received venetoclax-based regimens compared to other therapies. All ALL patients received intensive chemotherapy, with no further impact of anti-CD20 immunotherapy on serological response. Understanding the impact of disease subtypes and therapy on vaccine response is essential to enable decisions on modifying or delaying treatment in the context of either SARS-CoV-2 infection or vaccination.

Humoral response to mRNA-based COVID-19 vaccine in patients with myeloid malignancies.

Data on the response to the COVID-19 vaccine in patients with myeloid malignancy, who are at severe risk in case of infection, have not emerged. In a study of 69 patients with myeloid malignancies, including 46 patients with acute myeloid leukaemia (AML) and 23 patients with myelodysplastic syndrome (MDS), anti-spike SARS-CoV-2 antibody titres were measured 3 months after the second mRNA-based vaccination. Seroconversion rates for AML and MDS were 94.7% and 100% respectively, with no significant difference from healthy controls (HCs). Patients with MDS showed a significantly lower antibody titre than that in HCs or AML patients. In AML patients, the antibody titres were comparable to those in HCs when treatment was completed, but lower in patients under maintenance therapy. The response to COVID-19 vaccine appears to be related to disease and treatment status. Patients with myeloid malignancies may be more responsive to vaccines than patients with lymphoid malignancies.

Oral hypomethylating agents: beyond convenience in MDS.

Oral hypomethylating agents (HMAs) represent a substantial potential boon for patients with myelodysplastic syndrome (MDS) who have previously required between 5 and 7 visits per month to an infusion clinic to receive therapy. For patients who respond to treatment, ongoing monthly maintenance visits represent a considerable burden to quality of life, and for those who are early in therapy, these sequential visits may tax transportation and financial resources that would be optimally distributed over the treatment cycle to facilitate transfusion support. The availability of oral HMAs may support the optimal application of these agents by contributing to adherence and lessening the burden of therapy, potentially encouraging patients to stay on longer-term treatment. Distinct pharmacokinetic profiles for the recently approved oral HMAs (oral azacitidine and decitabine-cedazuridine) result in differential toxicity profiles and have prompted their clinical trial development in lower- and higher-risk MDS, respectively.

Immunogenicity of COVID-19 mRNA Vaccines in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome (preprint)

Immunocompromised patients are particularly susceptible to serious complications from infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Two mRNA vaccines, BNT162b2 and mRNA-1273, have been shown to have excellent clinical efficacy in immunocompetent adults, but diminished activity in immunocompromised patients. In this study, we measured anti-spike SARS-CoV-2 antibody response, avidity, and surrogate neutralizing antibody activity in Coronavirus Disease 2019 (COVID-19) vaccinated patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Anti-spike SARS-CoV-2 antibody was present in 89% of AML and 88% of MDS patients, but median antibody levels for were lower than in healthy controls (p=0.001 and p=0.04, respectively). SARS-CoV-2 antibody avidity and neutralizing antibody activity from AML patients were significantly lower than controls (p=0.028 and p=0.002, respectively). There was a trend toward higher anti-spike SARS-CoV-2 antibody levels after mRNA-1273 vaccination. Antibody avidity was greater in patients after mRNA-1273 versus BNT162b2 (p=0.01) and there was a trend toward greater neutralizing antibody activity after mRNA-1273 versus BNT162b2 vaccination.

Hematologic Neoplasms As Risk Factor For Severe COVID-19: A Systematic Review Protocol (preprint)

