When Thalassemia Trait is Not a Trait …

17 September, 2019

Kevin Kuo, MD, MSc, FRCPCClinician-Investigator and Staff Hematologist

Red Blood Cell Disorders Program, Therapeutic Apheresis ProgramDivision of Medical Oncology and Hematology, University Health Network

Division of Hematology, Department of Medicine, University of Toronto

Conflict of Interest Disclosures

• Consultancy: Abfero, Agios, Alexion, Apellis, ApoPharma, Celgene, Novartis, Pfizer

• Honoraria: Alexion, Novartis• Data Safety Monitoring Board: Bioverativ• Research collaboration: Phoenicia Biosciences, Abfero

Objectives

• Appreciate the diverse presentation of a thalassemia intermedia patient, often masquerading as other diagnoses

• Screen for and monitor complications associated with thalassemia intermedia

• Weigh the risks and benefits and decide when to initiate transfusion in such patients

• Explore novel therapies undergoing clinical investigation for treatment of thalassemia intermedia

Epidemiology of Thalassemia in Canada• Toronto General Hospital (adult) is the largest thalassemia

comprehensive care centre in North America (N ~ 400)• More than Half are non-transfusion dependent thalassemia

patients• Sickkids have similar number of patients

• Canadian estimate is ~1200– Data accuracy is limited by lack of thalassemia registry

• 30 year-old female referred for severe microcytic anemia • Abdominal MRI showed hepatomegaly at 22 cm, splenomegaly

24 cm, numerous paraspinal extramedullary hematopoiesis• Hb 55, retic 408, MCV 68, Plt 120, bili 69 (indirect 50), LDH 428• b globin sequencing revealed bA / b0

• Further sequencing reveals a quadruplication

Wilber A, Nienhuis AW, Persons DA. Blood. 2011 Apr 14;117(15):3945-53.

Globin Genes > Hemoglobin > RBCs

12

Turning b-Traits into Thalassemia Intermedias• Phenotypic severity is driven in a large part by the degree of

Imbalance in globin chain production

a b

ab

a bEbA / bA

b0 / b0

bE / b+ or bE / b0

Normala b a b+a b+

bA / b0 b+ / b0b+ / b+

Trait

MajorIntermedia

a a a

Intermedia(+ aaa or aaaa)

g

Intermedia(+ HPFH)∴ In suspected cases, look for a globin duplications

(not a thalassemia)

2027551• 41 year-old gentleman• Referred for elevated indirect bilirubin, previously labeled as

Gilberts• History of chronic low back pain• Hb 120, retic 310, MCV 77, Plt 120, bili 69 (indirect 50), LDH 461• Hemoglobin electrophoresis: HbF 95%, HbA2 = 4%• On examination the patient has extensive skull and bony

deformations characteristic of thalassemia• MRI liver R2: liver iron concentration 14.5 mg/g dw• Spinal MRI: extramedullary hematopoiesis

Mild Anemia ≠ Mild Phenotype

• Hemoglobin = RBC production + destruction

• Ineffective erythropoiesis/hemolysis• Patients often have compensated

hemolysis• Complications from thalassemia can

often be mistaken as disparate diagnoses

Rund D and Rachmilewitz E. N Engl J Med 2005; 353:1135-1146

2027551• 33 year-old gentleman• Referred for chronic microcytic anemia, never received transfusion• History of insulin dependent diabetes mellitus diagnosed at age 20• Hb 86, retic 87, MCV 77, Plt 120, bili 69 (indirect 50), LDH 361• Liver MRI R2: liver iron concentration of 15.8 mg/g dw• Cardiac MRI T2*: 15 ms at mid-interventricular septum• DEXA: osteoporosis• Endocrine work-up: hypogonadotropic hypogonadism

ATP

Iron Overload in the Absence of Transfusion• LIC > 5 mg/g dw are

associated with increased morbidity in NTDT

• Increased risk of developing thrombosis, pulmonary hypertension, hypothyroidism, hypogonadism, and osteoporosis

