Hematologic Malignancies

Transcription

1 Hematologic Malignancies Elizabeth A. Griffiths, 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 (PV) Essenial Thrombocythemia (ET) Myelofibrosis (MF) Lymphoid Leukemia Acute (ALL) Chronic (CLL) Lymphoma Non-Hodgkin (NHL) Hodgkin (HL/HD) Multiple Myeloma (MM)

7 Bone marrow sites in adults

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

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

11 Leukemia cells express many abnormal receptors which promote growth JAK2 FLT-3 BCR-ABL T315I BCR-ABL C-Kit Leukemia cell

12 Leukemia cells express many abnormal receptors which promote growth Leukemia cell Many Leukemia cells

13 Inhibitors of tumor-specific receptors can inhibit leukemia growth JAK2 FLT-3 BCR-ABL T315I BCR-ABL C-Kit Blood cancer cell

14 Specific kinase receptor inhibitors for different leukemia patients Leukemia Abnormal receptor Inhibitor name AML (FLT-3 mut) FLT-3 Sorafenib, Midostaurin, AC220, et al. AML (Ph+) BCR-ABL Imatinib, Dasatinib (Sprycel), nilotinib (Tasigna) CML BCR-ABL Imatinib, dasatinib, nilotinib CML (resistant) BCR-ABL T315I mutation Ponatinib Myelofibrosis (MF) JAK2 Jakafi

15 Stem Cell Transplantation Requires compatible donor stem cell source: - Allogeneic, autologous, syngeneic, - Marrow vs. blood vs. cord blood cells! Pre-SCT chemotherapy/immunosuppression (termed conditioning) to prepare BM for new stem cells! Evaluation of immunologic consequences -Graft vs. Host, Graft vs. Leukemia

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18 Autologous Stem Cell Transplant= Means for High dose Chemotherapy

19 Allogeneic Stem Cell Transplant= Immune/Blood System Replacement

20 Types of Leukemias!! Myeloid Acute leukemia (AML) Chronic leukemia (CML) Lymphoid Acute leukemia (ALL) Chronic leukemia (CLL) Acute= fast growing (days-weeks) Chronic=slow growing (months-years)

21 Acute leukemias Leukemia is cancer of the white blood cells- cancer 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 All Maladies)

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

24 AML ß à AML

25 Acute Myeloid Leukemia 80% of acute leukemia in adults 12,000 cases per year Median age of AML = 64 years Incidence in USA rises by

26 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

27 Prognostic Factors in AML Disease Biology: Unfavorable cytogenetics (most important) Gene mutations (FLT-3 mutations)! Clinical Features: Age > 65 years old Performance status Prior hematologic disorder Therapy-related AML High white blood cell count at diagnosis

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

29 AML Treatment Goals Diagnosis: stabilize pt, treatment decision (high/low/no go)! Induction: achieve CR and normal hematopoiesis! Post remission: prevent relapse Consolidation chemotherapy Allogeneic vs. Autologous stem cell transplantation! Refractory/relapsed disease: prolong survival/qol Clinical trials Ara-C/anthracycline based re-induction Allogeneic vs Autologous SCT Supportive care, hospice

30 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

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

32 FLT-3 kinase receptor in normal hematopoietic stem cells FLT-3 kinase activation in hematopoietic cells results in stimulation of myriad downstream ( PI3K, ras, Stat) pathways promoting growth

33 FLT-3 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

34 FLT-3 mutated AML is associated with worse clinical 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

35 FLT-3 inhibitors in mutant FLT3 AML patients Sorafenib AML cell with FLT3 mutation FLT-3 FLT-3 FLT-3 Abnormal FLT-3 receptor autophosphorylates in the absence of FL

36 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)

37 APL ß

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

39 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:

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

41 Arsenic treatment for APL

42 APL Therapy: A new Paradigm Lo-Coco F et al. N Engl J Med 2013;369:

43 Myeloproliferative Neoplasms

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

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

46 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

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

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

49 CML therapy Inhibitors of the BCR-ABL kinase receptor - Imatinib mesylate (Gleevec, formerly STI571) - Dasatinib (Sprycel) - Nilotinib (Tasigna) Allogeneic stem cell transplantation (SCT) IFN-alpha, chemotherapy: hydroxyurea

50 Mechanism of BCR-ABL Inhibition by Imatinib (Gleevec)

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

52 Development of Imatinib Resistance in CML cells

53 Defined mutations in BCR-ABL kinase lead to imatinib resistance

54 Newer generation BCR-ABL inhibitors

55 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 All Maladies)

56 Myeloproliferative Neoplasms (MPN)

57 Aberrant JAK2 signaling has been identified in most MPN

58 Development of JAK2 inhibitors for MPN

59 Myelodysplastic syndrome (MDS)

60 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 Less than 20% immature myeloid blasts in BM

61 Treatment options for MDS Supportive care: transfusions, growth factors! Allogeneic stem cell transplantation! Hypomethylating agents 5-azacytidine (Vidaza ) Decitabine (Dacogen )

62 Hypomethylating Agents

63 Hypomethylating treatment improve transfusion needs in MDS patients

64 Azacitidine 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.

65 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

66 OS For MDS Patients with del(5q) MDS treated with Lenalidomide Pierre Fenaux et al. Blood 2011;118:

67 Mean Hgb Change From Baseline Over Time Pierre Fenaux et al. Blood 2011;118:

68 Change in FACT-An scores from baseline in Patients Who Became Transfusion Independent Pierre Fenaux et al. Blood 2011;118:

69 Questions?? Questions??