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Current Options and New Developments for Treating Myelodysplastic Syndromes

This article discusses the diagnosis, risk factors, treatment options, and supportive care for Myelodysplastic Syndromes (MDS), a clonal disorder of the bone marrow characterized by low blood counts and ineffective production of blood cells. It also explores the incidence of MDS and challenges in caring for MDS patients in Canada, as well as the goals of therapy and the risk of iron overload associated with transfusion dependency.

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Current Options and New Developments for Treating Myelodysplastic Syndromes

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  1. Current Options and New Developments for Treating Myelodysplastic Syndromes Oct 19, 2019

  2. Myelodysplastic Syndromes (MDS) • Clonal disorders of the bone marrow characterized by: • Low blood counts • Ineffective production of blood cells • Abnormal red cells, neutrophils and platelets • Increased risk of developing acute myeloid leukemia (AML)

  3. Bloodwork abnormalities • Low hemoglobin, white blood cells (neutrophils) • usually low platelets (occasionally high), • sometimes immature white cell precursors in blood (blasts) MDS Wikipedia.org Normal cells

  4. Diagnosis • Bone marrow biopsy • Morphology • Chromosome studies • Flow cytometry • Gene mutation tests • next generation sequencing (NGS)

  5. Incidence of MDS increases with age SEER registry online

  6. Frequency in Alberta • 45-50 newly diagnosed MDS on bone marrow examinations/year in Calgary* • Disproportionate number of RARS/RAEB (higher risk) (8.5%) (11) (21/18.5) (0) (2.2) (RCMD 39%) Leukemia Research 24(12): 983-992, 2000 Courtesy AdnanMansoor

  7. Challenges in care of MDS patients in Canada Geology.com

  8. Risk factors for Myelodysplastic Syndromes Acquired Rare disorders: Constitutional (Down’s, trisomy 8, monosomy 7) Congenital neutropenia and DNA repair disorders ieFanconi’s Inherited • Senescence • Mutagens • Chemotherapy • Radiation • Smoking (small increased risk) • Environment ie benzene • AplasticAnemia, PNH • Obesity List et al Wintrope 1999

  9. MDS-U (cytopenias, <1% blasts, <10% dysplastic cells + cytogenetic abnormality) MDS with isolated del 5q Refractory anemia with excess blasts-1 (5-9%) Refractory anemia with excess blasts-2 (10-19%) Myelodysplastic syndrome –unclassified MDS with isolated del(5q) Refractory anemia, /Refractory anemia with ringed sideroblasts Refractory cytopenias with multilineage dysplasia/RCMD-RS Refractory cytopenias with unilineage dysplasia (RCUD), RA, RN, RT 2008 WHO Classification WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. 2008.

  10. IPSS-RRevised International Prognostic Scoring System Very good = del(11q) Good = Normal, del(5q), del(12p), del(20q), double including del(5q) Intermediate = del(7q), 8, 19, i(17q), any other single or double independent clones Poor = inv(3)/t(3q)/del(3q), double including 7/del(7q), complex: 3 abnormalities Very poor = Complex: 3 abnormalities Greenberg P, Tuechler H, Schanz J, et al. Blood. 2012;120(12):2454

  11. MDS in Canada • MDS patient registry helping us to understand course of disease • Quality of life and strength/frailty • 15 sites in Canada; 966 patients enrolled since 2011 • Track number of patients, type of MDS, disease characteristics and treatment • Measures of quality of life and frailty • Opportunity for collaborative clinical trials

  12. MDS in Canada • Publications include: • new prediction score of who may respond to erythropoietin (red cell growth hormone) • quality of life studies

  13. Sites of MDS Registry in Canada

  14. Types of MDS in Canadian Patients

  15. Goals of Therapy • Prolong survival • Quality of life • Improve symptoms • Reduce transformation to acute leukemia

  16. Supportive Care Transfusions Antibiotics Iron chelation Growth Factors Hypomethylating agents Lenalidomide Immunosuppression Chemotherapy Bone marrow transplantation Treatment Options

  17. Supportive care • Goal is to improve quality of life and also survival • Antibiotics • Transfusions of red cells and platelets • Home care support, mobile labs • Medications to prevent bleeding • Avoid iron supplements unless iron deficient

  18. Approach to treatment of MDS

  19. How do we decide if patients have lower risk or higher risk MDS? • Blood counts • Chromosome analysis • Blast counts in bone marrow • Age • Type of MDS

  20. Lower risk MDS • Expected survival relatively long but patients can experience fatigue • impact on quality of life • Sometimes transfusion dependent for red cells and platelets • Low risk of transformation to acute leukemia

  21. Recommendations for patients with low / intermediate-1 IPSS risk Low / Int-1 IPSS Risk Not symptomatic Symptomatic anemia MDS del(5q) Not del(5q) Younger patients, BM blasts <5%, normal cytogenetics Serum EPO<500 mU/mL and/or RBC transfusion <2 U/month Other progression Consider immunosuppressive therapy with ATG + cyclosporine Transfusion and iron chelation therapy ATG, anti-thymocyte globulin. BM, bone marrow. EPO, erythropoietin. G-CSF, granulocyte colony-stimulating factor. IPSS, International Prognostic Scoring System. RBC, red blood cell Watchful waiting Lenalidomide EPO +G-CSF National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 2.2014. 22

