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Refractory anemia case report mds

Refractory anemia case report mds

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A case report of MDS presenting as refractory anemia, followed by overview of treatment of MDS and comparison of hypomethylating agents (HMAs)

A case report of MDS presenting as refractory anemia, followed by overview of treatment of MDS and comparison of hypomethylating agents (HMAs)

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Refractory anemia case report mds

  1. 1. With case report of MDS presenting as anemia Approach to Myelodysplastic Syndrome (MDS) & Overview of Treatment Dr. Jaykumar Sejpal, Medical Advisor, Oncology.
  2. 2. Scope of presentation  Clinical presentation  Diagnostic workup  Management approach  Choosing agent for treatment
  3. 3. Clinical presentation  64 year-old male  Presented with new-onset decreased exercise tolerance of two months duration  Also complaint of fatigue, weakness & occasional dizziness  Past Medical History:  Hypertension  Negative previous hematologic disorder  Treated with iron supplements  Physical Examination:  No hepatosplenomegaly
  4. 4. Complete Blood Count Macrocytic anemia  Peripheral Smear:  RBC: Ansisocytosis and macrocytosis  No poikilocytosis  WBC:  Predominantly mature neutrophils and lymphocytes  No dyspoiesis  No blasts  WBC 2 x 103 /μL  RBC 1.84 x 10 6 /μL  Hgb 5.1 g/dL  Hct 19.5 %  MCV 127 fL  Platelet 1,10,000 /μL  Differential:  55% PMN, 32% Lymph, 12% Mono, 1% Eos
  5. 5.  No aspirate smear  Bone marrow biopsy- Touch Prep:  Dyserythropoiesis  Two possible megakaryoblasts  Blast count about 4%  Flow:  Mixed population, slightly abnormal myeloid maturation, no increase in blasts.  Iron Stain:  Increased stores without ringed sideroblasts
  6. 6. Immunohistochemistry (IHC)  CD34 IHC stains of bone marrow (BM) aspirates helps to distinguish between hypocellular myelodysplastic syndrome (hMDS) and aplastic anemia (AA)
  7. 7. Immunohistochemistry (IHC)
  8. 8. Cytogenetics  Multiple Complex Abnormalities:  Monosomy 2,5,7 and 15  Trisomy 8  Unbalanced translocation b/t 17p and 2q  Additional chromosomic material of unknown origin replacing 7q (of the remaining 7) and on 17q and 12p
  9. 9. Differential Diagnosis  Chronic Myeloproliferative Disorders  No splenomegaly, no leukoerythroblastic smear  Acute Myeloid Leukemia  Blasts <5%, cytogentics  Myelodysplastic Syndrome (MDS)  Cytogenetic, BM blasts, peripheral smear
  10. 10. MDS FAB Classification  RA: Refractory anemia  RARS: refractory anemia with ringed sideroblasts  RAEB: refractory anemia with excess blasts  CMML: Chronic myelomonocytic leukemia  RAEB-T: refractory anemia with excess blasts in transformation
  11. 11. MDS Type Blood Marrow Refractory cytopenia with unilineage dysplasia (RCUD) Refractory anemia (RA) Refractory neutropenia (RN) Refractory thrombocytopenia (RT) Uni- or bicytopenia <1% blasts Unilineage dysplasia <5% blasts <15% sideroblasts Refractory anemia with ring sideroblasts (RARS) Anemia No blasts Erythroid dysplasia <5% blasts ≥15% sideroblasts Refractory cytopenia with multilineage dysplasia (RCMD) Cytopenia(s) <1% blasts <1 × 109/L monocytes Dysplasia in ≥2 lineages <5% blasts <15% sideroblasts Refractory anemia with excess blasts-1 (RAEB-1) Cytopenia(s) <5% blasts <1 × 109/L monocytes Dysplasia 5%–9% blasts Refractory anemia with excess blasts-2 (RAEB-2) Cytopenia(s) 5%–19% blasts <1 × 109/L monocytes Dysplasia 10%–19% blasts Myelodysplastic syndrome - unclassified (MDS-U) Cytopenias ≤1% blasts Dysplasia <5% blasts MDS associated with isolated del(5q) Anemia, normal or elevated platelets <1% blasts <5% blasts Isolated del(5q) WHO classification 2008
  12. 12. Signs and symptoms  Non-specific presentation  Many patients are asymptomatic  Diagnosis on finding abnormalities found on routine blood counts (e.g., anemia, neutropenia, and thrombocytopenia)  Symptoms or complications resulting from cytopenia (eg, infection, fatigue, bleeding, easy bruising)  Anemia:  Most common cytopenia  Fatigue, weakness, exercise intolerance, angina, dizziness  Infection:  Bacterial infections, skin infections  Fungal, viral, mycobacterial infection  Thrombocytopenia:  Petechiae and/or purpura, bleeding  Autoimmune abnormalities 
  13. 13. Evaluation  Myelodysplastic syndrome (MDS) is characterized by abnormal cell morphology (dysplasia) and quantitative changes in one or more of the blood and bone marrow elements (ie, red cells, granulocytes, platelets)  Complete blood count  Anemia  Leukopenia  Thrombocytopenia  Periphreral blood smear  Dysplastic blood cells  Bone marrow aspirate/ biopsy  Evaluation of the blasts and other cells  Fibrosis of marrow  Genetic features [del(7q), del(5q), del(13q),del(11q), del(12p),del(9q)]  Distinguishes between MDS and acute myeloid leukemia (AML)  Prognostic
