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Description : Check out this medical presentation on Ataxia-Telangiectasia, which is titled "Acute and Chronic Myeloid Leukemia", to know about acute and chronic myeloid leukemia.

Tags : Ataxia-Telangiectasia, Acute, Chronic, Myeloid Leukemia, Myeloid Neoplasms, Cytogenetic Lesions, Leukemogenesis, Leukemia Predispositions, Marrow failure syndromes

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Slide 1-

Acute and Chronic Myeloid Leukemia Patrick Brown, MD
Slide 2-

This talk will follow the topical structure suggested by the ABP: Part 1: AML / Part 2: CML
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Classification of Myeloid Neoplasms WHO, 4th edition, 2008
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Part 1: Acute Myeloid Leukemia Basic Science and Pathophysiology Epidemiology and Risk Assessment Diagnosis Management and Treatment
Slide 5-

Acute Myeloid Leukemia Basic Science and Pathophysiology Epidemiology and Risk Assessment Diagnosis Management and Treatment
Slide 6-

Recurring Cytogenetic Lesions Correlate clinical characteristics with chromosomal abnormalities in acute myeloid leukemia Understand the significance of rearrangements of the ATRA receptor gene in M3 acute myeloid leukemia Recognize specific clinical syndromes associated with t(8;21), inv(16), t(9;11), t(15;17), and monosomy 7 or 7q- in acute myeloid leukemia Know the molecular abnormalities with which specific and recurring chromosomal abnormalities are associated in acute nonlymphoblastic leukemia
Slide 7-

“The Big 4”
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t(15;17) and ATRA Understand the significance of rearrangements of the ATRA receptor gene in M3 AML myeloblast promyelocyte metamyelocyte band neutrophil myelocyte promyelocyte metamyelocyte band neutrophil myelocyte promyelocyte normal PML-RARα PML-RARα + ATRA Production of abnormal RARα protein Repression of RARα target genes Blocked differentiation APL ATRA-induced myeloid differentiation
Slide 9-

Leukemogenesis Know which constitutional and genetic conditions predispose to the development of leukemia
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Major Leukemia Predispositions Marrow failure syndromes – MDS, AML JMML-related conditions (NF1, Noonan) Down syndrome – ALL, TMD/AMKL Others Ataxia-telangiectasia (ALL, NHL) – ATM mutations; defective DNA repair, immunodeficiency Bloom syndrome (broad) – BLM mutations; short stature, sun rash, sister chromatid exchanges Li-Fraumeni syndrome (broad) – TP53 mutations
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Marrow Failure and MDS/AML Pancytopenia
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Marrow Failure and MDS/AML Anemia
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Marrow Failure and MDS/AML Neutropenia
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Marrow Failure and MDS/AML Thrombocytopenia
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t-AML Know the characteristic chromosomal abnormalities and clinical characteristics in secondary acute myeloid leukemia resulting from topoisomerase II inhibitors and from alkylators, respectively
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t-AML Alkylating agents and radiation Long latency (5 -7 year) from exposure, common preceding MDS Cytogenetics: -7, del(7q), -5, del(5q); complex cytogenetics Topoisomerase II inhibitors (etoposide > anthracyclines) Short latency (1-2 years) from exposure, rare preceding MDS Cytogenetics: 11q23 rearrangements most common, but t(8;21), t(15;17), t(9;22) and inv(16) can also occur Regardless of age at presentation or etiology, t-MDS/t-AML tends to be more refractory to therapy than de novo MDS or AML
Slide 17-

Acute Myeloid Leukemia Basic Science and Pathophysiology Epidemiology and Risk Assessment Diagnosis Management and Treatment
Slide 18-

Epidemiology Know the incidence of ALL, AML and CML, and the peak age at which each of these occur
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CML Epidemiology
Slide 20-