Background: Patients with hematologic neoplasm may have compromised immunity due to their malignancy and/or treatment, and may be at elevated risk of severe COVID-19. However, the studies bring together patients with hematologic neoplasms and solid tumors into a single group, making no distinction about the types of hematological tumors and their treatments. This systematic review is designed to explore the risk of severe COVID-19 in patients with hematologic neoplasm. Studies about patients, adult or children, with hematologic neoplasm and COVID-19 will be included. Methods: : A systematic review according to Joanna Briggs Institute methodology for systematic reviews of etiology and risk will be performed. The review will consider as participants adults or children with COVID-19 infection detected by RT-PCR or serology (SARS-CoV-2 antibody). We will be included studies without routine labs confirmation of COVID-19 if the patients presented clinical/physical exam and computed tomography suggesting COVID-19. The exposure of interest will be hematologic neoplasm, which include lymphomas, acute and chronic leukemias, myeloma, myelodysplastic syndrome, and myeloproliferative diseases. We will consider cohort, case-control, analytical cross-sectional studies. Outcomes among patients with COVID-19 are critical symptoms, hospitalizations, intensive care unit admissions, mechanical ventilation and deaths. We will exclude studies with other neoplasms than hematologic neoplasms. Search strategies have been created for the Embase, Medline and LILACS. Two reviewers independently will assess the studies for their eligibility, will extract data and will evaluate their risk of bias. Similar outcomes measured in at least two studies will be plotted in the meta-analysis using the Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information. Discussion: This systematic review aims to evaluate if patients with hematologic neoplasm may be at elevated risk of severe COVID-19. This review will differ from the previous ones because we will include controlled studies and groups with only hematologic neoplasm, excluding other cancers. The main hypothesis of our research is that not all hematological cancer patients have high risk of severe COVID-19. Trial registration number: PROSPERO CRD42020199318.

Implementation of a hospital-at-home (HAH) unit for hematological patients during the COVID-19 pandemic: safety and feasibility.

BACKGROUND: "Hospital-at-home" (HAH) programs have been shown to optimize resource utilization, shorten hospitalization and prevent nosocomial infection. METHODS: We retrospectively analysed data regarding implementation of an HAH unit for caring patients with hematological malignancies in our center, during the COVID-19 pandemic. RESULTS: Between January and November 2020, 105 patients were treated in the HAH unit for a total of 204 episodes. Nine patients with multiple myeloma (MM) received autologous HSCT (auto-HSCT). Three patients with acute myeloid leukemia (AML) received consolidation therapy, 32 patients underwent clinical and analytical monitoring, 20 were transplant recipients early discharged (5 auto-HSCT and 15 allo-HSCT) and 2 had received CART cells therapy. Azacitidine, bortezomib and carfilzomib were administered at home to 54 patients with AML, myelodysplastic syndrome (MDS) or MM. A median of 17 (IQR 13-19) days of admission per patient and a total of 239 visits to the Hematology day-care hospital were avoided. Overall, 28 patients (14% of all episodes) needed admission to the hospital, 4 of them due to COVID-19. CONCLUSIONS: Implementation of a Hematology HAH unit was feasible and safe, and provided thorough advanced care to a high-risk population. Advanced care-at-home strategies can be crucial during times of COVID-19 to minimize treatment interruptions and reduce the risk of cross-infections.

Azacytidine targeting SARS-CoV-2 viral RNA as a potential treatment for COVID-19 (preprint)

The COVID-19 pandemic is a global health disaster. Moreover, emerging mutated virus strains present an even greater challenge for existing vaccines and medications. One possible solution is to design drugs based on the properties of virus epigenome, which are more common among coronaviruses. Here, we reported an FDA-approved drug for myelodysplastic syndrome, azacytidine (5Aza), limited virus infection and protected mice against SARS-CoV-2. We demonstrated that this antiviral effect is related to 5Aza incorporation into viral RNA, which disrupt m5C RNA methylation modification profile. This work suggests that targeting viral epigenomes is a viable therapeutic strategy, potentially opening new pathways for treating COVID-19.

Thromboembolism after COVID-19 vaccine in patients with preexisting thrombocytopenia.

While vaccination is the single most effective intervention to drastically reduce severe disease and death following SARS-CoV-2 infection, as shown in UK and Israel, some serious concerns have been raised for an unusual adverse drug reaction (ADR), including vaccine-induced immune thrombotic thrombocytopenia (VITT) with concurrent low platelets as well as capillary leak syndrome. In fact, the overall safety of the vaccine is highlighted by the low frequency of ADR considering that in UK, by the early June, 40 million first doses and 29 million second doses have been injected; nonetheless, 390 thrombotic events, including 71 fatal events have been reported. Interestingly, the cases reported low platelet counts with the presence of anti-platelet factor-4 (PF4) antibodies, indicating an abnormal clotting reaction. Here, out of three referred cases, we report a post-vaccine clinical case of fatal thrombosis with postmortem examination and whole exome sequencing (WES) analysis, whose pathogenesis appeared associated to a preexisting condition of thrombocytopenia due to myelodysplasia.