Myelodysplastic Syndromes

Transcription

1 Myelodysplastic Syndromes Jennifer Rogers MS, FNP Cancer Center of the Carolinas Greenville, SC The Myelodysplastic Syndromes Overview Clonal disorder characterized by hypercellular marrows, peripheral cytopenias, and cell functional abnormalities Dominant feature: Ineffective hematopoiesis with peripheral blood cytopenias Bone marrow failure Majority succumb to infection or bleeding Transformation to acute leukemia in 35-40% range High mortality rate Supportive Care has been the standard treatment Kurzrock R. Semin Hematol Jul;39(3 Suppl 2): Miller KB. Curr Treat Options Oncol Apr;1(1):63-9. The Myelodysplastic Syndromes Epidemiology 15,000 new cases/year in US (Adults) More common than AML Median survival years Predominantly a disease of the elderly Median age > 60 Incidence greater in Males than Females Incidence increases with age MDS Definition The myelodysplastic syndromes (MDS) are a group of diseases in which the production of blood cells is severely disrupted. In MDS, bone marrow is injured. Defect occurs in one of the stem cells within the bone marrow. All cells produced from that point forward carry the same defect. Defective stem cells crowd out and overwhelm normal, healthy cells. Defect in normal differentiation (dysplasia). Kurzrock R. Semin Hematol Jul;39(3 Suppl 2): Steensma DP, Tefferi A. Leuk Res Feb;27(2): Kurzrock R. Semin Hematol Jul;39(3 Suppl 2): Hamblin TJ. Epidemiology of MDS. In: Bennett JM (ed). MDS: Pathobiology and Clinical Management. New York: Marcel Dekker Inc.; hmds.org..org.uk/mds.html MDS Definition Marrow is less able to produce normal blood cells, leading to low blood counts. Characterized by 1 or more peripheral blood cytopenias secondary to bone marrow dysfunction. Secondary MDS has poorer prognosis. Etiology Primary (de novo) MDS (unknown cause) Secondary MDS Environmental Exposure Benzene Petrochemicals Cigarette smoking Insecticides Organic Solvents Treatment Related Ionizing Radiation Chemotherapeutic Agents alkylating agents Cisplatin etoposide Kurzrock R. Semin Hematol Jul;39(3 Suppl 2): Hamblin TJ. Epidemiology of MDS. In: Bennett JM (ed). MDS: Pathobiology and Clinical Management. New York: Marcel Dekker Inc.; hmds.org..org.uk/mds.html List AF, et al. The Myelodysplastic Syndromes. In: Wintrobe s Hematology 2003

2 Pathophysiology: Contributing Factors Apoptosis Pathophysiology of MDS Cytokines Epigenetic Immunologic Signal Stem Pathway Cell Cytokine Receptors - Nl HGF Differentiation Stem Cell Changes Angiogenic Molecules With Permission of J Maciejewski,M.D. Taussig Cancer Center/ Cleveland Clinic Foundation MDS Genetic Loss of Signal Environmental Molecular Gain of Function Microenvironment TNF α TGF- β IL-1 β γ-interferon CD95 Aberran t Apoptosis Leukemia Immune system? Silverman, LR. The Oncologist. 2001;6(suppl 5):8-14. Pathologic Correlates Clinical Presentation Apoptosis Hallmark of MDS Difference b/t MDS and AML Decreases as blast % increases Microvessel density MVD Increased in MDS Highest in RAEB-T and CMML Increased TNF-α Increased VEGF Patients in early stages are most likely asymptomatic. Most often discovered by accident on routine exam or blood test. Lab evaluation often prompted by signs or symptoms. Fatigue (anemia) Infections (neutropenia) Bleeding (thrombocytopenia) Bennett J, et al. Int J Hematol Aug;76 Suppl 2: Clinical Presentation Basic Diagnostic Evaluation Cytokine release (Occurring within the Bone Marrow environment) may result in constitutional symptoms such as: Anorexia Weight loss Low-grade fevers Peripheral blood counts + reticulocyte count Bone marrow biopsy and aspiration Cytogenetics Auxiliary tests Iron saturation, ferritin B12, folate levels EPO level Establish diagnosis of MDS & Assess FAB/WHO Classification IPSS score