CML Epidemiology
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Epidemiology Know the concordance rate of ALL and AML in identical twins
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Monozygotic twins Index case < 1 yo Very high (close to 100%) concordance with short latency (weeks) Prenatal preleukemic event (MLL-r, e.g), intrauterine transfer MLL-r promotes rapid development of cooperating “hits” Index case 1-6 yo ~10-20% concordance (most clonal), longer latency Prenatal preleukemic event (TEL-AML1, AML1-ETO, e.g), intrauterine transfer Compared to MLL-r, relatively low risk of cooperating “hits” Index case > 6 yo Minimal increased risk No prenatal preleukemic event
Slide 23-

Prognostic Factors & Risk Stratification Know prognosis of various sub-types of acute myeloid leukemia Know the prognostic significance of the non-random cytogenetic abnormalities in acute myeloid leukemia Know the prognostic importance of Down syndrome in acute nonlymphoblastic leukemia Risk Stratification is the prospective use of prognostic factors to assign patients to specific treatments. Only a subset of prognostic factors are used in risk stratification
Slide 24-

Prognostic Factors not used Host characteristics Age and sex: not independent on most recent studies Race: non-whites - inferior survival BMI: under- or over-weight - inferior survival Pharmacogenomics Disease characteristics High WBC – no longer used, except in APL (> 10K is high risk – use anthracycline immediately) FAB – supplanted by cyto/molecular
Slide 25-

Recent Risk Stratification Favorable Down syndrome-related (esp. if < 4 y.o.) APL with t(15;17) or variant Cytogenetics: inv(16), t(8;21) Molecular: NPM1, CEBPA Unfavorable t-AML, MDS-related AML Cytogenetics: -7, 5q-, abn(3q) Molecular: FLT3/ITD (high allelic ratio) Primary induction failure (>5% blasts after course 2) Intermediate: everything else Separate protocols
Slide 26-

Update: incorporation of MRD Intermediate Risk Sub-classified into favorable or unfavorable according to end-course 1 flow cytometric MRD centralized laboratory, using +/- threshold of 0.1% Grouped with “traditional” favorable/unfavorable groups Republished with permission of Blood: Journal of the American Society of Hematology, from Residual disease detected by multidimensional flow cytometry signifies high relapse risk in patients with de novo acute myeloid leukemia: a report from Children's Oncology Group, Loken, et all, 120, 8, 2012; permission conveyed through Copyright Clearance Center, Inc.
Slide 27-

Current Risk Stratification Favorable (Low Risk, LR) Down syndrome-related (esp. if < 4 y.o.) APL with t(15;17) or variant Cytogenetics: inv(16), t(8;21) Molecular: NPM1, CEBPA Intermediate with end course 1 MRD negative Unfavorable (High Risk, HR) t-AML, MDS-related AML Cytogenetics: -7, 5q-, abn(3q) Molecular: FLT3/ITD (high allelic ratio) Primary induction failure (>5% blasts after course 2) Intermediate with end course 1 MRD positive Separate protocols
Slide 28-

Acute Myeloid Leukemia Basic Science and Pathophysiology Epidemiology and Risk Assessment Diagnosis Management and Treatment
Slide 29-

Classification Know the FAB (old) and WHO (new) classifications of AML Know the characteristic clinical presentations of AML, and associate these with specific AML subtypes DIC/bleeding Hyperleukocytosis CNS leukemia Leukemia cutis Chloromas
Slide 30-

FAB: morph/phenotype; 30% blasts
Slide 31-

WHO: clinical/molecular; 20% blasts Is the AML due to prior XRT/chemo? If yes: Dx is Therapy-related AML (t-AML) Is the AML in a child with Down syndrome? If yes: Dx is DS-related AML Is major (“Big 4”) recurring abnormality present? If yes: Dx is AML w/ t(8;21); inv(16); t(15;17); MLL-r NOTE: No minimum blast % needed Is there dysplasia, prior MDS and/or MDS-related mutation (-7, del(5q), etc.)? If yes, Dx is AML with MDS-related changes If no to all: Dx is AML, NOS - use FAB to subclassify
Slide 32-

