Nicole Pearsall Clonal hematopoietic Disorders V Dr. Silberstein (#19) 9/23/03 The first 2 pages of Dr. Silberstein s notes are according to him the Gospel. This is what we are suppose to know for exam purposes. Since that is what we are all interested in I have retyped the first two pages below for quick reference. Following is the rest of his lecture. He will not hold us accountable for drugs except what is on the first two pages. Thank GOD! He only made a few comments about his power point presentation and mainly referred back to his first two pages so know those already, okay. Here we go! Myeloproliferatvie disorders 1. Chronic Myelogenous Leukemia (CML) -Philadelphia Chromosome (9,22) -Goal treatment is prevent blast crisis -Gleevec (tyrosine kinase inhibitor) very effective -Blood smear: increased myeloid line (polys, bands, metamyelocytes, myelocytes, promyelocytes) and basophils, and eosinophils 2. Polycythemia Vera -Decreased serum erythropoietin lvl (distinguish from secondary polycythemia) -Increased risk of clotting (stroke) -Goal therapy reduce Hct < 45% to reduce risk of clotting -Rx: Phlebotomy or Hydroxyurea 3. Essential Thrombocytosis -Elevated platelet ct. often > 1 million -Untreated pts. can bleed or clot -Low risk pts. ------ don t need treatment -Hi risk pts. w/ risk factors for vascular disease and stroke -Rx: hydroxyurea or anagrelide 4. Agnogeneic Myeloid Metaplasia (Myelofiborsis) -Bone marrow full of fibrosis tissue (scar) -Splenomegaly -Difficult to treat; need transfusion ACUTE MYELOGENOUS LEUKEMIA (AML) Poor prognosis w/ older age or prior history of myelodysplastic syndrome (pre-lukemia) Splenomegaly is uncommon Chemo: Cyarabine (Ara-C) + an anthracycline (Daunorubicin or Idarubicin) High Dose Ara-C w/ consolidation or relapse Induction therapy will cause complete remission in most pts., but w/out consolidation therapy, most pts. will relaspse and require reinduction Rx. Mylotarg (specific antibody therapy)- new therapy in cancer. Antibody linked w/a posion which goes right to the cancer cells and kills them. Antibody against CD33 Linked w/ potent-anti tumor antibiotic called calicheamicin M3, Acute Promyelocytic Leukemia (APL), is treatable w/ ATRA (all trans retinoic acid) unlike other AMLs Chromosomal abnormality, t(15,17), is associated w/ good prognosis Auer rods are present in blast cells DIC is assoc. w/ this type of AML Treatment: ATRA + chemo: ATRA is a differentiation agent (makes blast cancer cells more mature)- only drug that does this Complete remission in 70-80% of APL pts and cure in 30-35% of pts. 1
Someone forgot to take the sticky note off this part when they copied it so we were missing a few words, I did the best I could DEFINITIONS Induction: (A.K.A. remission induction) therapy directed at getting rid of all visible leukemia (usually involves the 2 drug chemotherapy listed above for AML) Consolidation: High dose treatment is given after induction of remission to destroy remaining leukemia cells and prevent a relapse. Treatment options in AML are high-dose cytarabine and either allogenic (from genetically different individual of the same species) or autologous (from self) stem cell transplant Maintenance: An example is ATRA used to treat M3 AML, the goal is to prevent recurrence w/ low dose treatment MYELODISPLASIA (MDS) -Stem cell disorder that can progress to acute leukemia (AML) Disease of the elderly -The FAB classification (1999) of RARS, RA, RAEB, RAEB-t and CML -Prognosis based on IPSS scoring system (1997-table below) -Treatment: Supportive w/ transfusions and erythropoietin Allogenic Bone Marrow Transplant for a younger pt. -Alkylating agents (see Scofield s lect 9/22 e.g., cytoxan, chlorambucil) and radiation therapy can cause MDS International Prognosis Scoring System (IPSS) in MDS Variable 0 0.5 1 1.5 2 Bone Marrow Blasts (%) <5 5-10 - 11-20 21-30 Karyotype* Good Intermediate Poor - - Cytopenias 0/1 2/3 - - - *Karyotype def: Good-Normal;-Y; del(5q); del(20q) Poor-Complex ( 3 abnormalities); abnormal chromosome 7 Intermediate- all others Risk Group/IPSS score Low / 0 Intermediate-1 / 0.5-1.0 Intermediate-2 / 1.5-20. High / 2.5-3.5 Cytopenia def: RBC Hgb < 10g/dl WBC- Absolute neutrophil ct. < 1800 / µl Median Survival (in Years) in Myelodysplastic Syndrome According to IPSS and Age IPSS risk group Age 60 Age > 60 Age > 70 Low 11.8 4.8 3.9 Intermediate 1 5.2 2.7 2.4 Intermediate -2 1.8 1.1 1.2 High 0.3 0.5 0.4 Now on to the power point slides (he skipped a lot of slides especially pictures) 1.2 Presentation of Acute Leukemia: weakness, pallor (pale), fever, infection and bleeding -w/ bleeding you can get petechiae (tiny red dots due to low platelets) or purpura (big red dots due to low platelets 1.3 CBC in Acute Leukemia: will show the following, -Increased WBC: particularly blasts -Anemia -Thrombocytopenia -Rare cases of pancytopenia (reduction of all blood cells) which also causes a low Hgb 2
