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Neoplasias II
Track 1 Lecture 3
| Question | Answer |
|---|---|
| What is chronic leukemia | proliferation of WELL-DIFFERENTIATED lymphoid or myeloid cells |
| CML | Chronic Myeloid Leukemia |
| CLL | Chronic Lymphocytic Leukemia |
| CML | also includes polycythemia vera and essential thrombocytosis |
| What are the clinical manifestations of CLL and CML? | gradual onset diagnosed by WBC count (>100,000/uL) |
| What is the first nonspecific clinical manifestation of CML and CLL? | Increasing Fatigue Weight Loss Anorexia |
| What are late clinical manifestations of CML and CLL? | 1. Enlargement of superficial lymph nodes, spleen 2. Secondary immune defects, such as infections 3. Anemia, thrombocytopenia |
| How long does FULL development of the CML and CLL take? | Several Years |
| What is the the TRIPHASIC course that CML take? | 1. Chronic Phase 2. Accelerated Phase 3. Terminal Blast Crisis |
| Chronic Lymphocytic Leukemia | CLL |
| CLL occurs mostly in what age group? | older persons over 50 |
| In CLL one | can be asymptomatic for years |
| CLL is caused by | malignant transformation of relatively MATURE B lymphocytes |
| The malignant B lymphocytes are | immunologically incompetent, non-responsive to stimulation |
| The lack of responsiveness in malignant B lymphocytes and thus suppression of normal B-cell function in CLL leads to | 1. HYPO-gamma-Globulinemia = low globulin 2. Infections (potentially lethal) |
| Abnormal immunoregulation in CLL leads to | immune-mediated HEMOLYTIC ANEMIA and THROMBOCYTOPENIA |
| T or F. CLL is the most common cause of leukemia in adults in the WESTERN world? | True |
| Most early cases and asymptomatic patients w/ CLL need not specific treatment for how long? | Up to 10 years after diagnosis |
| If symptomatic, CLL patients receive treatment of what type? | Chemotherapy |
| What are CLL patients treated with if the DO NOT respond to chemotherapy? | Monoclonal antibodies directed against cell surface proteins |
| What is an example of a MONOCLONAL antibodies that is used to treat CLL? | Alemtuzumab against CD52 |
| What type of treatment can young patients with CLL receive if they are unresponsive to chemotherapy? | STEM CELL TRANSPLANT with or w/o prior destruction of the bone marrow |
| CML | Chronic Myelogenous Leukemia |
| At what ages does CML usually occur? | Mostly between 30-50 yrs of age |
| Where does CML originate from? | Pluripotent hemopoietic stem cell |
| What is NOT inhibited in CML | Cell differentiation (most frequently to granulocytes) is NOT inhibited |
| 90% of the time CML is due to | characteristic CHROMOSOMAL TRANSLOCATION |
| What chromosomal translocation does CML produce? | Philadelphia chromosome |
| What is the difference between the CLL vs CML blood smear | CLL = flooded with small lymphocytes CML = mature neutrophils, some metamyelocytes, myelocytes |
| When are most patients dx w/ CML | in the CHRONIC or STABLE phase of the disease |
| What are the three phases of CML | 1. Chronic or latent phase 2. Acceleration phase 3. Terminal blast crisis |
| Chronic or latent phase of CML | There is an excess number of MYELOID CELLS, but they function normally |
| Accelerated phase begins when | the MYELOID cells no longer function NORMALLY |
| The accelerated phase is marked by | gradual failure in response to treatment increasing anemia new thrombocytopenia |
| Blast crisis | Large clusters of blasts in the bone marrow on biopsy |
| The progression to the terminal blast crisis is due to what | accumulation of molecular abnormalities--loss of differentiation |
| Blast crisis | final phase in the evolution of CML, and behaves like an acute leukemia, with rapid progression and short survival. |
| From myeloid stem cells | derive erythrocytes, granulocytes, neutrophils, megakaryocytes, etc. |
| ALL | happens in children-> Leukocytes are much bigger b/c they are blast cells |
| Blast Cells | immature precursors of either lymphocytes (lymphoblasts), or granulocytes (myeloblasts) |
| Blast Cells signify Acute Leukemia if they are found in the blood and are | They do not normally appear in peripheral blood. When they do, they can be recognized by their large size, and primitive nuclei (ie the nuclei contain nucleoli), as in the picture. |