  14. 14. International Prognostic Scoring System (IPSS):most widely used prognostic system Variable Score 0 0.5 1.0 1.5 2.0 Bone marrow blasts (percent) <5 5 to 10 - 11 to 20 21 to 30 Karyotype* Good Inter- mediate Poor - - Cytopenias• 0/1 2/3 - - - Risk group IPSS score Median Survival (years) without therapy Low 0 5.7 Intermediate-1 0.5 to 1.0 3.5 Intermediate-2 1.5 to 2.0 1.2 High 2.5 to 3.5 0.4 * Karytope definitions: Good: Normal;-Y; del (5q); del (20q) Poor: Complex (≥3 abnormalities); abnormal chromosome 7 Intermediate: All others • Cytopenia definitions: Red blood cells: Hemoglobin <10 g/dL (100 g/L) White blood cells: Absolute neutrophil count <1800/microL Platelets: Platelet count <100,000/microL Greenberg et al. Blood 1997;89(6):2079–88.
  15. 15. Revised International Prognostic Scoring System (IPSS-R) in MDS Prognostic Variable Scores 0 0.5 1.0 1.5 2.0 3.0 4.0 Cytogenetics Very Good Good Intermedi ate Poor Very Poor Bone marrow blast (%) ≤2 >2 to <5 5 to 10 >10 Hb (g/dL) ≥10 8 to <10 <8 Platelets (cells/uL) ≥100 50 to 100 <50 Absolute Neutrophil Count (cell/uL) ≥0.8 <0.8 Risk Group IPSS-R Score Median Survival (years) Very Low ≤1.5 8.8 Low >1.5 to 3.0 5.3 Intermediate >3 to 4.5 3.0 High >4.5 to 6 1.6 Very High >6 0.8 Greenberg et al. Blood. 2012;120(12):2454–65. * Cytogenetic definitions: Very good: -Y, 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: -7, inv(3)/t(3q)/del(3q), double including -7/del(7q), complex: 3 abnormalities. Very poor: Complex: >3 abnormalities.
  16. 16. Overview of Treatment 1. Supportive Care Important adjunct to the management of all patients with MDS  Red cell transfusions  Antibiotics for infection  Platelet transfusion  Erythropoiesis stimulating agents (ESAs)  Iron chelation therapy (ICT)
  17. 17. Overview of Treatment 2. Disease-Modifying Agents  Lenalidomide: only for del(5q) MDS  Immunosuppressive therapy  Antithymocyte globulin (ATG)  Alemtuzumab  Low-dose cytarabine, Intensive chemotherpy like daunorubicine+ cytarabine  DNA methyltransferase inhibitors:Azacitidine, Decitabine 3. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)  Only potentially curative treatment for MDS  Cure rates in selected patients ranging from 30%-60%
  18. 18. Treatment: Changing paradigms  Earlier it was believed that , apart from supportive treatment with transfusion and antibiotic, there was no other possible therapeutic strategy.  But with availability of hypomethylating agents (Deciabine, Azacitidine); therapy for MDS has evolved and changed at rapid pace
  19. 19. Management Algorithm* * Based on NCCN,SIE, SIES, GITMO guidelines
  20. 20. Management Algorithm* * Based on NCCN,SIE, SIES, GITMO guidelines
  21. 21. Disease burden in India  Higher number of Indian patients in intermediate to high-risk group1  Higher frequency of disease observed in young age (<45 years), unlike global scenario1  With improved awareness & more thorough clinical workups, it is likely that the number of new patients diagnosed with MDS each year will increase in the future 1. Indian J. Med. Res. 2009 Aug;130(2):155–9.
  22. 22. Limitations of currently available treatment in India  Supportive care & most of the medical therapies do not prolong survival in MDS  Allogeneic HSCT  Only treatment for MDS with the potential for cure  Limitations  Possible in ~5% patients only  Lack of donor availability  High costs  Co morbidities in elderly, poor performance status- ineligible for transplant
  23. 23. DNA methyltransferase inhibitors  Also called hypomethylating agents  Azacitidine  Decitabine  Constitute an essential tool in the treatment of myelodysplastic syndrome (MDS)  Allowed the treatment of higher-risk elderly and frail patients, who in the past were treated exclusively with the best supportive care  Although do not achieves final cure,  Induce an improvement in hematopoiesis &  Azacitidine, a demonstrated prolonged overall survival
  24. 24. Comparison of HMAs for treatment of MDS
  25. 25. Comparison between Decitabine and Azacitidine for MDS: A Meta-analysis with 1,392 Subjects  Clinical choice between HMAs is not clear  One more meta-analysis was performed to compare survival advantage of decitabine and azacitidine in patients with MDS.  Eleven trials with a total of 1392 patients with MDS (decitabine, n = 768; azacitidine, n = 624) were included for analysis. Mixue et al Clinical Lymphoma,Myeloma and Leukemia (2014).
