Presentation is loading. Please wait.

Presentation is loading. Please wait.

Myelodysplastic Syndromes: An Update

Similar presentations

Presentation on theme: "Myelodysplastic Syndromes: An Update"— Presentation transcript:

1 Myelodysplastic Syndromes: An Update
Thuy Le, MD Texas Cancer Associates Internal Medicine Grand Round April 19, 2006

2 HF 80 yo male: OSA, gout, CAD, and prostate cancer who was referred for progressive anemia. Past few months: noticed his health started to decline. Localized prostate cancer: end of 2005, tx external beam radiation. Prior to any radiation: wbc 4.1 Hg Plt 193 and MCV of 102. One month after radiation: Hg 8.6 and plt Progressive weakness and DOE. No chest pain. No GIB. He received 2 units of prbcs while waiting for results of work-up.

3 HF A week later: shortness of breath, worsening DOE, and generalized weakness. His hemoglobin dropped down to 8.2 from 10. Admitted to the hospital: found to have a non-ST elevation myocardial infarction. Underwent a cardiac catherization which showed a 3-vessel disease. CABG was recommended. Path of the bone marrow biopsy showed MDS. Question: Should this patient undergo a CABG?

4 HF PMH: OSA on CPAP; Gout
CAD: diagnosed 30 years ago; told to have blockage Prostate cancer: diagnosed Dec 2005 undergoing radiation Social: widow, 60 pack year, quit 30 years ago; occasional etoh; former lawyer Meds: Lortab, Vytorin, Toprol XL, Digitek

5 HF Pex: appears tired, DOE from door to room No LAD, no oral lesions
Chest: bilateral rales about ¼ up CV: regular RR with 3/6 murmur Abd: unremarkable Ext: 1+ edema of LLE to knee Neuro: non-focal, alert, oriented

6 HF Laboratory data: Wbc 4.1 hg 8.9 hct 26.7 plt 158 mcv 103 ANC 3321
Creatinine 1.2 Folate >24 Ferritin B Reticulocyte count 3.4 with an absolute of 84K Serum erythropoeitin level 498

7 Bone marrow biopsy Cellularity: 70-75%, increased for patient’s age
Myeloid: adequate, immature cells/blasts not increased Megakaryocytes: many atypical megakaryocytes noted; mononuclear forms and micromegakaryocytes Erythroid precursors: dyspoietic changes are present in up to 10% of erythroid series Flow cytometry: normal, blasts not increased Cytogenetics: normal

8 Hypercellular BM

9 Mononuclear megakaryocyte

10 Dyspoietic red cell precursors

11 Introduction MDS: disorders of hematopoietic stem cells
Characterized by dysplastic and ineffective blood cell production Peripheral blood cytopenias Variable risk of transformation to acute leukemia Arise de novo or years after exposure to mutagenic therapy (radiation or chemotherapy)

12 Background MDS: first recognized in 1938
100 pts with refractory anemia without associated illness 1976 French-American-British (FAB): defined RA with excess blasts (RAEB) and CMML as preleukemic states 1982: added 3 more categories to this classification…adopted MDS 2001 WHO classification

13 French-American-British

14 World Health Organization

15 De novo MDS: incidence not known
Exceeds the incidence of AML in the elderly 10-15K cases per year in US Risk increases with age Per 100,000 0.5 for < age 50 5.3 for age 50-59 15 for age 60-69 49 for age 70-79 89 for age >80 Median age: 65

16 Clinical Presentation
Signs and symptoms are non-specific Many asymptomatic Routine laboratory screening Others present with sxs from anemia Fatigue, weakness, angina, dizziness Infection, easy bruising, bleeding: less common Fever and wt loss: uncommon

17 Clinical presentation
Infection: while neutropenia is largely responsible for the high incidence of infection, granulocyte dysfunction may contribute Bacterial infections predominate Skin is most common Infection: principal cause of death in pts with MDS Fungal, viral, and mycobacterial infx can occur, rare without concurrent immunosuppressive agents

18 Physical Exam Hepatomegaly, splenomegaly, LAD: uncommon
Except CMML Cutaneous manifestations: uncommon Sweet’s syndrome( neutrophilic dermatosis): transformation to acute leukemia ( IL-6) Granulocytic sarcoma (chloroma): herald disease transformation into acute leukemia