Immunophenotype Know the immunophenotypic differences between acute lymphoid and acute myeloid leukemia Know how to identify lymphoid/myeloid mixed lineage acute lymphoblastic leukemia and biphenotypic leukemia (by immunophenotyping)
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Immunophenotype Pan-myeloid: 13, 33, MPO (except M7) Monocytic: 11b, 14 Erythroid: Glycophorin A (235a) Megakaryocytic: 41a, 42, 61, absent MPO APL: auto-fluorescence, bright 33, HLA-DR neg, 34 neg t(8;21): often CD19+ Reprinted from Journal of Immunological Methods, 243, Campana, Behm, Immunophenotyping of leukemia, 59-75, © 2000, with permission from Elsevier
Slide 34-

Acute Leukemia of Ambiguous Lineage Acute Undifferentiated Leukemia (AUL) Express no lineage-specific markers Mixed Phenotype Acute Leukemia (MPAL) Distinct populations of blasts of different lineages; and/or single population of blasts co-expressing antigens of multiple lineages Often MLL-rearranged T/myeloid, B/myeloid most common
Slide 35-

Acute Myeloid Leukemia Basic Science and Pathophysiology Epidemiology and Risk Assessment Diagnosis Management and Treatment
Slide 36-

Therapy Know which drug combinations are most effective in the treatment of acute myeloid leukemia Know that high-dose cytarabine is effective in the treatment of acute myeloid leukemia Know the role of CNS prophylaxis in the treatment of acute myeloid leukemia Know the evidence against the use of extended maintenance therapy for AML Know the indications for allogeneic HSCT in AML Know the various components of prophylactic and acute supportive care for children with acute myeloid leukemia receiving treatment
Slide 37-

Current Standard Therapy Remission induction 2 courses of intense chemotherapy (Ara-C, Doxo, Etoposide); high risk of invasive infection; CR rate ~ 75-80% Current protocol “switches” 2nd induction course to mitoxantrone/ HD Ara-C for HR patients Post-remission consolidation BMT All HR with best donor (matched sib preferred, MUD/UCB donors acceptable) No LR (even with matched sib) Additional chemo “intensification” courses (2) HR w/o any donor, and all LR Usually HD Ara-C combined with drugs not used in induction (mitoxantrone, L-asp, e.g.)
Slide 38-

Current Standard Therapy CNS Prophylaxis Much less intense than in ALL due to low rates of CNS relapse with standard therapy For CNS+ at diagnosis, weekly IT Ara-C until CSF clears, then once per course; no cranial XRT Maintenance Unlike ALL, there is no role for extended maintenance (a survival benefit has never been demonstrated)
Slide 39-

Current Standard Therapy Supportive care Admission during periods of neutropenia recommended, due to significant risk of life-threatening infections Most infections are episodes of bacteremia and sepsis Strep. Viridans Gram negative enterics (E. coli, Klebsiella, Pseudomonas, etc.) Aggressive empiric treatment with broad spectrum antibiotics to cover these organisms is standard Bacterial prophylaxis is controversial and not considered standard due to concerns re: antibiotic resistance Fungal and pneumocystis prophylaxis are commonly used G-CSF and other growth factors are not commonly used due to concerns re: promoting leukemia cell growth/survival
Slide 40-

Clinical aspects of APL High risk of life-threatening bleeds (~10% mortality) due to DIC/fibrinolysis + low plts Basics: close monitoring of PT, aPTT, fibrinogen, D-dimer, plts with liberal use of products: plts, cryo, FFP Start ATRA immediately with suspected APL: rapidly improves coag parameters and reduces bleeding risk Other interventions controversial (heparin, amicar, rVIIa, …) Differentiation syndrome Fever, edema, pulm infiltrates, hypoxia, resp distress, hypotension, renal/hepatic dysfunction, effusions, rash Risk correlates with high WBC; can occur in absence of ATRA Rx: Prompt recognition and use of dexamethasone, hold ATRA until resolving Arsenic Trioxide Increasingly incorporated into consolidation for APL in effort to reduce cumulative anthracycline exposure - recent data suggests that “low risk” APL (<10k WBC) is curable with ATRA and Arsenic only!
Slide 41-