| CLL | happens in adults-> leukocytes are smaller and the size of RBC’s |
| Are granulocytes differentiated in CML? | No so see a lot of different granulocytes in CML |
| Acute Leukemia is characterized by proliferation of immature WBCs (blast cells) and Chronic Leukemia is characterized by proliferation of ______________. | mature WBCs (post-mitotic cells) |
| Acute Leukemia has _______ onset and if NOT treated are fatal w/in a _______ whereas Chronic Leukemia have more insidious onset (may even be asymptomatic) and are NOT cured with chemotherapy but patients w/ CL may live for years w/o __________ or _______. | rapid, month treatment or minimal treatment |
| Chronic lymphocytic leukemia (CLL) | is a malignant clonal disorder of relatively mature, indolent B lymphocytes (95%) or T lymphocytes (5%) which multiply slowly and do nothing useful |
| In CLL, the abnormal clone either | replaces normal B cells or inhibits their growth and maturation, depressing immunoglobulin levels and impairing humoral immunity. |
| CML is due to a | chronic proliferation of the myeloid stem cell, which results in the production of excess myeloid cells. |
| CML is comprised of | proliferation of myeloid cells in the peripheral blood and bone marrow.This proliferation is primarily of mature myeloid cells, i.e. myelocytes, metas, bands, and polys. Although an occasional blast cell may be seen in CML |
| blast cells (usually > 80%) are seen in what? | AML--ACUTE LEUKEMIA |
| Ages | ALL-primarily in children 2-10--most common malignancy in children CLL-older age (middle-elderly)w/increasing dz frequency w/age AML-malignancy of adults CML-young and middle aged but can occur in children |
| Past Treatment of CML--chemotherapy (w/hydroxyurea) or Interferon-alpha is not used because | It reduced the WBC count but DID NOT eradicated the neoplastic cells |
| What treatment has been used for CML as of 2001? | Imanitib mesylate (Gleevac) is a specific inhibitor of the BCR-ABL tyrosine kianse, and is NOW the standard of therapy for CML |
| Leukopenia treatment after chemotherapy of leukemia should NOT be treated with | hematologic growth factors |
| Gleevac | translation of the philadelphia chromosome into therapy for CML |
| There is also what type of treatment available for younger patients w/ CML? | Allogeneic (hematopoietic) stem cell transplantation |
| What is the Philadelphia Chromosome | chromosomal translocation--in which parts of 2 chromosomes, 9 and 22, swap places and the result is a oncogenic gene fusion, BCR-ABL which encodes Bcr-Abl fusion protein |
| Philadelphia Chromosome is the 1st example | of a link btw chromosomal abnormality and specific malignancy |
| The end result is a shortened chromosome 22, the so called Philadelphia (Ph) chromosome, which is the | product of a reciprocal translocation between the long arms of the chromosomes 9 and 22 |
| A transforming gene, v-ABL, was identified in the Abelson murine leukemia virus, coding for | tyrosine kinase |
| c-ABL | is the normal cellular homolog that was mapped to the long arm of the human chromosome #9 |
| BCR | breakpoint cluster gene located on the narrow region of chromosome #22 |
| In CML there is a BCR-ABL fusion hybrid gene that | encodes mutant tyrosine kinase |
| The BCR-ABL chimeric protein has | enhance TYROSINE KINASE activity |
| Abnormally large ABL mRNA is seen in CML patients which indicated the formation of | a FUSION GENE between ABL and BCR |
| Abnormally large ABL protein with tyrosine kinase activity was found in CML patients | the translated product of BCR-ABL mRNA into a chimeric protein |
| The BCR-ABL tyrosine acitivty has shown to do what? | TRANSFORM CELLS |
| BCR-ABL is established as a | molecular oncogene and been shown to induce leukemia in animal models |
| The signaling pathways are impacted by BCR-ABL, the mutant tyrosine kinase resulting in | 1. Increased proliferative rate due to activation of the RAS pathway 2. Protection from apoptosis through a. STAT5 up-regulaton of BCLXL and b. AKT phosphorylation and inactivation of BAD 3. Reduced adhesion to fibronectin Many more |
| BCLXL | anti-apoptotic molecule |
| BAD | pro-apoptotic molecule |
| Reduced adhesion to fibronection in the CML molecular pathogeneis could be due to | downstream effects of CRKL Phosphorylation |