  26. 26. Comparison between Decitabine and Azacitidine for MDS: A Meta-analysis with 1,392 Subjects  Azacitidine vs BSC  Significantly improved overall survival (hazard ratio [HR], 0.69; 95% CI, 0.54-0.87)  Significantly delayed and time to acute myeloid leukemia transformation (HR, 0.51; 95% CI, 0.35-0.74).  But these benefits were not found with decitabine.  Among patients with higher risk (IPSS >=3) or older >75 years, treatment with azacitidine was a favorable factor, whereas decitabine showed no advantage.  Therefore, with higher overall response rates and better survival benefits, azacitidine is recommended as the first-line hypomethylating agent for MDS, especially in elderly patients or those with high risk. Mixue et al Clinical Lymphoma,Myeloma and Leukemia (2014).
  27. 27. Key Comparison: Azacitidine vs Decitabine Parameter Azacitidine Decitabine MOA • Azacitidine is incorporated into both RNA and DNA • Direct cytotoxicity on bone marrow blasts (Additional MOA) • Decitabine is primarily incorporated into DNA • No direct cytotoxic effect Route of administration Preferred route of administration: SC Can be given IV also Should be administered by IV only Storage for delayed use Reconstituted solution using refrigerated (2° -8°C) water for injection can be stored up to 22 hours at 2˚C - 8˚C Diluted solution for infusion prepared using cold (2˚C - 8˚C) infusion fluids can be preserved for maximum of 4 hours at 2˚C - 8˚C Survival advantage in MDS over BSC (months) 9.5 months (AZA-001) (p<0.0001) 1.6 months (Lubbert et al, 2011) (p=0.38)
  28. 28. Key Comparison: Azacitidine vs Decitabine Parameter Azacitidine Decitabine Indirect meta- analysis Favors Azacitidine for survival benefit Do not favour decitabine Study in AML Azacitidine vs Decitabine showed • Superior survival • Less hospitalization NCCN recommendation Category 1 agent in Higher risk MDS Category 2A EHA 2014 recommendation Azacitidine is standard of care for high risk MDS Less preferred NICE guidelines Recommends Azacitidine Doesn’t recommend Decitabine
  29. 29. Guidelines recommendations  NCCN Guidelines  NCCN recommends azacitidine for…  Low/Intermediate-1 risk MDS with clinically relevant thrombocytopenia or neutropenia or increased marrow blasts  Intermediate-2, High risk MDS patients who are not transplant candidates or donor is not available. (category 1) (While the response rates are similar for both drugs azacitidine & deciatabine, survival benefit from a Phase lll randomized trial is reported for azacitidine and not for decitabine)  ESMO Guidelines  Randomized comparisons of 5-azacytidine against low- dose cytarabine or BSC have shown survival benefit
  30. 30.  NICE Guidelines  Azacitidine is a clinically effective treatment for myelodysplastic syndrome.  Compared with other treatment options, azacitidine was associated with  Relief from fatigue  Fewer hospitalisations because of infections  Decreased need for blood and platelet transfusion, &  Increased ability to perform day-to-day activities  Azacitidine is licensed as first-line treatment for myelodysplastic syndromes or acute myeloid leukaemia and would replace best supportive care, low-dose and standard-dose chemotherapy. Guidelines recommendations
  31. 31. Summary  HMAs are most essential group for treatment of myelodysplastic syndrome (MDS)  For MDS patients who are not eligible for transplant; NCCN recommends azacitidine as prefrred category 1 agent  Only chemotherapeutic agent showing survival benefits in MDS  Azacitidine vs supportive care or coventional care  Significant survival benefit  Delays progression to AML  Reduces transfusion burden  Improves Quality of Life parameters  Convenient administration by SC route  Fewer infection-related hospitalizations, decreases need for blood and platelet transfusion  Superior choice over decitabine  Strong recommendations for azacitidine by guidelines like NCCN, NICE, ESMO
  32. 32. Thank You

Editor's Notes

  • Ring sideroblasts are named so because of the arrangement of the iron granules in a ring form in mitochondria around the nucleus
  • Auer rods are clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts.
  • autoimmune conditions in patients with MDS were chronic rheumatic heart disease (7 percent), rheumatoid arthritis (6 percent), pernicious anemia (6 percent), psoriasis (2 percent), and polymyalgia rheumatica (2 percent)
    A minute red or purple spot on the surface of the skin as the result of tiny hemorrhages of blood vessels in the skin
    Any of several blood diseases causing subcutaneous bleeding
  • Shown is the strategy for treatment choices for patients with IPSS lower-risk MDS according to type of cytopenias and with sequential treatment in case of relapse/resistance after first-line therapy. EPO indicates erythropoietin; ICT, iron chelation therapy; HSCT, hematopoietic stem cell transplant; ESA, erythropoietic stimulating agents; and BSC, best supportive care.

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