SIZE XSSIZE SMSIZE MDSIZE LG

Membership

Article Index

Page 8 of 11

Benign Hematology for the Oncology Pharmacist

Alexis Kuhn, PharmD BCOP
Pediatric Oncology Pharmacist—Ambulatory Services
Mayo Clinic
Rochester, MN

Most people think of hematology as malignant hematology. This penchant for malignant hematology is reflected in the oncology pharmacy residency standards and the Board Certified Oncology Pharmacist (BCOP) content outline.1,2 Despite this, hematology/oncology pharmacists are often called upon to care for benign hematology patients in clinical practice. The goal of this review is to familiarize hematology/oncology pharmacists with fundamental benign hematology concepts that can be employed during care for this population.

Meet the Players

Erythrocytes
“Normal” adult hemoglobin (HbA) consists of two α- and two β-globin subunits (α2β2). Fetal hemoglobin (HbF) consists of two α- and two γ-globin subunits (α2γ2) and has greater oxygen-binding affinity than HbA. HbF production nadirs in the postnatal period.3

Leukocytes
Hematopoietic progenitors differentiate into either myeloid lineage (neutrophils and other granulocytes) or lymphoid lineage (T and B cells). Both elements are crucial for immune function.4

Platelets
Platelets are vital for hemostasis. GPIbα on the platelet surface binds to endothelial-bound von Willebrand factor (vWF) to initiate platelet adhesion.5,6

Meet the Disorders

Hemostatic disorders
Von Willebrand disease (VWD) is the most common inherited bleeding disorder. In addition to its role in platelet adhesion, vWF also stabilizes circulating factor VIII (FVIII). Types 1 and 3 VWD are quantitative disorders of vWF, and Type 2 is a qualitative disorder.6,7 Hemophilia is an X-linked disorder that arises from absent or diminished production of FVIII (hemophilia A) or factor IX (FIX; hemophilia B). Hemophilia severity is defined by baseline factor activity level: severe (<1%), moderate (1%–5%), or mild (5%–40%).8 Severe disease is characterized by spontaneous and potentially life-threatening bleeds. Neutralizing antibodies produced in response to exogenous factors, known as inhibitors, afflict ~30% of patients with severe hemophilia A and ~3%–5% of patients with hemophilia B.9

Hemoglobinopathies
Thalassemias are quantitative disorders of hemoglobin, resulting from diminished production of either α- or β-globin. They can be categorized by affected gene, major/intermedia/minor designation, and transfusion-dependent/independent status. Transfusions often begin at a young age, making potentially fatal siderosis a lifelong concern.10

Sickle cell disease arises from a point mutation in the β-globin gene. Mutant hemoglobin (HbS, α2βS2) polymerizes when deoxygenated, which results in the characteristic sickled shape of affected erythrocytes.11 Clinical sequelae include pain crises, acute chest syndrome, and stroke. In general, patients with HbSS and HbSβ0 thalassemia tend to have more severe clinical phenotypes than patients with other heterozygous genotypes (i.e., HbSC, HbSβ+ thalassemia).11

Cytopenias
Cytopenias result from either inherent marrow failure or immune destruction. Bone marrow failure syndromes can be inherited or acquired, and they result in either single- (e.g., severe congenital neutropenia) or multi-lineage loss (e.g., aplastic anemia).12 Common immune cytopenias include immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and Evans syndrome (typically coincident ITP + AIHA). Characterization of the causative antibody is particularly useful in AIHA, where thermoreactivity directs treatment approach.13,14

Meet the Drugs

Treatment of hemostatic disorders
Possible treatment options for VWD include desmopressin and vWF concentrates. Desmopressin increases vWF and FVIII, also making it useful for treating mild or moderate hemophilia A.7

The treatment of choice for severe hemophilia has traditionally been prophylaxis with clotting factor concentrates.8 Major differentiating features between concentrates include factor (FVIII, FIX, vWF, etc.), source (plasma-derived vs. recombinant), and presence of modifications. Concerns of viral transmission have plagued the plasma-derived concentrates, but modern manufacturing practices minimize the risk of transmission.15 Recombinant factors carry no risk for viral transmission, but conflicting reports suggest that certain recombinant factors may have a higher risk of inhibitor development than plasma-derived factors containing vWF.16 Extended half-life (EHL) factors employ various modifications (e.g., pegylation, albumin fusion) to reduce the frequency of infusion. EHL FIX products have achieved a 4–6 times half-life extension in contrast to the 1.5–2 times extension of the EHL FVIII products.17