3 Bone Marrow Findings Usually hypercellular,, although can be hypocellular Degree of cellularity may interfere with diagnosis Dysplasia Ringed sideroblasts (RARS) Excess blasts (> 5%) (RAEB, RAEB-T, CMMoL) Cytogenetic Features Normal karyotype may be present Most common abnormalities: 5q- Monosomy 7 7q - Trisomy 8 Complex abnormalities (3 or more abnormalities) Bennett J, et al. Int J Hematol Aug;76 Suppl 2: MDS Risk Group & Prognosis Scoring systems identify the risk group of the patient. The risk group helps predict disease progression. Determine patient s risk group to decide on best course of treatment. MDS Classification Systems French American British (FAB) World Health Organization (WHO) International Prognostic Scoring System (IPSS) Bennett J, et al. Int J Hematol Aug;76 Suppl 2: Bennett J, et al. Int J Hematol Aug;76 Suppl 2: MDS Classification Systems FAB Classification In use for approximately 20 years. Requires morphologic findings of dysplastic changes in cell lines. Classification has been shown to be predictive of prognosis. Primarily based on % blasts AML > 30% blasts WHO Classification Recently introduced Attempt to address deficiencies with MDS especially with RAEB and CMMoL Re-classified RAEB-T T as AML 20% blasts MDS FAB Classification Classification Refractory anemia (RA) RA with ringed sideroblasts (RARS) BM Blasts <5% RA with excess blasts (RAEB) 5-20% RAEB in transformation (RAEB-T) 21-30% Chronic myelomonocytic leukemia (CMMoL) <20% List, AF, et al. The Myelodysplastic Syndromes. In: Wintrobe s Hematology 2003.

4 MDS - WHO Classification Refractory Anemia with ringed sideroblasts without ringed sideroblasts Refractory cytopenia multilineage dysplasia (RCMD) Refractory Anemia with Excess Blasts (RAEB I and II) RAEB I:5-9% blasts; RAEB-II: 10-19% 19% blasts 5q- syndrome MDS unclassifiable RAEB-T AML MDS/Myeloproliferative disease (MPD) CMMoL Atypical CML Juvenile Myelomonocytic leukemia Steensma DP, et al. Leukemia Research. 2003;27: Brunning RD, et al. Pathology and genetics of tumors of hematopoietic and lympoid tissues. IARC Press, Lyon, France, International Prognostic Scoring System (IPSS): The most commonly used system to score a patient s disease in terms of risk (shortened life expectancy & chances of transformation to AML). Based on three items: Cytogenetic finding- The karyotype (profile of chromosomal abnormalities) Blood cell count- Extent of cytopenias (deficiencies in blood) Blasts- Percentage of marrow blasts (immature blood cells) Greenberg P, et al. Blood. 1997;89(6): International Prognostic Scoring System (IPSS) Prognostic Variable Greenberg P, et al. Blood. 1997;89(6): Score Value BM Blasts (%) < Karyotype* Good Interm. Cytopenias 0/1 2/3 Scores: Low: 0 Int-1: Int-2: High: 2.5 Poor Cytogenetics: Good: Normal - Y del (5q) del (20q) Poor: Complex ( ( 3 abn) Chr.. 7 abn Int.: Other Use of International Prognostic Scoring System Median Score IPSS Survival % Leukemia 0 Low Int Int >2.0 High percent The Myelodysplastic Syndromes FAB Classification A Survival years Greenberg P, et al. Blood. 1997;89(6): RARS 125 pts RA 294 pts CMMoL 126 pts RAEB 208 pts RAEB-T 61 pts percent B AML Evolution RARS RA years CMMoL RAEB RAEB-T 109 pts 272 pts 118 pts 198 pts 60 pts Sample Patient #1 64 y/o female Labs reveal: WBC 4.5, HGB 6.0, ANC 2600, plat 200,000. BMbx hypercellular,, 3% blasts, cytogenetics-5q(del) IPSS Score? # of cytopenias (1) score = 0 % of blasts (<5%) score = 0 cytogenetics (good) score = 0 Total Score = 0 Prognosis = Good

