Hematologic Malignancies. Eunice S. Wang MD Leukemia Service, Department of Medicine Roswell Park Cancer Institute SUNY-UB School of Medicine

Transcription

1 Hematologic Malignancies Eunice S. Wang MD Leukemia Service, Department of Medicine Roswell Park Cancer Institute SUNY-UB School of Medicine

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4 Blood cancers are normal blood cells gone bad Jordan C et al. N Engl J Med 2006;355:

5 Hierarchy of Hematopoiesis

6 Types of Blood Cancers Myeloid Leukemia Acute (AML) Chronic (CML) Myelodysplasia (MDS) Myeloproliferative (MPD) Polycythemia vera Thrombocythemia Lymphoid Leukemia Acute (ALL) Chronic (CLL) Lymphoma Non-Hodgkin (NHL) Hodgkin (HL/HD) Multiple myeloma (MM)

7 Diagnosis of blood cancers 1. Appearance (morphology) Protein Cancer cell X X Protein 4. Specific gene mutations 2. Abnormal protein expression (flow cytometry) (histochemistry) 3.Chromosome abnormalities (cytogenetics)

8 Treatments for Blood Cancers Cytotoxic chemotherapy Stem cell (bone marrow) transplantation Biological therapies (some experimental) Receptor tyrosine kinase inhibitors Antibodies Immunomodulating agents Differentiating agents

9 Hematopoietic Stem Cell Transplantation Stem cell source: - Allogeneic, autologous, syngeneic, - Marrow vs. blood vs. cord blood cells Conditioning regimens (prepare BM) Immunologic consequences -Graft vs. host, Graft vs leukemia

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12 Autologous Stem Cell Transplant= Means for High dose Chemotherapy

13 Allogeneic Stem Cell Transplant= Immune/Blood System Replacement

14 Acute leukemias Leukemia is cancer of the white blood cellscancer in one of its most explosive, violent incarnations Its pace, its acuity, its breathtaking, inexorable arc of growth forces rapid, often drastic decisions; it is terrifying to experience, terrifying to observe, and terrifying to treat. The body invaded by leukemia is pushed to its brittle physiological limit.. Siddartha Mukherjee (The Emperor of Maladies)

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16 Acute myeloid leukemia (AML) Immature myeloid blasts Auer rods (coalesced granules)

17 Acute myeloid leukemia (AML): Clinical features Most common acute leukemia in adults (median age 65 yrs) Rapidly growing disease over days-weeks Presents with infection, bleeding or bruising, fatigue due to high or low white blood cell counts, low hemoglobin and low platelets May arise from prior hematologic disease such as myelodysplasia, myeloproliferative disorders, or prior chemotherapy/radiation for other cancers

18 AML: Diagnosis Morphology: increased numbers of immature myeloid blood cells in blood/marrow (M1-M7) Cytogenetics: most important prognostic factor for AML (new classification system) Gene mutations: One third of AML have FLT3 gene mutation associated with chemotherapy resistance and early relapse Flow cytometry: Majority of AML express CD33 protein

19 AML: Poor Prognosis Unfavorable cytogenetics (most important) Age > 65 years old Low performance status Prior hematologic disorder Therapy-related AML High white blood cell count at diagnosis

20 Overall AML survival by cytogenetics Slovak ML et al Blood 2000: 96: , 2000

21 Standard AML therapy Induction: Admission to hospital for inpatient chemotherapy with two drugs: cytarabine (7 days) and anthracycline (3 days); requires a 30 day inpatient stay for chemo, antibiotics, transfusions until normal blood counts recover Remission= absence of leukemia on BM; does not equal cure (disease gone forever) All Pts in remission will require consolidation chemotherapy (1-4 shorter rounds of chemotherapy) OR stem cell transplantation for long term cure

22 AML: Allogeneic Stem Cell Transplantation HLA matched donor (sibling vs unrelated) Only cure for pts (generally <55 yo) High risk leukemia Refractory to initial chemotherapy Relapsed leukemia Second remission after relapse Mortality/morbidity with SCT: 25-30%

23 Flt-3 kinase receptor signaling FLT-3 kinase activation in hematopoietic cells results in stimulation of myriad downstream ( PI3K, ras, Stat) pathways promoting growth