Emicizumab is a monoclonal antibody approved for hemophilia A. By binding FIXa and FX, emicizumab mimics the activity of FVIII, making it a therapeutic option for patients with and without inhibitors as evidenced in the HAVEN trials.18-21 Unlike the intravenous clotting factor concentrates, emicizumab is a subcutaneous injection that can be given one to four times per month.21,22 Other therapeutic options for patients with inhibitors include bypassing agents (FEIBA and rFVIIa) and immune tolerance induction.9,23

Treatment of hemoglobinopathies
Iron chelators are paramount in managing chronic transfusion therapy associated with hemoglobinopathies. Deferoxamine is given as daily subcutaneous infusions, or, less commonly, as intermittent high-dose intravenous infusions.24 Deferasirox and deferiprone are enteral options, but deferiprone carries a risk for agranulocytosis. Combination chelation can be deployed for refractory cases.25,26

Therapeutic options for sickle cell disease have expanded in recent years. Hydroxyurea has been used for several decades; it induces HbF production and reduces the frequency of pain crises, acute chest syndrome, and transfusions.27,28 The first approved novel agent, L-glutamine, works by maintaining reduction and oxidation balance. L-glutamine was shown to reduce pain crises compared to placebo (three vs. four episodes per year, p = .005) in a phase 3 trial.29 Crizanlizumab is an intravenous P-selectin inhibitor that interrupts adhesion of cells to the vascular endothelium. In the SUSTAIN trial, high-dose crizanlizumab was shown to reduce pain crises compared to placebo (1.6 vs. 3 episodes per year, p = .01).30 Voxelotor is an oral agent that inhibits HbS polymerization. In the HOPE trial, voxelotor increased hemoglobin >1 g/dL from baseline in 51% participants.31 Studies of voxelotor, crizanlizumab, and L-glutamine included patients with and without concomitant hydroxyurea; however, there is currently no standard for how to sequence these agents in clinical practice.32

Treatment of cytopenias
Inappropriate immune system activity can be dampened by various approaches: corticosteroids, intravenous immunoglobin, rituximab, and other immunosuppressants.13,14 Warm AIHA is typically more responsive to immunosuppressants than cold AIHA.14 Immunosuppression with equine antithymocyte globulin plus cyclosporine, with or without eltrombopag, is the standard of care for transplant-ineligible patients with severe aplastic anemia.33,34 Eltrombopag is a thrombopoietin (TPO) receptor agonist thought to have hematopoietic stem cell-stimulatory effects and is approved by the U.S. Food and Drug Administration for refractory aplastic anemia; larger trials are under way to confirm early positive results in front-line therapy.34,35 In addition to its activity in aplastic anemia, eltrombopag is used to treat chronic ITP, as is the parenteral TPO agonist, romiplostim.36 Caplacizumab is an anti-vWF antibody with activity in acquired thrombotic thrombocytopenia purpura. 37,38