5 Sample Patient #2 70 y/o male with hx: : CAD. Presents with c/o fatigue, SOB X 3 mos. WBC 1.2, HGB 7.0, ANC 500, Plat. 50,000. BMbx reveals hypercellular marrow, 15% blasts, Cytogenetics: 46 xy abn.. 7 in 5 metaphases. IPSS Score? # of cytopenias (3) score =.5 % marrow blasts (15%) score=1.5 Cytogenetics (poor) score =1.0 Clinical Course Transformation is usually fatal Durable remissions are rare Toxic death rate of chemotherapy is equal to or exceeds response rate Morbidity and mortality due to marrow failure or AML, infection. Total Score = 3.0 Prognosis = Poor Skeel R. Handbook of Cancer Chemotherapy. 5 th Edition: 472 Goals of Therapy Select therapy best suited for the individual Minimize toxicity Improve blood counts Decrease transfusions Decrease infections Improve quality of life Prolong survival Cheson BD, et al. Blood. 2000;96: Observation Treatment Options Best Supportive Care (BSC) Transfusions (RBC, platelets) Antibiotics Colony stimulating factors EPO +/- G-CSF (or GM-CSF) Bone marrow transplant Chemotherapy Approved therapies Investigational therapies Bennett JM (ed). MDS: Pathobiology and Clinical Management. New York: Marcel Dekker Inc.; Gordon MS. Semin Hematol Oct;36(4 Suppl 6):21-4. Transfusions Majority of patients require transfusion support Thresholds based on symptoms, co- morbidities: PLTs 10-20K may be well tolerated in absence of bleeding. Degree of dysfunction may require higher threshold. Multiple transfusions lead to complications Allo-sensitization. Iron overload. Chelation for > 25U prbc. Iron absorption may be seen in RARS. Gordon MS. Semin Hematol Oct;36(4 Suppl 6):21-4. Tricot GJ, et al. Semin Oncol Dec;14(4): Bone Marrow Transplant Allogeneic transplant: : when the patient receives stem cells from another person or donor. Non-myeloablative transplant: : is a stem cell transplant from a donor (allogeneic) that uses a less toxic regimen of chemotherapy and/or radiation to prepare the patient for the transplant Generally not an option for majority of patients with MDS because of age and lack of suitable donor Allogeneic hematopoietic stem cell transplant (HSCT) remains the only potential curative option Anderson, JE. Allogeneic Bone Marrow Transplantation in the Myelodysplastic Syndromes. In: Bennet, JM (ed). MDS: Pathobiology and Clinical Management. New York. Marcel Dekker, Inc Aplastic Anemia & MDS International Foundation, Myelodysplastic Syndromes Basic Explanations, 2003

