Emerging Therapies in Hematology

Introduction

Genetic mutations in HBA1, HBA2, and HBB lead to hemoglobinopathies by impairing the structure-function of hemoglobin (Hb)'s α- and β-globin chains. Mutations in the β-globin gene together are called β-thalassemia (BT) 1. At the molecular level, mutations in the HBB exhibit remarkable heterogeneity, with more than 300 variations found. Though the mutations vary widely, most lead to an imbalance in the α- and β-globin levels, impairing the spleen and liver extramedullary hematopoiesis (EMH) and erythropoiesis (IE) over an extended period. A variety of chronic hemolytic anemias, transfusion dependency, and elevated iron absorption are caused by ineffective erythropoiesis. BT treatments involve pharmacological and gene therapy approaches that target pathways that affect iron homeostasis and erythropoiesis.

What Are the Emerging Therapies in Clinical Practice?

• Clinical trials have demonstrated the efficacy of Sotatercept (ACE-011) and Luspatercept (ACE-536).

• Originally intended to treat bone-loss problems, statins were shown to raise hematocrit and Hb levels in people receiving treatment unexpectedly. These peptides function as ligand traps for TGFβ-like molecules and are structurally engineered to compete with the extracellular domains (ECDs) of Activin Receptor A Type 2A (ACVR2A) or 2B.

• The TGFβ superfamily member growth differentiation factor 11 (GDF11) has been identified as Luspatercept's ligand target. It is believed that Luspatercept treatment causes GDF11 to be removed from the bloodstream, which raises Hb levels. It is widely known that GDF11 functions as a ligand that can activate the SMAD2/3 pathway using ACVR2A or 2B.

What Are the Innovative Treatments for Diseases?

1. Acute Leukemia and Myelodysplastic Syndrome: For kids with ALL, regular thromboprophylaxis has no benefit.

2. Myeloproliferative Neoplasms and Chronic Leukemias:

• Rusfertide for polycythemia vera patients to lessen therapeutic phlebotomy.

• Venetoclax in addition to Ibrutinib for untreated CLL/SLL.

• Pirtobrutinib for CLL/SLL relapses.

3. Lymphomas:

• There is no benefit to high-dose Methotrexate prophylaxis of the central nervous system in diffuse large B cell lymphoma patients.

• After chimeric antigen receptor (CAR)-T cell treatment, rare secondary T cell lymphomas.

• Market withdrawal of Copanlisib.

4. Multiple Myeloma and Other Disorders Involving Plasma Cells:

• For multiple myeloma, four versus three medication induction is used.

• Uses of Ibrutinib and Zanubrutinib for Waldenström macroglobulinemia.

• G-CSF and Migsafortide together for patient mobilization in multiple myeloma patients.

• In patients with hard-to-treat multiple myeloma, Talquetamab generates a high response rate.

5. Anemias and Disorders of the Red Blood Cells:

• New global guidelines regarding PK (pyruvate kinase) deficiency.

• Editing genes to treat beta-thalassemia.

• Infants with methemoglobinemia as a result of tainted hospital water supplies.

• In sickle cell disease, gene editing and gene therapy.

• Disparities in anemia during pregnancy between races.

• Patients receiving gene therapy for beta-thalassemia achieve a better quality of life and sustain transfusion independence.

6. Hemostasis and Thrombosis:

• Updates to the antiphospholipid antibody syndrome categorization criteria.

• Risk of sickle cell disease-related venous and arterial thrombosis during pregnancy.

• Experimental treatment of immunological thrombocytopenia with Efgartigimod.

• In Ehlers-Danlos syndromes, bleeding occurs.

• Postponed identification of acquired hemophilia A.

• It has been determined that gene therapy is a fair and possibly cost-effective treatment option for people with sickle cell disease in Western nations.

7. Transfusion:

• Transfusion of whole blood in cases of acute trauma hemorrhage. Transfusion of whole blood in cases of severe traumatic bleeding.