2.1 Physical Findings in Acute Leukemia: Splenomegaly, lymphadenopathy, skin involvement called leukemia curtis, and gum hypertrophy mainly associated w/ monocytic leukemia 2.2 Work up of Acute Leukemia: -CBC, chemistries -Coagulation tests to R/O DIC (DIC is more common in M3 AML) -HLA typing to determine if the pt is a potential transplant candidate -Bone marrow tests: morphology, histochemistry, immunophenotyping, cytogenetics (most important) -Chest X-ray -Spinal tap indicated w/ high-risk pts. 2.3 Supportive Care Acute Leukemia: -Leukapherisis (mechanically filter out WBC) when the pt has >100,000 blasts to prevent coagulation and clotting -Prevent tumor lysis syndrome by giving: 1. IV hydration, 2. Sodium bicarbonate to alkalinize urine, 3. Allopurinol *Tumor lysis syndrome occurs when chemo. is too effective; breaking down the cells to quickly will cause a build up of the broken down cellular products in the kidneys. This syndrome is a problem in Acute Leukemia, Burkitt lymphoma and cancers where chemo works very quickly. -Blood transfusion is done w/ Hgb <8 -Platelet transfusion is done w/ platelet ct < 10,000 3.1 Treatment of Acute Leukemia (repeated from the first 2 page handout---remember these) Induction: one cycle of therapy to obtain complete remission which is followed by consolidation The purpose of therapy is to get complete remission, w/out this treatment is worthless. Even w/complete remission most people relapse so consolidation is very important. Get the pt. in complete remission and keep them there. This is very difficult especially w/ acute leukemia. Consolidation: 2-3 rounds of high dose therapy to consolidate complete remission Maintenance: low dose therapy to maintain complete remission W/ acute leukemia, therapy usually gets 70% of adult pts in complete remission however, only about 30% will be cured. Which means that over 50% of pts will relapse. Treatment of a relapsed pt: Use of bone marrow/stem cell transplant (allogenic(from same speicies), autologous (self), or unrelated) for consolidation or relapse *review AML on first page of handout 3.2-3.3: Acute lymphocytic (lymphoblastic) leukemia (ALL) and pretty picture of it. 4.1: Poor prognosis Childhood ALL: well studied and more advances have been made for childhood cancers unlike adult cancers -ages less than 1 and more than 9 (ages 2-8 yo have good prognosis) -WBC> 50,000 -Slow early response therapy -CML: Phil. Chrom (9,22) occurs in 25% of ALL cases -Rearrangement MLL (11q23)- secondary ALL -CNS, testicular disease -Hypodiploidy *this stuff is not on his handout so he gave us a hint that he probably won t test on it 4.2: Induction therapy w/ Childhood ALL Good risk pts: treat w/ Vaincristine and Prednisone and the complete remission rate is > 95% High risk pts: treat w/ add anthracyline to above and may also give radiation therapy however this is used less because secondary side effects can be bad like growth and mental retardation. 4.3: Consolidation w/ Childhood ALL Good Risk pts: high does Methotrexate High Risk pts: treatment is very, very complicated (5-10 drugs given over 2-5 yrs.) 3
5.1: Maintenance Therapy w/ Childhood ALL: give daily oral mercaptopurine and sometimes weekly oral methotrexate. 5.2: Relapse w/ Childhood ALL: give pt. transplant or reinduce w/ chemotherapy. Once you relapse your prognosis is much worse. A short story from Dr. S. *dose reduction: After chemo., pt gets sick. With adults, oncologists reduce the dose however, pediatric oncologists ignore the sickness and keep pushing the high dose treatment. A recent study showed that when teenagers were treated by pediatric oncologist their results were good which suggests (according to Dr. S) that high dose therapy is better. Or pediatric oncologists are better, I am not sure. 5.3: Poor Prognosis ALL in Adults -age > 25 -Elevated beta-2 microglobulin -CML - Phil. Chrom. (9,22) or bcr-abl fusion gene -t(4,11) -Late B cell (surface immunoglobulin, t (8,14), L3 morphology) *adults do worse overall than kids 6.1: Treatment of B cell ALL: treat like aggressive non-hodkin s Lymphoma (burkitt s) -give Cyclophosphamide, high dose methrexate *side note: the difference between lymphoma and leukemia -Lymphoma: cancer in the lymph nodes -Lukemia: cancer in the blood Very often cancer in the lymph nodes goes into the blood and vise versa. 