Myelodysplastic Syndromes: Myelodysplastic Syndromes: An UpdateAn Update
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 9.5 Plt 193 and MCV of 102.
One month after radiation: Hg 8.6 and plt 138. Progressive weakness and DOE. No chest pain. No GIB. He received 2 units of prbcs while waiting for results of work-up.
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?
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
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
Laboratory data: Wbc 4.1 hg 8.9 hct 26.7 plt 158 mcv 103 ANC 3321 Creatinine 1.2 Folate >24 Ferritin 222 B12 352 Reticulocyte count 3.4 with an absolute of 84K Serum erythropoeitin level 498
Bone marrow biopsyBone 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
Hypercellular BMHypercellular BM
Mononuclear megakaryocyteMononuclear megakaryocyte
Dyspoietic red cell precursorsDyspoietic red cell precursors
IntroductionIntroduction
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)
World Health OrganizationWorld Health Organization
Clinical PresentationClinical 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
Clinical presentationClinical 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
Physical ExamPhysical 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
Laboratory findingsLaboratory 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
Red cell seriesRed 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
Red cell seriesRed 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
Ringed sideroblastsRinged sideroblasts
Granulocytic seriesGranulocytic series
Leukopenia: found in approximately 50% at time of diagnosis– Granulocytes: display reduced segmentation, aka
pseudo-Pelger-Huet Often with reduced or absent granulation
Pseudo-Pelger-HuetPseudo-Pelger-Huet
PlateletsPlatelets
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
Bone marrow alterationsBone 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
Auer rodsAuer 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
Auer RodsAuer Rods
DiagnosisDiagnosis
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
Differential diagnosisDifferential diagnosis
Above findings not unique to MDS Exclude other contributing conditions
– Alcohol – Megaloblastic anemia– HIV– Medications– Heavy metals
Differential diagnosisDifferential 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
Differential diagnosisDifferential 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
DiagnosisDiagnosis
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
IPSSIPSS
Median Survival in MDSMedian Survival in MDS
TreatmentTreatment
Control of symptoms due to cytopenias Improving quality of life, minimizing toxicity of
therapy Improving overall survival Decreasing progression to AML
National Comprehensive Cancer NetworkNational 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
Hematopoietic cell transplantationHematopoietic 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
ChemotherapyChemotherapy
High dose– young– MDS with >10% blasts in BM
Intermediate dose chemotherapyIntermediate 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
Low dose chemotherapyLow dose chemotherapy
Immunomodulatory agents– Thalidomide– Lenalidomide
Thalidomide– 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.
5q- syndrome5q- 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
Lenalidomide (Revlimid, CC-5013)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
Hematopoietic growth factorsHematopoietic 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
Hematopoietic growth factorsHematopoietic 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
Hematopoietic growth factorsHematopoietic 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
Our patientOur patient
WBC 4.1 ANC 3321 Hemoglobin 8.9 Platelets 158 Normal cytogenetics Blasts in bone marrow <5%
Our patientOur patient
Our patientOur patient