References

  1. Required competency areas, goals, and objectives for postgraduate year two (PGY2) oncology pharmacy residencies. American Society of Health-System Pharmacists website. https://www.ashp.org/-/media/assets/professional-development/residencies/docs/pgy2-newly-approved-oncology-pharmacy-2016.ashx. Accessed May 13, 2020.
  2. Board of Pharmacy Specialties. Board of Pharmacy Specialties Oncology Pharmacy Specialist Certification Content Outline/Classification System. https://www.bpsweb.org/wp-content/uploads/OncContentOutline2017.pdf. Accessed May 13, 2020.
  3. Schechter AN. Hemoglobin research and the origins of molecular medicine. Blood. 2008;112:3927-3938.
  4. Ogawa M. Differentiation and proliferation of hematopoietic stem cells. Blood. 1993;81:2844-2853.
  5. Holinstat M. Normal platelet function. Cancer Metastasis Rev. 2017;36:195-198.
  6. Peyvandi F, Garagiola I, Baronciani L. Role of von Willebrand factor in the haemostasis. Blood Transfus. 2011;9(Suppl 2):s3-s8.
  7. Leebeek FW, Eikenboom JC. Von Willebrand’s disease. N Eng J Med. 2016;375:2067-2080.
  8. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia. 2013;19:e1-47.
  9. Carcao M, Goudemand J. Inhibitors in Hemophilia: A Primer. 5th ed. Montreal, Canada: World Federation of Hemophilia; 2018.
  10. Viprakasit V, Ekwattanakit S. Clinical classification, screening and diagnosis for thalassemia. Hematol Oncol Clin North Am. 2018;32:193-211.
  11. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med. 2017;376:1561-1573.
  12. Sieff CA. Introduction to acquired and inherited bone marrow failure. Hematol Oncol Clin North Am. 2018;32:569-580.
  13. Kim TO, Despotovic JM. Primary and secondary immune cytopenias: evaluation and treatment approach in children. Hematol Oncol Clin North Am. 2019;33:489-506.
  14. Go RS, Winters JL, Kay NE. How I treat autoimmune hemolytic anemia. Blood. 2017;129:2971-2979.
  15. Farrugia A. Guide for the Assessment of Clotting Factor Concentrates. 3rd ed. Montreal, Canada: World Federation of Hemophilia; 2017.
  16. Peyvandi F, Mannucci PM, Garagiola I, et al. A randomized trial of Factor VIII and neutralizing antibodies in hemophilia A. N Eng J Med. 2016;374:2054-2064.
  17. Graf L. Extended half-life factor VIII and factor IX preparations. Transfus Med Hemother. 2018;45:86-91.
  18. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377:809-818.
  19. Young G, Liesner R, Chang T, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019;134:2127-2138.
  20. Mahlangu J, Oldenburg J, Paz-Priel I, et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med. 2018;379:811-822.
  21. Pipe SW, Shima M, Lehle M, et al. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. Lancet Haematol. 2019;6:e295-e305.
  22. Shima M, Nogami K, Nagami S, et al. A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors. Haemophilia. 2019;25:979-987.
  23. Carcao M, Escuriola-Ettingshausen C, Santagostino E, et al. The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab. Haemophilia. 2019;25:676-684.
  24. Kalpatthi R, Peters B, Kane I, et al. Safety and efficacy of high dose intravenous desferrioxamine for reduction of iron overload in sickle cell disease.Pediatr Blood Cancer. 2010;55:1338-1342.
  25. Kontoghiorghe CN, Kontoghiorghes GJ. Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent. Drug Des Devel Ther. 2016;10:465-481.
  26. Gomber S, Jain P, Sharma S, Narang M. Comparative efficacy and safety of oral iron chelators and their novel combination in children with thalassemia. Indian Pediatr. 2016;53:207-210.
  27. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the multicenter study of hydroxyurea in sickle cell anemia. N Engl J Med. 1995;332:1317-1322.
  28. Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet. 2011;377:1663-1672.
  29. Niihara Y, Miller ST, Kanter J, et al. A phase 3 trial of L-glutamine in sickle cell disease. N Engl J Med. 2018;379:226-235.
  30. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376:429-439.
  31. Vichinsky E, Hoppe CC, Ataga KI, et al. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381:509-519.
  32. Bradt P, Spackman E, Synnott PG, et al. Crizanlizumab, Voxelotor, and L-Glutamine for Sickle Cell Disease: Effectiveness and Value. Boston, MA: Institute for Clinical and Economic Review; 2020. Available at https://icer-review.org/wp-content/uploads/2019/08/ICER_SCD_Evidence-Report_031220.pdf
  33. Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Eng J Med. 2011;365:430-438.
  34. Scheinberg P. Activity of eltrombopag in severe aplastic anemia. Blood Adv. 2018;2:3054-3062.
  35. Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Eng J Med. 2017;376:1540-1550
  36. Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3:3829-3866.
  37. Peyvandi F, Scully M, Kremer Hovinga JA, et al. Caplacizumab for acquired thrombotic thrombocytopenia purpura. N Eng J Med. 2016;374:511-522.
  38. Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab treatment for acquired thrombotic thrombocytopenia purpura. N Eng J Med. 2019;380:335-346.
xs
sm
md
lg