  22. Risk of Iron Overload in MDS Transfusion dependency associated with complications of iron overload • Conduction/rhythm disturbance (4x risk) • Diabetes (5x risk) • Liver dysfunction (3x risk)

  23. Percent of patients with cardiac iron deposits prior to chelation era Buja AJM 51, 1971

  24. Strategies to reduce iron overload 1) Decrease iron load by decreasing transfusions 2) Chelation therapy – bind iron out of the body and help the body excrete it - iv/subcutanous continuous infusion or oral 3) Phlebotomies (blood removed) in some patients where bone marrow failure is no longer a problem I.e. post bone marrow transplant, treated aplastic anemia

  25. Lower risk MDS • Iron chelation for iron overload from transfusions • Usually if ferritin>1000 and/or 20 transfusions red cells • Oral more often than IV, expensive • Covered by Alberta Blue Cross and most private plans • co-pay program for amounts not covered by Blue Cross

  26. Lower risk MDS • Growth factors i.e. erythropoietin • increase red cells and reduce transfusions • Transfusions, antibiotics, supportive care • B12 and folate therapy in patients with nutritional deficiencies • Clinical trials – ie newly transfusion dependent patients erythropoietin vsluspatercept

  27. Decrease iron by decreasing transfusions • Choose threshold for transfusion based on symptoms • Erythropoietin in MDS to reduce transfusions based on risk factors: • ≥2 units RBCs/month • Erythropoietin level >500 Improvement in global quality of life with borderline significance for fatigue Median duration of response 23 months

  28. Hematopoietic Growth FactorsFor Lower Risk MDS Response rates to erythropoietin overall: • 30-40% overall in low risk disease • Certain factors predict response • Sometimes combine with granulocyte colony stimulating factor to try and induce a response Overall Survival by Treatment 1.0 0.9 0.8 0.7 0.6 0.5 Probability 0.4 0.3 0.2 0.1 Log Rank Test p=0.28 0.0 0 10 20 30 40 60 50 70 80 90 100 110 120 Month Treatment Total Fail Supportive care 57 48 EPO 150 U/kg/d 53 38 Greenberg PL, et al. Blood 2009. 114(12):2393-400

  29. Luspatercept in lower risk MDS patients not responding to erythropoietin

  30. Duration of transfusion independence with luspatercept

  31. Clinical trials • How to determine if new treatments are effective • Compare older treatments to new therapies • Varies from center to center; ask your physician • Calgary and Edmonton study opening in next few months: • Patients with lower or intermediate 1 risk myelodysplastic syndromes who are not responding to erythropoietin or have high erythropoietin levels • Imetelstatvs standard care (transfusions, etc)

  32. Can we modify the course of disease in MDS?

  33. Del 5q syndrome • 10-15% of MDS • Anemia • Mild low white blood cells • Atypical megakaryocytes, normal to elevated platelets • Transfusion dependence • Normal blast count Long term survival with low frequency of AML transformation (10%)

  34. Lenalidomide: RBC Transfusion Independence in Del(5q) MDS N Eng J Med, 2006; 355: 1456

  35. Higher risk MDS • Supportive care, transfusions • Higher impact on quality of life and survival

  36. Recommendations for patients with intermediate-2 / high IPSS risk Intermediate-2 / high IPSS risk SCT candidate? Yes No Refer to transplant centre for allogeneic SCT assessment Hypomethylating agents:Azacitidine SCT, stem cell transplant. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 2.2014. 37

  37. Azacitidine (Vidaza) in higher risk MDS • Azacitidine approved for Intermediate-2 and High risk MDS, low blast count AML • 7d monthly subcutaneous infusions • Continued as long as continues to be effective; can take 3-6 months to see maximal effect • Associated with improved survival, lower rate of developing acute leukemia • Improved quality of life

  38. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 5 10 15 20 25 30 35 40 Overall Survival: Azacitidine vs Conventional Care Regimen p=0.0001 Proportion Surviving AZA Conventional Care Time (months) from Randomization Survival difference 9.4 months Oral azacitidine in development Lancet Oncol 2009; 10:223-32.

  39. Role of Bone Marrow Transplantation • 8-10 patients per year from Alberta • Patients under age 65y, medically well with high risk MDS • Offered as part of first line therapy for eligible patients with higher risk disease

  40. Between a rock and a hard place Transplantation is currently the only curative therapy for myelodysplastic syndromes Median age at diagnosis is 65-70 Toxicity of transplantation can be prohibitive

  41. Treatment of Higher Risk MDS • Clinical trials – speak with your physician about trials available at your centre

  42. Other supports available • Home care • Wellspring • AAMAC • Leukemia and lymphoma society • Psychosocial services • Dieticians • Social work, home care, mobile lab

  43. Questions?

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