• Use of liberal transfusion strategy in cases of acute myocardial infarction.

• Different transfusion procedures in the intensive care unit (ICU).

• Convalescent plasma in COVID-19 patients on mechanical ventilation.

• Transfusion-related polymicrobial sepsis using platelets.

• Cryoprecipitate had no advantage in the massive transfusion regimen for trauma patients.

• Intensive care unit anemia can be decreased by using small-volume blood collection tubes.

• Effectiveness of intraoperative blood salvage in lowering allogeneic transfusion requirements.

• Transfusion recipient’s risk of intracerebral hemorrhage.

• Platelet count improvements were found in over half of ITP (immune thrombocytopenic purpura) patients receiving Efgartigimod.

What Are the Other Hematological Enhancements?

• Updated Recommendations for Protoporphyria (March 2024): Rare cutaneous porphyrias that induce severe, non-blistering photosensitivity and liver illness are erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). Because of their rarity, evidence-based management of these conditions is difficult. To aid in the diagnosis and treatment of XLP and EPP, the Rare Diseases Clinical Research Network has released two new guidelines.

  • Consensus guidelines include genetic and biochemical tests, Afamelanotide, avoiding ineffective medicines, sun protection techniques, and preventing liver disease.

  • Liver-specific recommendations talk about liver disease screening, prevention, and therapy. For advanced illnesses, talk about liver and hematopoietic stem cell transplantation.

• Adults With Paroxysmal Nocturnal Hemoglobinuria Can Use the Pegcetacoplan Self-Injector (November 2023):

  • A pegylated peptide called Pegcetacoplan can prevent adult patients with paroxysmal nocturnal hemoglobinuria (PNH) from experiencing intravascular and extravascular hemolysis. Pegcetacoplan in a single-use self-injector was recently approved by the US Food and Drug Administration (FDA) for use by the patient or carer following preparation and administration instructions. As with other complement inhibitors, Pegcetacoplan is contraindicated in patients with severe infections. Additionally, the FDA label includes a boxed warning about an increased risk of meningococcal infections. The Pegcetacoplan self-injector is regarded as a suitable therapeutic option for people suffering from symptomatic PNH.

How Does the Hematology Lab Employ Computer Vision, and What Does It Mean?

Artificial intelligence (AI) algorithms that can analyze, combine, and extrapolate from any image are widely used in computer vision. These intricate computer programs are believed to simulate human intellect in certain aspects. Algorithms that could automatically distinguish digital pictures of one type of cell or tissue from another, such as various blood cell types or cancerous cells and tissues from benign ones, would be a practical example.

AI and computer vision are mostly used sparingly in the hematology lab. It has been observed that most approved devices are limited to the morphologic study of blood smears. These technologies automatically locate and pre-classify white cells, red cells, and platelets on digitized images of blood smears into a small but significant number of categories (for example, neutrophils, blasts, sickled red cells, platelet clumps, etc.) based on trained and validated computer algorithms. After that, cell pictures are forwarded to a human specialist for final categorization, such as a technologist, hematopathologist, or hematologist. Since humans are the final arbitrators in this situation, using these algorithms fits within what is known as a decision-support role.

While not perfect, these computer vision and artificial intelligence (AI) systems partially automate the process of blood smear review, which has been done manually by microscopy with glass slides for decades. This is a terrific advancement as it allows one to continue being more efficient in the lab. Blood smear review is one of the most common lab tests.

Conclusion

Several types of research have been going on in hematology to manage disorders. New drugs have been employed, and gene therapy has been employed in some cases. The field of hematology has been constantly evolving. Scientists are trying to make further changes that were once considered impossible. With the help of new drugs and gene therapy, hematology is greater. Computer vision and artificial intelligence (AI)-based systems, while not perfect, partially automate the process of blood smear review, which has been done manually by microscopy with glass slides for decades. This integration into the workflows allows the systems to continue improving the efficiency in the lab, which is a fantastic advancement. Blood smear review is widely performed in laboratories.