6.2: Induction w/ Adult ALL (again he is not holding us responsible for this, stick the summary on first 2 pgs) -Prednisone, Vincristine, Anthracycline: some regimens add L-asparaginase, cyclophosphamide -CNS prophylaxis: Intra-thecal methotrexate and optional cranial irradiation, high dose systemic methotrexate 6.3: Post Remission Therapy for Adults w/ ALL -Better results w/ aggressive multi-agent chemo. (very complicated but effective) T cell ALL has a better prognosis -Bone marrow transplant results are similar to aggressive chemo. 7.1: Prognosis for ALL: 75% of kids go into long term remission w/ therapy whereas only 40% of adults have long term remission. So it is better to be a kid with ALL than and adult. 7.2-7.3 Acute Myeloid Leukemia (AML) another pretty picture 8.1: Poor Prognosis w/ AML -elderly (> 60) -prior myelodysplasia; secondary to chemo. -poor preformance status -consider supportive care only: if you are old and have prior myelodysplasia the chance of cure is so small that oncologists usually do not treat these pts. 8.2: Chromosomes associated with AML prognosis Good prognosis: t (15,17)=M3 AML; t (8,21); inv 16 Poor prognosis: bcr-abl (CML) t (9,22); deletions on 5, 7; and trisomy 8 8.3: Results of AML: 70% achieve complete remission however only 30% are cured. 7% of AML pts are cured after a bone marrow transplant in second remission. Remember that this leukemia is more common and more deadly in the elderly. 4
9.1: Treatment of non-apl AML -Give the pt antracycline + Ara-C -Provide intensive post-remission care w/ high dose Ara-c or a bone marrow transplant -With relapse bone marrow transplant or high dose Ara-c are given 9.2: Treatment of Acute Promyelocytic Leukemia (APL) = M3 AML -remember this is due to a t (15, 17) -*ATRA is the therapy used which differentiates promyelocytes -Induction/Consolidation: ATRA+ anthracyline which results in 80% remission -Maintenance: ATRA -*Relaplse: Arsenic Trioxide, this is one instance where aresnic is a good drug 9.3: Post-induction therapy -High dose Ara-C -Transplant -*Mylotarg: Ab to CD33 w/ calicheamicin; used for 1 st relapse in elderly pts 10.1: Myeloproliferative disorders: skipped 10.2-10.3: CML pretty picture Cells found in CML: everything---bands, promeylocytes, meylocytes, metamylocytes, eosinophils, basophils, blasts AML remember is just one set of blasts 11.1 Leukemoid Rxn: How do you tell the difference between CML and a Leukemoid rxn (Stedman s def. - leukemoid rxn: leukocytosis similar to leukemia but not the result of a leukemic disease. Leukemoid rxns are sometimes observed as a feature of infectious disease, intoxication, malignant neoplasms, and acute hemorrhage or hemolysis.) With a leukemoid rxn, you are stressed out, sick, have pneumonia: with pneumonia there is not near as many cells present as w/ CML. CML has all cell types, with infection there is basically just bands and polys. -Leukemoid Rxn characteristics: WBC < 100,000; No basophils or promyelocytes; cytoplasmic inclusions (toxic granulation); elevated leukocyte alkaline phosphatase; and an underlying etiology like infection or shock 11.2: CML - Philadelphia chromosome: translocation on the long arm 9,22 Abl on 9 fused to BCR on 22 which activates abl proto-oncogenes BCR-ABL genes make tyrosine kinase (the target of GLEEVEC) 11.3: Phases of CML -Chronic: initial, no symptoms, feel fine -Accelerated: starting to gallop; peripheral blast > 15% -Blast Crisis: galloping way out of control, this is very bad, just as bad as AML, you are dead in a couple of months, at this point you have blasts > 30% *the whole purpose of therapy is to stay out of blast crisis 12.1: Clinical presentation of CML: 50% of pts show no symptoms and demonstrate an abnormal CBC only. Splenomegaly is present in 50% of cases. 90% of cases are not dx until they are in the chronic stage. Common symptoms when they present are lethargy, weakness, abdominal pain, discomfort, night sweats, and weight loss. 12.2: Treatment of Chronic Phase CML- Gleevec and Stem cell trasplant are the best way to prevent blast crisis. Interferons are not used any more. Hydrea lower blood ct in blood but does not do anything to prevent blast crisis. 12.3: GLEEVEC- if you remember one word about CML remember Gleevec - It is a tyrosine kinase inhibitor (the specific enzyme is STI-571) - With chronic cases there is a 91% response rate and a 36% complete cytogenetic response - With accelerated cases there is 17% complete cytogenetic response. - With blast crisis there is only a 7% complete cytogenetic response 5