| Regulatory changes are the result of pathologic defects in CML | 1. Increased proliferation 2. Decreased apoptosis of hematopoietic stem cell or progenitor cells |
| What happens as a result of decreased apoptosis and increased proliferation of hematopoietic stem cells or progenitor cells? | 1. Massive increase in myeloid cell numbers 2. Premature release of immature myeloid cells into circulation due to a defect in adherence of myeloid progenitors to marrow stroma 3. Genetic instability resulting in dz progression |
| Molecular pathogenesis of CML | Chromosomal Translocation producting the Philadelphia chromosome, which results in fusion of two separate genes, creating an oncogene which encodes a MUTANT tyrosine kinase (BCR-ABL protein) |
| What does the mutatant BCR-ABL protein cause | regulatory failure-- 1. inhibitor apoptosis 2. decreases the requirement of growth factors 3. decrease cell adhesion which leads to UNCONTROLLED PROLIFERATION |
| Despite the seemingly endless complexity of the pathways affected by BCR-ABL | all of the transforming functions of BCR-ADL are dependent on its TYROSINE KINASE ACTIVITY thus BCR-ABL is an ideal therapeutic target in CML |
| BCR-ABL as an ideal therapeutic target | It is expressed in ALL CML patients as an active tyrosine kinase and an inhibitor was perdicted to be an effective and selective therapeutic target for CML |
| Initial concerns w/ development of tyrosine kinase inhibitor | 1.inhibitors of ATP binding would lack sufficient target specificity to be useful 2. Tyrosine kinase inhibitors would be extremely toxic 3. Targeting of a single molecular defect would not suffice to treat a highly heterogeneous malignancy |
| Best compound found in the search for a kinase inhibitor | imatinib |
| Imatinib mesylate binds to | the active site of ABL |
| The MOA of Imatinib | it blocks the bind of ATP to the BCR-ABL tyrosine kinase, thus inhibiting kinase activity |
| Where does imatinib bind? | To the ATP BINDING SITE |
| Imatinib selectivity | inhibits BCR-ABL, but minimal activity against other Tyrosine Kinases and serine-theonine kinases |
| Imatinib in Phase 1 Clinical Trials | Well tolerated (some nausea, muscle cramples) |
| At what dose were therapeutic benefits seen w/ imatinib in phase 1 clinical trials? | 300 mg and above 53/54 paitents (98%) had complete hematologic response (remission) and 1 year follow-up only 1 of these patients relapsed |
| Imatinib | possible one of the most successful phase 1 trials ever and it was approved 2001 |
| Phase 3 Trial of Imatinib at 18 months | Accelerated phase or blast crisis DOWN 3% and after 18 mos most patients crossed over to Imatinib |
| IRIS Trial--Imatinib--conclusion 6+ years later | Imatinib has substantially increased survival for pt w/ CML, offering a generally well-tolerated, oral therapy |
| Despite complete cytogenetic response | most patients test + for BCR-ABL by reverse transcriptase PCR |
| With Imatinib there has been a decrease in the risk of ____ | relapse |
| As a result of Imatinib, ___ could be a long-term, controllable illness | CML |
| Mechanism of relapse for CML | Patients who respond to imatinib and then relapse have reactivation of the BCR-ABL kinase |
| What the reason for the 50% of the relapses w/ patients on BCR-ABL? | they have a BCR-ABL point mutation in at least 40 different amino acids |
| What are the 2nd generation drugs? | dasatinib and nilotinib |
| Are dasatinib and niltinib more or less potent than imatinib? | They are more potent and show activity in relapsed patients but have adverse effects |
| How can resistance be overcome in patients tx for CML w/ imatinib? | combination of inhibitor therapy |
| Phase 3 Trial | In 97% of gleevec patients -> complete hematological response Cytogenetic response: Disappearance of the ABL-BCR gene Hematologic response: No tumor cells visible or seen. |
| ABL-BCR Gene Resistance to Imantinib | The ABL-BCR protein can become resistant to gleevec drug…majority of the time it’s due to point mutations in the amino acids of the protein. |
| To get over the gleevec resistance | they developed 2nd generation Tyrosine Kinase inhibitors. |
| Lessons for other malignancies | Targeting the molecular pathogenetic event is essential! |