19 Sweet’s syndrome

20 Laboratory findings Quantitative changes of one or more blood and bone marrow elements are the hallmark of the disease Red cell series Granulocytic series Platelets Bone marrow findings

21 Red cell series Anemia is almost uniformly present
Inappropriately low reticulocyte response Anemia may be the only cytopenia or be accompanied by thrombocytopenia or neutropenia Less than 5% present with an isolated neutropenia or thrombocytopenia in the absence of anemia

22 Red cell series Erythrocyte morphology: normocytic or macrocytic
Peripheral smear: basophilic stippling, Howell-Jolly bodies, and nucleated red cells Ringed sideroblasts: iron granules occupy more than 1/3 of the nuclear rim

23 Ringed sideroblasts

24 Granulocytic series Leukopenia: found in approximately 50% at time of diagnosis Granulocytes: display reduced segmentation, aka pseudo-Pelger-Huet Often with reduced or absent granulation

25 Pseudo-Pelger-Huet                                      

26 Pseudo-Pelger Huet

27 Platelets Thrombocytopenia: varying degrees are present in ~25% of pts with MDS Rarely represent an isolated early manifestation of the disease Giant plts or circulating megakaryocyte fragments may be present May have increased bleeding tendency despite adequate plt number

28 Bone marrow alterations
BM: usually hypercellular Accompanied by single or multilineage dysplasia Hypercellular BM/pancytopenia: reflects premature cell loss via intramedullary cell death Hypocellular: rare See in therapy-related MDS Megakaryocytes are normal or increased in number

29 Auer rods Within leukemic blasts FAB: belongs to category of RAEB-T
WHO: its presence should lead to the suspicion that patient has already transformed into AML

30 Auer Rods


32 Diagnosis Considered in any patient with unexplained cytopenia(s)
Nuclear hyposegmentation of granulocytes (Huet anomaly) Mononuclear megakaryocytes, micromegakaryocytes, or megakaryocytes with dysplastic nuclei Hypogranular neutrophils Macrocytic or acanthocytic red blood cells Ring sideroblasts in developing red cell precursors

33 Differential diagnosis
Above findings not unique to MDS Exclude other contributing conditions Alcohol Megaloblastic anemia HIV Medications Heavy metals

34 Differential diagnosis
Other causes of macrocytic anemia B12 and folate deficiency Megaloblastic anemia have high MCV, reduced retic count, and pancytopenia Reduced neutrophil lobulation is characteristic of MDS Combination of increased neutrophil lobulation and macrocytosis is pathognomonic of megaloblastic anemia

35 Differential diagnosis
HIV: dysplastic hematopoiesis and variable degrees of cytopenia are common findings in HIV Myelodysplasia was found up to 69% in BM of pts with HIV Dysplasia can be reversible depending on the cause (meds vs infection) Medications: associated with acquired dysplastic changes Valproic acid, mycophenolate, gancyclovir, alemtuzumab Reversible on reduction or discontinuation of medications

36 Diagnosis Need bone marrow biopsy, flow cytometry, immunochemical studies, and cytogenetics Clonal chromosomal abnormality of 5q- and monosomy 7 confirms the dx of MDS Deletion 5q

37 Prognosis FAB: less useful for determination of prognosis
International prognostic scoring system: 1997 Take into account age, sex, clinical data, cytopenias, and cytogenetics


39 Median Survival in MDS

40 Treatment Control of symptoms due to cytopenias
Improving quality of life, minimizing toxicity of therapy Improving overall survival Decreasing progression to AML

41 National Comprehensive Cancer Network
Age, performance status, IPSS-defined risk category Low intensity Outpatient tx, hematopoietic factors, differentiation-inducing agents, low intensity chemotherapy High intensity Intensive combination chemotherapy and hematopoietic cell transplantation May reduce risk of death from disease

42 Who to Treat Type of treatment Age PS IPSS survival High intensity
</= 60 good Intermediate-2 or high 0.3 to 1.8 yrs Low intensity or supportive care Low or intermediate-1 5-12 years Consider high intensity >60 3-5 yrs Supportive care any poor

