Prognostic Value of Pretreatment Fetal Hemoglobin Levels in Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia Treated with Azacitidine: A Single-center Retrospective Study.

Objective Azacitidine (AZA) has been the standard of care for elderly patients with high-risk myelodysplastic syndromes (MDS). However, reliable clinical predictors of outcome have yet to be identified. The prognostic value of fetal hemoglobin (HbF) levels has been reported for decitabine therapy. We evaluated pretreatment HbF levels in AZA monotherapy as a prognostic marker in MDS/acute myeloid leukemia (AML). Methods This study included chemotherapy-naïve patients who had received seven-day treatment schedules of AZA and whose HbF levels were measured at the onset of treatment between March 2011 and July 2020. Patients were grouped into HbF-normal (<1.0%) or HbF-elevated (≥1.0%) groups. Responses were classified according to the International Working Group 2006 criteria. Patients Twenty-nine patients were included and classified as having either MDS (n=21), chronic myelomonocytic leukemia (n=5), myelodysplastic/myeloproliferative neoplasm unclassifiable (n=1), or AML with <30% marrow blasts (n=2) based on the World Health Organization 2016 diagnostic criteria. According to the revised International Prognostic Scoring System classification, 20/29 patients were at intermediate, high, or very high risk. Pretreatment HbF levels were elevated in 13/29 patients. Results The median follow-up duration was 13.0 (range 1.5-93.5) months. The HbF-elevated group was associated with a significantly higher hematologic improvement rate (76.9% vs. 25%, p=0.009) and better overall survival (median, 21.0 vs. 13.0 months, p=0.048) than the HbF-normal group. Conclusion These results suggest that elevated pretreatment HbF levels can predict better outcomes in patients with MDS/AML treated with AZA.

Determinants of splenic preservation among patients with sickle cell disease in North-Eastern Nigeria.

OBJECTIVE: In patients with sickle cell disease (SCD), the spleen commonly enlarges during early childhood, but undergoes reduction in size and fibrosis from repeated episodes of vaso-occlusion and infarction. The rate of progression of this process varies markedly among these patients. The aim of current study was to explore clinical and laboratory factors associated with the preservation of the spleen among these patients. METHODS: Two hundred four patients with SCD (103 females; age 1-45 years) underwent abdominal ultrasonography at the University of Maiduguri Teaching Hospital, Nigeria between October 2020 and November 2021 to assess for splenic visualisation and echotexture. Steady-state clinical parameters and blood samples for full blood count, serum chemistry, high-performance liquid chromatography and malaria parasitemia were obtained from all the patients. RESULTS: The spleen was visualised in 107 (52.4%; 95% confidence interval [CI], 46%-59%) patients with SCD on ultrasonography. While the spleen was visualised in all children less than 5 years of age, it was visualised in only 23.5% of those aged 15 years and older. Visualisation of the spleen was significantly associated with low mean corpuscular haemoglobin concentration and high haemoglobin F (HbF) in those younger than 10 years. The odds of visualisation of the spleen on ultrasonography increased by a factor of 1.17% for every 1% increase in HbF level. Only 32 (15%) patients were on regular hydroxyurea therapy. The HbF level was significantly higher among patients on hydroxyurea (median 12.7 vs. 7.4; p < 0.0001). CONCLUSION: In patients with SCD, failure to visualise the spleen was not found in children less than 5 years old. Patients with visualised spleens had a higher level of HbF than those with non-visualised spleens. HbF was significantly associated with visualisation of the spleen before 10 years of age. Since early administration of hydroxyurea will increase HbF level, we expect that it would help to preserve the spleen.

Sickle cell disease in the new era: advances in drug treatment.