6 Chemotherapy Intensive chemotherapy or standard induction/remission chemotherapy similar to AML Patient selection Advanced disease (RAEB, RAEB-T) or high risk Younger Associated with significant treatment related morbidity and mortality in the elderly (prolonged hypoplasia) Chemotherapy AML treatment Low dose ARA-C Topotecan Combo of ARA-C/ C/Topotecan dewitte, TM. Intensive Chemotherapy, Including Autologous Stem Cell Transplantation, in the Myelodysplastic Syndro In: Bennet, JM (ed). MDS: Pathobiology and Clinical Management. New York. Marcel Dekker, Inc Other treatments ATG (Atgam( Atgam)- Hypoplastic marrow Cyclosporine Hypoplastic marrow Amifostine (Ethyol) Steroids, androgens, and pyridoxine VIDAZA VIDAZA is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. Hypomethylation of DNA may restore normal function to genes that are critical for differentiation and proliferation. Direct cytotoxicity on abnormal hematopoietic cells in the bone marrow causes death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to VIDAZA. VIDAZA TM (azacitidine for injectable suspension) Dosing Regimen 75 mg/m 2 azacitidine for 7 days every 28 days Doses greater than 4 ml should be divided into 2 syringes and administered in different sites Patients should be pre-medicated for nausea & vomiting VIDAZA Administration Dose may be increased to 100 mg/m 2 if no beneficial effect is seen after two treatment cycles,, and no toxicity other than nausea and vomiting Recommend that patients be treated for a minimum of 4 cycles. CR or PR may require more than 4 treatment cycles. Treatment may be continued as long as the patient continues to benefit. VIDAZA TM (azacitidine for injectable suspension) VIDAZA TM (azacitidine for injectable suspension)

7 Nursing Implications of Therapy With VIDAZA Most common adverse events: Nausea and vomiting Myelosuppression Injection site reaction Constipation Nursing Implications of Therapy With VIDAZA Nausea and Vomiting 1/3 will not experience N/V 2/3 will Premedicate with 5-HT5 3 (e.g. e.g. Zofran 8mg po x1) 30 min prior to dose or immediately before the dose 95% effective No delayed N/V Breakthrough N/V rare Myelosupression Platelet Nadir: ~Day ANC Nadir: ~Day Hgb Nadir: ~Day Nursing Implications of Therapy With VIDAZA : Injection Site Reaction Pruritus Erythema Ecchymosis Grade 1 (pain or itching or erythema) Grade 2 (pain or swelling w/inflammation) Grade 3 is extremely rare Pruritus: : /grade 1 (mild or localized) Antihistamine (OTC) cream/lotion Oral Antihistamines if necessary Cold/warm compress 24 hrs post Caladryl cream, Tylenol Pruritus: : Generalized Atarax Nursing Implications of Therapy With VIDAZA : Injection Site Reaction Erythema May be mild to moderate (similar to a first degree burn) Skin dries up and peels off Gets better over time Apply cool/warm compress 24hrs post Ecchymosis Due to thrombocytopenia Patients may apply cool compress Hold the injection site for minutes Nursing Implications of Therapy With VIDAZA : Allergic Reaction 1% have had allergic drug reaction Generalized maculopapular rash, pruritic on trunk, arms, legs Prednisone 10mg QD x7 days each cycle Goes away with antihistamine and/or steroids Rechallenged all with VIDAZA - no problems Constipation 50% of patients have constipation Start bowel regimen Increase intake of fluids and fiber Stool softener (Colace 100mg po TID) Thalidomide Approved for leprosy 1 st antiangiogenic agent evaluated for MDS Potent inhibitor of angiogenesis through action of VEGF Majority of responders are patients with low risk disease Erythroid responses

8 Arsenic Trioxide FDA approved for relapsed/refractory APL Orphan drug status for many diseases/mds Responses as single agent Responses with ARA-C, Thalidomide Responses seen in all cell lines Follow ECG (QT prolongation), Potassium, Magnesium Agents Under Investigation Antiangiogenic Compounds: CC5013 (Revlimid( Revlimid ) Bevacizumab (Avastin ) Arsenic trioxide (Trisenox ) Receptor tyrosine kinase (RTK) inhibitors (Gleevec( Gleevec) Agents Under Investigation Immunomodulatory Drugs (IMiD( IMiD ) CC5013 (RevLimid( RevLimid ) COX-2 2 induction inhibitors (mrna destabilization) DNA Methylation Inhibitors Decitabine Lenalidomide New IMID (analog of thalidomide) 5q- syndrome High responses Low risk patients/females Few patients transform to AML Neutropenia/thrombocytopenia major side effect Waiting for approval by FDA