24 FLT3 Mutations in AML Result in constitutive activation of FLT3 kinase Activation of growth-related signaling pathways FLT3 inhibitors (CEP-701, PKC412, MLN518, SU4516) block receptor kinase activity

25 FLT3 mutations in AML are associated with worse outcomes Frequency CR Rate* ITDs 71 (32%) 65% Asp835 Mutations 32 (14%) 82% *vs. 76% DFS OS p =.03 p =.0004 Frohling, et al., Blood 2002;100:4372

26 Acute promyelocytic leukemia (APL) APL is characterized by the malignant proliferation of immature promyelocytes.. the blood fills up with these toxin-loaded promyelocytes. Moody, mercurial, and jumpy, the cells of APL can release their poisonous granules on a whim- precipitating massive bleeding or simulating a septic reaction in the body Most cancers contain cells that refuse to stop growing. In APL, the cancer cells also refuse to grow up. Siddartha Mukherjee (The Emperor of Maladies)

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28 Acute promyelocytic leukemia (APL) APL cells contain a translocation between chr 15 & 17 (here seen by FISH)

29 APL: PML/RAR-alpha Fusion Protein Balanced Translocation between Chr 15 and 17 Results in a maturation arrest of cells at the promyelocyte stage Warrell R et al. N Engl J Med 1993;329:

30 APL Therapy: Chemotherapy + Differentiation Therapy Immature APL cell Retinoic Acid (ATRA, Vesanoid) t(15;17) Arsenic Mature normal WBC

31 Arsenic treatment for APL

32 Chronic Myeloid Leukemia (CML)

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34 Chronic Myeloid Leukemia (CML) Elevated neutrophils in all stages of maturation

35 CML is defined by presence of t(9;22) Philadelphia chromosome

36 Translocation (9;22) results in aberrant BCR-ABL protein 9 9 q+ 22 Ph ( or 22q-) bcr bcr-abl abl FUSION PROTEIN WITH TYROSINE KINASE ACTIVITY

37 Detection of bcr-abl by FISH Interphase Metaphase Courtesy of Charles Sawyers, UCLA.

38 Natural history of CML disease Chronic phase Accelerated phase Advanced phases Blast crisis Median 5 6 years stabilization Median duration 6 9 months Median survival 3 6 months Accelerated and blast phase CML cells represent transformation to acute leukemia states

39 CML therapy BCR-ABL tyrosine kinase inhibitors - Imatinib mesylate (Gleevec, formerly STI571) - Dasatinib (Sprycel) - Nilotinib (Tasigna) Allogeneic stem cell transplantation (SCT) IFN-alpha, chemotherapy: hydroxyurea

40 Mechanism of Action of BCR-ABL and Inhibition by Imatinib (Gleevec)

41 Survival and Progression to the Accelerated Phase of CML Patients Receiving Imatinib Druker B et al. N Engl J Med 2006;355:

42 Mechanism of Resistance to imatinib (Gleevec) in CML cells

43 Mutations in BCR-ABL kinase leading to imatinib resistance in CML cells

44 Second generation BCR-ABL inhibitors

45 Chronic myeloid leukemia (CML) Before the year 2000, when we saw patients with CML, we told them they had a very bad disease, that their course was fatal, their prognosis was poor with a median survival of maybe 3-6 years.. Today when I see a patients with CML, I tell them that the disease is an indolent leukemia with an excellent prognosis, that they will usually live their functional life span provided they take an oral medicine, Gleevec, for the rest of their lives. Siddartha Mukherjee (The Emperor of Maladies)

46 Other Myeloproliferative neoplasms

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48 JAK2 signaling in MPN

49 Role of JAK2 in MPN biology

50 Jakafi (JAK2 inhibitor) in MPN

51 Myelodysplastic syndrome (MDS)

52 Myelodysplastic syndrome (MDS) Clonal hematopoietic stem cell diseases characterized by dysplasia and ineffective hematopoiesis in 1+ myeloid lineages Pancytopenia Infections, bleeding complications Transfusion dependence Risk of transformation to AML

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54 Myelodysplastic Syndrome Hypomethylating agents 5-azacytidine (Vidaza ) Decitabine (Dacogen ) Supportive care: transfusions, growth factors Allogeneic stem cell transplantation

55 Hypomethylating Agents

56 Hypomethylating agents improve transfusion needs

57 Vidaza treatment Improves MDS survival Proportion Surviving months Log-Rank p= HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = 113 Difference: 9.4 months 50.8% 24.4 months 26.2% Time (months) from Randomization CCR AZA Fenaux P et al. Lancet Oncology 10: , March 2009.