| The common feature shared among multiple myeloma and the plasma cell dyscrasias is that | all originate from a clone of B cells that differentiates into plasma cells and secreted a single complete or partial immunoglobulin |
| Multiple myeloma is connected to other plasma cell dyscrasias in that it | 1. originate from B-cell clone 2. differentiates into plasma cells 3. secretes 1 homogenous ("monoclonal") immunoglobulin or its fragments (heavy or light chains) |
| B cells differ from each other in the | variable regions |
| The plasma cells often contain excessive amounts of immunoglobulin and thus these d/o are often called monoclonal gammopathies and the the associated immunoglobulin is called | an M component |
| M Component presence is NOT always indicative of what | overt B-cell malignancy Not always malignant (dyscrasias); M proteins (monoclonal Ig’s) can be found in 1-3 % of the population |
| M components are common in what population | in elderly persons |
| The M component is a common component of | multiple myeloma and other plasma cell dyscrasias |
| Mulitple Myeloma | is by far the MOST common of the malignant plasma cell dyscrasias |
| Multiple Myeloma causes ___ of cancer death in the Western countries. | 1% |
| What are the risk factors for multiple myeloma? | 1. Chronic Immune Stimulation 2. Radiation 3. Agrochemicals 4. Agent Orange 5. Possible Viruses |
| Called multiple myeloma because the tumors are | disseminated all over the body in multiple regions |
| Multiple myeloma | is a clonal proliferation of neoplastic plasma cells in the bone marrow that is usually associated with multifocal lytic lesions throughout the skeletal system |
| myeloma cell | aka neoplastic plasma cell |
| In multiple myeloma normal bone marrow cells are largely replaced by ________. | plasmas cells--some with cytoplasmic droplets containing immunoglobulin |
| Multiple myeloma can be found in the skull and are characterized by punched out ____ | lesions |
| Pathogenesis of multiple myeloma | chromosomal translocation, involving the Ig gene and growth factor receptors |
| Masses of plasma cells are scattered throughout the ________, _________, and rarely in _______. | 1. Skeletal system in BONES 2. lymph nodes 3. skin |
| M proteins can be | 60% IgG 20% IgA or Bence-Jones proteins (light chains of Ig; also excreted in the urine) |
| Myeloma cells are dependent on cytokines, mostly ____ which is elevated in patients. | IL-6 |
| How does multiple myeloma lead to bone destruction | Myeloma cells secrete factors that stimulate OSTEOCLASTS!! |
| The light chains are of a low molecular and are thus excreted in the urine | termed Bence-Jones Proteins |
| Why should we NOT see plasma cells in the bone marrow? | b/c B cells mature after they leave the bone marrow and become plasma cells. |
| If one bone contains myelomas | we can assume that others will contain them |
| IF high amounts of light chains are detected in the urine | this is called Bence-Jones proteins |
| IL-6 is elevated | in patients w/multiple myeloma |
| Manifestation of multiple myeloma | 1. weight loss 2. weakness 3. bone lesions can cause localized pain, pathological fractures 4. predisposes pt to anemia, leukopenia |
| Manifestation of multiple myeloma | 5. suppression of immunity causes recurrent ifxns 6. renal insufficiency in 50% (Bence-Jones protein is toxic to tubular cells) |
| B/c plasma cells are in the bone marrow, there are less of them elsewhere and this leads | to anemia and immunosuppression |
| Large amounts of Ig’s going into the kidneys | is harmful and leads to renal insufficiency. |
| Diagnosis of multiple myeloma | Classic Triad 1. Bone marrow plasmacytosis 2. Bone lesions 3. M protein in serum (by electrophoreis) or Bence-Jones protein in urine |
| Therapy for multiple myeloma | High dose of chemotherapy w/ autologous stem cell transplantation |
| New therapies for multiple myeloma | thalidomide (inhibiting angiogenesis) proteasome inhibitors |
| Prognosis of multiple myeloma | risk of relapse is HIGH and only younger pt undergoing allogeneic marrow transplant survive |
| Plasmacytosis | is a condition in which there is an unusually large proportion of plasma cells in tissues, exudates, or blood |
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cwjlamh
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