Sickle cell disease is an inherited blood disorder afflicting an estimated 100,000 individuals in the United States and over 20 million people worldwide. The disease is heralded as the first molecular disease. However, despite its genetic simplicity, the pathophysiologic processes leading to its clinical sequelae are complex, heterogeneous and interrelated, making drug development to treat the disease challenging. For over two decades only one drug, hydroxyurea, had been used as disease-modifying therapy. New pharmacologic agents are rapidly evolving with three new drugs, with different mechanisms of action, approved by the United States Food and Drug Administration in recent years (L-glutamine, crizanlizumab and voxelotor). Several therapeutic approaches targeting different pathways in the disease pathophysiology are being investigated. These include inhibition of hemoglobin S polymerization such as by fetal hemoglobin induction or by increasing hemoglobin oxygen affinity, as well as intervention of downstream pathways including inhibiting cellular adhesion, reducing inflammation and oxidant stress, modulating platelet activation and coagulation abnormalities, and targeting nitric oxide signaling. This review will provide an overview of these therapeutic strategies, discuss the four currently approved drugs in detail, and summarize ongoing clinical trials of new drugs or drug indications for the treatment of sickle cell disease in different phases of development excluding those related to cellular therapies.

Hemoglobin F (HbF) Inducers; History, Structure and Efficacies.

Inherited beta-thalassemia is caused by irregular production of hemoglobin through reducing beta-globin chains. It has been observed that increasing fetal hemoglobin (HbF) production improves symptoms in the patients; thus, it has been an operative approach to treat patients with betathalassemia. This review represents compounds with biological activities and pharmacological properties that can be useful in promoting the HBF level in ß-thalassemia patients. Various natural products with different mechanisms of action can be helpful in this medication cure. Clinical trials were efficient in improving the signs of patients. Association of in vivo, and in vitro studies of HbF induction and γ-globin mRNA growth displays that in vitro experiments could be an indicator of the in vivo response. The current study resulted that; (a) HbF inducers can be grouped into several classes based on their chemical structures and mechanism of actions; (b) According to several clinical trials, wellknown drugs such as hydroxyurea and decitabine are useful HbF inducers. (c) The cellular biosensor K562 carrying genes under the control of the human γ-globin and ß-globin gene promoters were applied during the researches. (d) New natural products and lead compounds were found based on various studies as HbF inducers.

Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and ß-thalassemia.

Hereditary persistence of fetal hemoglobin (HPFH) is a condition in some individuals who have a high level of fetal hemoglobin throughout life. Individuals with compound heterozygous ß-thalassemia or sickle cell disease (SCD) and HPFH have milder clinical manifestations. Using RNA-guided clustered regularly interspaced short palindromic repeats-associated Cas9 (CRISPR-Cas9) genome-editing technology, we deleted, in normal hematopoietic stem and progenitor cells (HSPCs), 13 kb of the ß-globin locus to mimic the naturally occurring Sicilian HPFH mutation. The efficiency of targeting deletion reached 31% in cells with the delivery of both upstream and downstream breakpoint guide RNA (gRNA)-guided Staphylococcus aureus Cas9 nuclease (SaCas9). The erythroid colonies differentiated from HSPCs with HPFH deletion showed significantly higher γ-globin gene expression compared with the colonies without deletion. By T7 endonuclease 1 assay, we did not detect any off-target effects in the colonies with deletion. We propose that this strategy of using nonhomologous end joining (NHEJ) to modify the genome may provide an efficient approach toward the development of a safe autologous transplantation for patients with homozygous ß-thalassemia and SCD.

Fetal haemoglobin in sickle-cell disease: from genetic epidemiology to new therapeutic strategies.

Sickle-cell disease affects millions of individuals worldwide, but the global incidence is concentrated in Africa. The burden of sickle-cell disease is expected to continue to rise over the coming decades, adding to stress on the health infrastructures of many countries. Although the molecular cause of sickle-cell disease has been known for more than half a century, treatment options remain greatly limited. Allogeneic haemopoietic stem-cell transplantation is the only existing cure but is limited to specialised clinical centres and remains inaccessible for most patients. Induction of fetal haemoglobin production is a promising strategy for the treatment of sickle-cell disease. In this Series paper, we review scientific breakthroughs in epidemiology, genetics, and molecular biology that have brought reactivation of fetal haemoglobin to the forefront of sickle-cell disease research. Improved knowledge of the regulation of fetal haemoglobin production in human beings and the development of genome editing technology now support the design of innovative therapies for sickle-cell disease that are based on fetal haemoglobin.