58 Lenalidomide for MDS therapy Derivative of thalidomide, a morning sickness pill associated with birth defects Effective for therapy of MDS with chromosome 5 abnormality Inhibits interactions between MDS cells and the local microenvironment

59 Acute Lymphoblastic Leukemia (ALL) Clonal expansion of immature lymphoblasts

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61 Acute Lymphoblastic Leukemia (ALL) 75% occur in children < 6 yrs old Comprise a minority of acute leukemia in adults B cell > T cell lineage Frequently involves central nervous system, lymph nodes, spleen, liver, and gonads Cytogenetic prognostic groups: Hyperdiploidy (51-65 chromosomes): GOOD Ph chromosome t (9;22): POOR MLL gene t(4;11): POOR

62 Improvement in Pediatric ALL survival 1962 to 2005 Pui C and Evans W. N Engl J Med 2006;354:

63 Clinical trial results in adult vs. pediatric ALL patients Pui C et al. N Engl J Med 2004;350:

64 ALL: Multiple alternating drugs for up to two years Induction: cyclophosphamide, daunorubicin, vincristine, high dose steroids, L-asparaginase 70-80% CR Consolidation: high dose cytarabine and methotrexate Central nervous system therapy: radiation or chemotherapy given via spinal taps Maintenance: Oral 6-MP + methotrexate for 18 months

65 ALL: Allogeneic Stem Cell Transplantation HLA matched donor (sibling vs unrelated) Indicated for young pts <50 yo High risk cytogenetics (Ph chromosome) High WBC at diagnosis (>100K) Central nervous system disease Disease refractory to initial chemotherapy Relapsed disease

66 Adult ALL associated with Ph chromosome t(9;22) benefit from Gleevec 9 9 q+ 22 Ph ( or 22q-) bcr bcr-abl abl FUSION PROTEIN WITH TYROSINE KINASE ACTIVITY

67 Bcr-abl inhibition may also improve outcomes of Ph+ ALL patients

68 Improved clinical outcomes of Ph+ ALL with addition of imatinib to standard chemotherapy Improved clinical outcomes of Ph+ ALL with addition of imatinib to standard chemotherapy

69 Antibody based therapies for B-cell ALL Blinatumomab Anti-CD19 Rituximab (Rituxan ) Anti-CD20 CD19 CD20 B-cell ALL CD22 Anti-CD22 Immunotoxin CAT-8015 (HA22) CD52 Alemtuzumab (Campath ) Anti-CD52

70 Chronic Lymphocytic Leukemia (CLL) Clonal expansion of mature lymphocytes

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72 CLL: Diagnosis Morphology: elevated numbers of mature lymphoid cells in the blood and bone marrow Flow cytometry: B-cell (CD5+ CD19+ CD20+) ZAP70 protein is associated with more rapid disease progression Molecular: Immunoglobulin H (IgH) mutations are associated with outcomes Cytogenetics: Associated with prognosis

73 CLL: Clinical features Patients of older age (median 70 yrs) Indolent slow growing disease (usually) Survival is stage-specific Presents with high white blood cell count, enlarged spleen and lymph nodes, anemia, and low platelets Associated with immune dysfunction Autoimmune mediated low counts

74 CLL: Therapy Multiple rounds of combination outpatient chemotherapy with antibodies chlorambucil, fludarabine steroids Antibodies Radiation to large lymph node sites Stem cell Transplantation Experimental therapies

75 Antibody therapies for CLL Antibodies against CD52 (Campath) and CD20 (Rituxan) markers expressed on CLL cells have anti-leukemia effects alone Studies are testing the effects of combining antibody therapy with chemotherapy Side effects: Allergic reactions, depletion of normal white cells leads to unusual virus infections

76 Ritixumab (Anti-CD20 Antibody) therapy for B-cell CLL

77 CLL Therapy: Revlimid (lenalidomide)

78 Lymphoma: cancers of the immune cells in lymph node and lymphatics Fifth most common cancer in the USA Two types: 1.Hodgkin disease (HD) 2. Non-Hodgkin lymphoma (NHL)

