Myelodysplastic Syndromes: An 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 B 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

Hypercellular BM

Mononuclear megakaryocyte

Dyspoietic red cell precursors

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)

World Health Organization

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

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

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

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

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

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

Ringed sideroblasts

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

Pseudo-Pelger-Huet

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

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

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

Auer Rods

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

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

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

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

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

IPSS

Median Survival in MDS

Treatment 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 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 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

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

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

Low 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- 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) 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 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 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 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 patient WBC 4.1 ANC 3321 Hemoglobin 8.9 Platelets 158 Normal cytogenetics Blasts in bone marrow <5%

Our patient