Determination of optimal timing of serial in-utero transfusions in red-cell alloimmunization.

OBJECTIVES: To assess the performance of middle cerebral artery peak systolic velocity (MCA-PSV) and of the expected daily decrease in fetal hemoglobin in determining the timing of serial in-utero transfusions (IUT) in red-cell alloimmunization. METHODS: This was a retrospective study of a continuous series of suspected anemic fetuses undergoing IUT between June 2003 and December 2012. Doppler measurement of MCA-PSV and pre- and post-transfusion hemoglobin levels were recorded at the time of the first, second and third IUT. Receiver-operating characteristics (ROC) curves and negative and positive predictive values of MCA-PSV in the prediction of severe fetal anemia were calculated. The daily decrease of fetal hemoglobin (Hb) between IUTs was calculated. Regression analysis was used to assess the correlation between pretransfusion fetal hemoglobin and MCA-PSV, and between observed and expected (by projection of daily decreases) pretransfusion fetal hemoglobin levels. RESULTS: One hundred and eleven fetuses required an IUT, of which 96 and 67 received a second and third IUT, respectively. The area under the ROC curve for MCA-PSV in the prediction of severe fetal anemia was not different for each rank of transfusion. The positive predictive value of MCA-PSV decreased from 75.3% at the first IUT, to 46.7% and 48.8% at the second and third IUTs, respectively, while the negative predictive value for a 1.5-MoM threshold remained high (88.9% at the second and 91.7% at the third IUT). The mean daily decrease in hemoglobin following each transfusion was 0.45, 0.35 and 0.32 g/dL, respectively. There was a persistent linear correlation between fetal hemoglobin and MCA-PSV and between observed and expected fetal hemoglobin levels. CONCLUSIONS: Both MCA-PSV and projection of daily decrease in hemoglobin are reliable means of diagnosing fetal anemia following previous IUTs. The high negative predictive value of MCA-PSV could allow subsequent IUTs to be postponed in selected cases.

Molecular crowding limits the role of fetal hemoglobin in therapy for sickle cell disease.

The dominant assumption central to most treatments for sickle cell anemia has been that replacement of sickle hemoglobin (HbS) by fetal hemoglobin (HbF) would have major clinical benefit. Using laser photolysis, we have measured polymerization kinetics including rates of homogeneous and heterogeneous nucleation on mixtures of 20% and 30% HbF with HbS. We find that the present model for polymerization, including molecular crowding, can accurately predict the rates of such mixtures, by using the single assumption that no significant amount of HbF enters the polymer. The effects of replacing HbS by HbF on the rates of polymer formation are found to be significantly lower than previous measurements appeared to indicate because the impact of the replacement is also highly dependent on the total hemoglobin concentration. This is because the molecular crowding of non-polymerizing HbF offsets substantially the effects of decreasing the concentration of HbS concentration, an effect that increases with concentration. Most strikingly, the demonstrated benefit of hydroxyurea therapy in slowing the kinetics of intracellular polymerization cannot be primarily due to enhanced HbF, but must have some other origin, which could itself represent a promising therapeutic approach.

Therapeutic fetal hemoglobin induction in sickle cell disease with butyrate, hydroxyurea and the combination of hydroxyurea and butyrate

Some recent data in the treatment of adult carriers o f sickle cell anemia with increased fetal hemoglobin are related in this article. Results of the use of butyrate and hydroxyurea either in isolation or combined are considered.

Neste relato são apresentados alguns dados recentes do tratamento de portadores adultos de anemia falciforme com indutores do aumento da hemoglobina fetal. Apresento os resultados do uso isolado e combinado do butirato e da hidroxiureia.