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80 Lymphoma: Diagnosis Over 40 different types of lymphoma!!! Hodgkin- 4 types Non-Hodgkin- 40+ types Lymph node biopsy - Morphology (small vs large cell) - Pattern: Diffuse vs follicular - Flow cytometry: B vs. T cell

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82 Lymphoma: Disease Staging Staging of disease - Bone marrow biopsies (both sides) - CT/PET/Gallium scans - Spinal tap (for high risk disease)

83 Lymphoma: Stages I: Single lymph node or extra-lymphatic site (IE) II: 2 or more lymph node regions on the same side of the diaphragm or localized involvement of an extra-lymphatic site (IIE) III: Lymph node regions on both sides of the diaphragm or localized involvement of an extra-lymphatic organ or site (IIIE) or spleen (IIIS) or both (IIISE) IV: Diffuse or disseminated involvement of one or more extralymphatic organs with or without associated lymph node involvement "A" for asymptomatic or "B" for constitutional symptoms.

84 Lymphoma: Stages I-IV

85 Hodgkin Lymphoma (HL) Age peaks and 50+ yrs Incidence 2.9/100,000 in USA Multi-agent chemotherapy effective for most patients Five year survival >80% (Not 100%) Refractory/relapsed to transplant Reed Sternberg Cell in HL

86 Non-Hodgkin Lymphoma (NHL): Indolent (low grade) Multiple painless enlarging nodes Wide spread disease including BM Slow growth over many years Long survival but largely incurable despite many therapies May be observed without treatment May progress to aggressive lymphoma

87 NHL: Aggressive (high grade) Single rapidly growing mass Disease outside of the lymph nodes is common Grows quickly with symptoms arising from large tumor volumes Responds well and can sometimes be cured by combination high-dose chemotherapy and radiation to involved sites

88 NHL: Poor prognostic factors Age > 55 years Low Performance status Advanced Stage of disease (III-IV) Presence of extranodal sites Elevated LDH (lactic dehydrogenase), a blood test indicating increased tumor cells

89 Non Hodgkin Lymphoma (NHL): Subtypes defined by cytogenetics Follicular lymphoma: Abnormal bcl-2 protein- t (14;18) Burkitt lymphoma: Abnormal c-myc protein- t (8;14) Mantle cell lymphoma: Abnormal bcl-1/ cyclin D1- t (11;14)

90 Aggressive B cell NHL: Therapy Multiple cycles of anti-cd20 antibody (rituxumab) and chemotherapy (cyclophosphamide, doxorubicin, vincristine, steroids) Radiation to focal extranodal sites For refractory/relapsed disease: - Radioisotopes conjugated to CD20 antibody - Hematopoietic stem cell transplant - Experimental therapies

91 Anti-CD20 antibody therapies for non-hodgkin lymphoma Rituxan (anti-cd20) CD20 CD20 NHL CD20 CD20 Bexxar Zevalin Radioactive isotopoes

92 Multiple myeloma

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94 Multiple myeloma (MM) Neoplasm of PLASMA CELLS (Immunoglobulin secreting terminally differentiated end-stage B cells in BM) Older patients, increased in African Americans Associated with bone pain, anemia, high calcium Clinically can be smouldering to aggressive disease

95 MM: Bony lytic lesions OSTEOLYTIC lesions with skeletal lesions and pathological fractures

96 MM Diagnosis: Serum protein electrophoresis Discovery of a serum M-component or monoclonal protein spike is suggestive of a clonal plasma cell disorder.

97 Multiple Myeloma Therapy Prevention of end-organ damage, fractures Management of symptomatic myeloma or radiographic evidence of bone disease Chemotherapy, steroids Radiation to painful bony lesions Proteosome inhibitors, thalidomide Autologous/Allogeneic stem cell transplantation

98 Types of Blood Cancers Myeloid Leukemia Acute (AML) Chronic (CML) Myelodysplasia (MDS) Myeloproliferative (MPD) Polycythemia vera Thrombocythemia Lymphoid Leukemia Acute (ALL) Chronic (CLL) Lymphoma Non-Hodgkin (NHL) Hodgkin (HL/HD) Multiple myeloma (MM)

99 Questions?? Questions??