43 Hematopoietic cell transplantation
Very limited donor availability, advanced age Upper age limit for allogeneic HCT ~60 75% of pts with MDS >60 Considered in pts <60, HLA-matched sibling donor, risk of disease progression, excellent PS Transplant-related mortality and relapse rate at 5 years as high as 40% Timing of transplantation: development of new cytogenetic abnormality, worsening cytopenia, progression to a higher IPSS group

44 Chemotherapy High dose young MDS with >10% blasts in BM

45 Intermediate dose chemotherapy
Azacitidine: pyrimidine nucleoside analog of cytidine Causes hypomethylation of DNA and direct cytotoxicity on abnormal BM hematopoietic cells Median time to leukemia was 21 mos vs 13mos Quality of life was significantly improved No difference in overall survival FDA: RA, RARS, RAEB and CMML

46 Low dose chemotherapy Immunomodulatory agents Lenalidomide (Revlimid)
Thalidomide Lenalidomide Low response rate Adverse side effects: fatigue, constipation, peripheral neuropathy, and drowsiness Lenalidomide (Revlimid) Thalidomide derivative without the neurologic toxicity FDA approved 12/27/05: transfusion-dependent anemia due to low or intermediate-1 risk MDS associated with deletion 5q.

47 5q- syndrome Karyotypic and clinical distinctiveness sets it apart from other subtypes Female predominance (7:3) median age 68 at dx Transfusion-dependent anemia 80% Low incidence of neutropenia, thrombocytopenia, infection and bleeding Low incidence of transformation into acute leukemia (16%) May respond dramatically to lenalidomide

48 Lenalidomide (Revlimid, CC-5013)
Efficacy of Lenalidomide in Myelodysplastic Syndromes. NEJ 352;6. Feb 2005 Dose: 25mg or 10mg per day; or 10mg per day for 21/28 days All pts had no response to recombinant erythropoietin or high epo level so low chance of responding Results 21/43 (49%) had either a >2g/dl increase in hg or became red cell transfusion independent Restoration of normal karyocyte was noted in 10/20 pts 9/12 pts with 5q- had restoration of normal karyocyte Neutropenia and thrombocytopenia most common adverse events

49 Hematopoietic growth factors
Recombinant human granulocyte colony-stimulating factor (GCSF) and recombinant human erythropoietin may be used Decreased responsiveness commonly seen Related to defective proliferation of hematopoietic precursors Erythropoietin Serum epo level: inversely related to the degree of anemia in pts with MDS Level may be suboptimally elevated in MDS Recombinant EPO : 20-40% with MDS respond Responses more likely if serum EPO level <100mU/mL

50 Hematopoietic growth factors
Response to EPO May be delayed One study of 281 pts with MDS: 18% responded by 12 wks 45% responded by 26wks Predictors of response: RA, good karyotype, EPO <150

51 Hematopoietic growth factors
Combination therapy (EPO+GCSF) In pts with MDS, G-CSF are synergistic with EPO Approximately 40-45% pts receiving combo have erythroid response Nearly all had neutrophil responses Responses more common in pts with Low or Intermediate-1 IPSS scores Generally occur within 6-8 weeks

52 Newer Agents Tipifarnib ( Zarnestra R115777) Kurzrock et al Blood 2004
82 pts; median age 67 IPSS int-1 17%, int-2 39%, high 44%; prior tx 37% Overall response 26/82 (32%) Side effects: myelosuppression, fatigue, nausea, diarrhea, rashes Lonafarnib (Sarasar SCH66336) Feldman et al ASH 2003 67 pts: RAEB-t 32; CMML 35 IPSS int int-2 high 25 Overall response 29%

53 TCA trial for MDS FGCL-SM2216-014
Objective: evaluate the efficacy of FG-2216 in lower-risk MDS FG-2216: inhibitor of HIF-PH enzymes

54 Our patient WBC 4.1 ANC 3321 Hemoglobin 8.9 Platelets 158
Normal cytogenetics Blasts in bone marrow <5%

55 Our patient

56 Our patient

57 Our patient Low risk Median survival of 4 years CABG? Yes

58 After CABG

59 Before CABG


Download ppt "Myelodysplastic Syndromes: An Update"

Similar presentations

Ads by Google