Taher A and Saliba AN. Hematology Am Soc Hematol Educ Program. 2017 Dec 8; 2017(1): 265–271. Musallam KM, et al. Haematologica 2011;96(11):1605-1612. Modified from: Rivella S. Haematologica. 2015; 100(4): 418

Origa R, et al. Haematologica May 2007 92: 583-588

Serum Ferritin Underestimates the Severity of Iron Overload

2027551• 22 year-old gentleman, recent immigration to Canada• Referred for management of thalassemia• Hb 79, retic 127, MCV 74, Plt 656, bili 122, LDH 528• Severe anemia despite splenectomy as a child• Severe extramedullary hematopoiesis causing multilevel spinal cord

compression secondary to lack of transfusion • Chronic microangiopathic changes on brain MRI likely secondary to

thalassemia• Severe hepatic iron overload: liver iron concentration 29.8 mg/g dw• Low bone mineral density• Hypogonadotropic hypogonadism

Intermedia versus TDT/NTDT• General shift from classifying thalassemia intermedias and

majors into transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemias (NTDT)

• TDT and NTDT are convenient labels for selecting patient for clinical trials

• No consensus on the definition of TDT and NTDT• Decision to transfuse is dependent on blood availability, blood

safety, and severity and types of complications• Major ≠ TDT Intermedia ≠ NTDT

Potential Therapeutic Targets

Modified from: Rivella S. Haematologica. 2015; 100(4): 418

ATP

NCT03342404

• A Study to Determine the Efficacy and Safety of Luspatercept in Adults With Non Transfusion Dependent β-Thalassemia

• GDF11 appears to inhibit differentiation and maintain the survival of immature erythroid progenitors

• Inhibition of GDF11 by Luspaterceptreleases the block

Paulson RF. (2014) Nature Medicine 20:334–335

NCT03692052

• A Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Participants With Non-transfusion-dependent Thalassemia

• Reduction in spleen size, ROS level, apoptosis and alpha globin aggregates and improvement in hematologic parameters in Hbb3th/+ mice

• Recruiting at University Health Network, Toronto

Matte A, et al. EHA- 8-12 June 2016; Ginzburg Y and Rivella S. 2011; Blood 118(16): 4321; De Franceschi, L., et al. J Oxidative Medicine and Cellular Longevity. 2013: 10

NCT03802201

• Study of PTG-300 in Non-Transfusion Dependent and Transfusion-Dependent Beta-Thalassemia Subjects With Chronic Anemia

• Hepcidin is suppressed by ERFE in thalassemia, leading to ineffective erythropoiesis

• PTG-300 is a hepcidin mimetic that was shown to improve erythropoiesis, RBC survival, decreased splenomegaly and hepatic iron overload in Hbb3th/+ mice

Bourne G. EHA 2018 Abstract S843

NCT03993613

• Apotransferrin in Patients With β-thalassemia• apotransferrin inhibits TfR1 expression independent of EPO- and iron-

related signaling, decreases TfR1 partitioning to reticulocytes during enucleation, and enhances enucleation of defective β-thalassemic erythroid precursors

• Decreased TfR1 upregulates hepcidin in an iron- and ERFE-independent manner

Li HH, et al. Blood 2017 129:1514-1526

NCT04059406

• Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS TMPRSS6-LRx

• Inhibition of TMPRSS6 expression can upregulate hepcidin expression

• TMPRSS6-LRx is a GalNAc-conjugated antisense oligonucleotide

• Phase 1 healthy volunteers study showed reduction in serum iron, transferrin saturation, and increase in plasma hepcidin levels

• Small reductions in Hb (-9±2%) and reticulocyte Hgb (-13±2%) at the 40 mg dose

Camaschella C. N Engl J Med 2013; 368:2325-2327

Summary• Thalassemia intermedia is phenotypically diverse• Recognition of the clinical relevance of this subgroup of patients

remains challenging• Management of these patients are often more complex than

thalassemia major patients• Targeting the pathogenesis of ineffective erythropoiesis and

hemolysis may reduce or ameliorate anemia and iron overload in thalassemia patients

• Clinical trials are essential in establishing the exact role of these agents in the treatment of thalassemia

Thank you