Transcript Myelodysplastic Syndromes

Myelodysplastic Syndromes:
An Update
Thuy Le, MD
Texas Cancer Associates
Internal Medicine Grand Round
April 19, 2006
HF
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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.
HF
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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 3vessel disease.
CABG was recommended. Path of the bone marrow
biopsy showed MDS.
Question: Should this patient undergo a CABG?
HF
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PMH: OSA on CPAP; Gout
– CAD: diagnosed 30 years ago; told to have blockage
– Prostate cancer: diagnosed Dec 2005 undergoing radiation
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Social: widow, 60 pack year, quit 30 years ago; occasional
etoh; former lawyer
 Meds: Lortab, Vytorin, Toprol XL, Digitek
HF
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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
HF
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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 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
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Hypercellular BM
Mononuclear megakaryocyte
Dyspoietic red cell precursors
Introduction
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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)
Background
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MDS: first recognized in 1938
– 100 pts with refractory anemia without associated
illness
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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
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2001 WHO classification
French-American-British
World Health Organization
Incidence
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De novo MDS: incidence not known
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Exceeds the incidence of AML in the elderly
10-15K cases per year in US
Risk increases with age
Per 100,000
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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
Clinical Presentation
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Signs and symptoms are non-specific
– Many asymptomatic
– Routine laboratory screening
– Others present with sxs from anemia
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Fatigue, weakness, angina, dizziness
– Infection, easy bruising, bleeding: less common
– Fever and wt loss: uncommon
Clinical presentation
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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 Exam
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Hepatomegaly, splenomegaly, LAD: uncommon
– Except CMML
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Cutaneous manifestations: uncommon
– Sweet’s syndrome( neutrophilic dermatosis):
transformation to acute leukemia ( IL-6)
– Granulocytic sarcoma (chloroma): herald disease
transformation into acute leukemia
Sweet’s syndrome
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Laboratory findings
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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 series
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Anemia is almost uniformly present
– Inappropriately low reticulocyte response
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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 series
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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 sideroblasts
Granulocytic series
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Leukopenia: found in approximately 50% at time
of diagnosis
– Granulocytes: display reduced segmentation, aka
pseudo-Pelger-Huet
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Often with reduced or absent granulation
Pseudo-Pelger-Huet
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Pseudo-Pelger Huet
Platelets
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Thrombocytopenia: varying degrees are present in
~25% of pts with MDS
– Rarely represent an isolated early manifestation of the
disease
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Giant plts or circulating megakaryocyte fragments
may be present
– May have increased bleeding tendency despite adequate
plt number
Bone marrow alterations
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BM: usually hypercellular
– Accompanied by single or multilineage dysplasia
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Hypercellular BM/pancytopenia: reflects
premature cell loss via intramedullary cell death
 Hypocellular: rare
– See in therapy-related MDS
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Megakaryocytes are normal or increased in
number
Auer rods
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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 Rods
Diagnosis
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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 diagnosis
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Above findings not unique to MDS
 Exclude other contributing conditions
– Alcohol
– Megaloblastic anemia
– HIV
– Medications
– Heavy metals
Differential diagnosis
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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 diagnosis
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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)
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Medications: associated with acquired dysplastic
changes
– Valproic acid, mycophenolate, gancyclovir,
alemtuzumab
– Reversible on reduction or discontinuation of
medications
Diagnosis
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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
Prognosis
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FAB: less useful for determination of prognosis
 International prognostic scoring system: 1997
– Take into account age, sex, clinical data, cytopenias, and
cytogenetics
IPSS
Median Survival in MDS
Treatment
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Control of symptoms due to cytopenias
 Improving quality of life, minimizing toxicity of
therapy
 Improving overall survival
 Decreasing progression to AML
National Comprehensive Cancer Network
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Age, performance status, IPSS-defined risk category
Low intensity
– Outpatient tx, hematopoietic factors, differentiation-inducing
agents, low intensity chemotherapy
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High intensity
– Intensive combination chemotherapy and hematopoietic cell
transplantation
– May reduce risk of death from disease
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
</= 60
good
Low or
intermediate-1
5-12 years
Consider high
intensity
>60
good
Intermediate-2
or high
0.5-1.1
Low intensity or
supportive care
>60
good
Low or
intermediate-1
3-5 yrs
Supportive care
any
poor
any
any
Hematopoietic cell transplantation
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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
Chemotherapy
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High dose
– young
– MDS with >10% blasts in BM
Intermediate dose chemotherapy
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Azacitidine: pyrimidine nucleoside analog of
cytidine
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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 chemotherapy
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Immunomodulatory agents
– Thalidomide
– Lenalidomide
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Thalidomide
– Low response rate
– Adverse side effects: fatigue, constipation, peripheral neuropathy,
and drowsiness
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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- syndrome
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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)
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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
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9/12 pts with 5q- had restoration of normal karyocyte
– Neutropenia and thrombocytopenia most common adverse events
Hematopoietic growth factors
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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
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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 factors
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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 factors
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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
Newer Agents
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Tipifarnib ( Zarnestra R115777)
– 82 pts; median age 67
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Kurzrock et al Blood 2004
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
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IPSS int-1 24 int-2 high 25
Overall response 29%
TCA trial for MDS
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FGCL-SM2216-014
 Objective: evaluate the efficacy of FG-2216 in lower-risk
MDS
 FG-2216: inhibitor of HIF-PH enzymes
Our patient
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WBC 4.1 ANC 3321
Hemoglobin 8.9
Platelets 158
Normal cytogenetics
Blasts in bone marrow <5%
Our patient
Our patient
Our patient
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Low risk
Median survival of 4 years
CABG? Yes
After CABG
Before CABG
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