13.1: Treatment of Accelerated/Blast Crisis CML- Gleevec and acute leukemia therapy along w/ transplant can be done but prognosis is pretty pore. *Remember Myeloproliferative disorders: proliferation of the normal myeloid cells Vs. Myelodysplasia: funny cells (dysplastic cells) produced by myeloid tissue 13.2 Polycythemia: too much Hgb due to increased RBC in the blood -Dx: M (Hct > 54) for F (Hct > 49) -Symptoms: facial plethora (red face), headaches, vision and metal status changes and stroke 13.3 Polycythemia Vera (true polycythemia): bone marrow spontaneously makes a lot of RBC -Serum erythropoietin is low -Splenomegaly w/ increased WBC and platelets -Mild proliferative disorder, there is often overlap w/ the other forms of polycythemia -Increased red cell mass 14.1: (this slide should be titled) Fake Plycythemia: Hgb high and low plasma vol., does not increase RBCs Other names for this are relative polycythemia, Gaisbock Syndrome, Middle age men who are hypertensive. Treatment is lose weight, and get BP down. This is really not a disease. Erythropoeitin is normal 14.2: Secondary Polycythemia: due to tissue hypoxia which stimulates erythropoietin -Stim. of epo due to tissue hypoxia can be caused by several things such as high alt., sleep apnea, COPD, cardiac shunt -causes increased red cell mass and hi serum epo -Surrepitious epo is used by long distance athletes to improve their performance (blood doping, exogenous epo, etc.) 14.3: Treatment of Polycythemia Vera: Want to prevent stroke -phleb to lower Hct below 45 -Hydroxyurea -Avoid P32 and alkylator -There is no clear use for aspirin 15.1: Essential Thrombocytosis: too many platelets -often have splenomegaly along with high Hgb and WBC due to crossover w/ polycythemia -platlet is usually > 1 million which may cause clotting and stroke becomes a major concern -Don t have to treat young asymptomatic healthy women but should treat males w/ risk factors that would cause thrombosis (get there platelet ct. down to normal) 15.2 Treatment of Essential Thrombocytosis: -Low risk: age < 60, no hx of thrombosis, platelets < 1.5 million and no CVS risk factors Don t treat, no risk -High risk: age > 60, hx of thrombosis Use hydrea or anagrelide to reduce platelets below 400,000 15.3: Myelofibrosis (AMM- Anogeneic Myeloid Metaplasia) -Median age of 60 -Marrow fibrosis (scar)-would not get anything (dry tap with a bone marrow aspirate) -Extramedullary hemopoiesis, splenomegaly, tear-drops -Clonal disorder -Tx: difficult, BMT, Transfusion, spleenectomy (difficult surgery because they are huge) 16.1: Myelodysplasia- aka: Pre-leukemia -increased monocytes, chromosomal abnormalities -common in the elderly -secondary to chemo/rad- alkylating agents -Tx is difficult: can try transfusion, BMT but may progress to AML 6
16.2: International Prognostic Scoring System (IPSS) for Myelodiysplasia *See table on 2 nd page. Don t memorize but realize that we are able to get a prognosis for specific types of cancer. The rest of this lecture consists of review questions. I know that this type of thing is not accepted by all, but they are a good review and I think they will benefit everyone after 19 pages of power point slides. 1. The four myeloporliferative disorders are: CML, Polycythemia, ET, and AMM 2. Risk factors for Poor prognosis in AML are: increased age, bad chromosomes, prior myelodysplasia 3. Define the following: Induction, Consolidation, and Maintenance therapy: You can do it!!!! 4. How do you prevent tumor lysis syndrome: IV hydration, Allopurenol, Bicarbonate to alkalize urine 5. The chromosome for CML is : Philadelphia 6. The drug of choice for CML is: Gleevec 7. In Polycythemia Vera EPO levels are: low 8. The therapy of choice for polycythemia vera is: phlebotamy 9. The EPO levels in secondary polycythemia are: high 10. In Relative polycythemia plasma vol is: low 11. In Relative polycythemia EPO levels are: normal 12. Is myelodysplasia related to myeloproliferative disorder: no 13. What term would describe myelodysplasia for lay people: pre-leukemia 14. Do the following characteristics belong to CML or Leukemoid Rxn? Has basophils, eosinophils, promyelocytes, blasts, and philadelphia chromosome Answer: CML 15. List the facts about AML-3: DIC, Auer rods, t(15,17),and ATRA (only drug that differentiates cells) ******Know the questions above and the first two pages and you will do fine!!!!!! 7