MDS vs. AML Know the relationship between myelodysplastic syndromes and acute myeloid leukemia In children (unlike adults), the vast majority of AML cases are “de novo” (i.e., not preceded by MDS) MDS in children commonly arises in setting of underlying constitutional disorder (DS, marrow failure syndrome, etc.) MDS in children has similar implications as in adults Eventual progression to AML is the general rule; pace of progression is variable Generally requires HSCT for cure Questionable role for pre-HSCT chemotherapy
Slide 42-

Hyperleukocytosis Recognize the potential complications of hyperleukocytosis in acute myeloid leukemia Plan the management of hyperleukocytosis in acute myeloid leukemia
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Hyperleukocytosis Risk factors: Elevated WBC (>100K); AML>ALL Etiology: Sludging of viscous blood in brain, lungs, kidneys, other organs Features: Management Treat leukemia ASAP Exchange transfusion or leukopheresis if symptomatic
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Late Effects in AML After chemotherapy only Anthracyclines: cumulative exposure ~ 450 mg/m2 doxorubicin equivalents – cardiotoxicity Etoposide: t-MDS/AML High dose Ara-C: neurotoxicity After HSCT Above, plus HSCT-related risks Recognize the late complications of therapy for AML
Slide 45-

Radiation in AML Generally limited to emergent treatment of life-threatening complications of chloromas (e.g., spinal cord compression) TBI is not a typical component of HSCT prep regimens for AML Cranial XRT is generally not required to control CNS disease in AML Know the indications for radiotherapy in AML
Slide 46-

Part 2: Chronic Myeloid Leukemia Basic Science and Pathophysiology Epidemiology and Risk Assessment Diagnosis Management and Treatment
Slide 47-

Chronic Myeloid Leukemia Basic Science and Pathophysiology Epidemiology and Risk Assessment Diagnosis Management and Treatment
Slide 48-

CML: Biology Know the clinical, laboratory, and prognostic features of CML Recognize the hematologic changes associated with a blast crisis in chronic myeloid leukemia Know that a blast crisis in chronic myeloid leukemia can involve other cell lines Know the association of BCR-ABL1 oncogene with chronic myeloid leukemia Know the clinical, laboratory and molecular characteristics that differentiate Ph+ chronic myeloid leukemia from Ph+ acute lymphocytic leukemia
Slide 49-

CML: Definition Myeloproliferative neoplasm (MPN) Origin: abnormal pluripotent HSC Ph+; t(9;22)(q34;q11.2); BCR-ABL1 Triphasic natural history: Chronic Phase (CP) Accelerated Phase (AP) Blast Crisis (BC)
Slide 50-

CML: Molecular Biology From Annals of Internal Medicine, Rosenbloom, Narrative Review: Fibrotic Diseases: Cellular and Molecular Mechanisms and Novel Therapies, 152, 3, 159. Copyright © 2010 American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc.
Slide 51-

Chronic Myeloid Leukemia Basic Science and Pathophysiology Epidemiology and Risk Assessment Diagnosis Management and Treatment
Slide 52-

CML: Clinical Features Most pts diagnosed in Chronic Phase (CP) 20-40% asx, dx’d due to abnl CBC (incidental findings of leukocytosis with left shift, +/- anemia, +/- thrombocytosis, basophilia, +/- eosinophilia) Sx: abd pain, dysphagia, inc abd girth (all from splenomegaly), fatigue, wt loss, night sweats, bleeding, (rarely) leukostasis/priapism(?) Natural history: progression (widely variable latency) Accelerated phase (AP): decreased response to treatment, clonal evolution, inc blasts (<20%), inc basophilia Blast crisis (BC): acute leukemia (2/3 AML, 1/3 ALL) Distinguishing CML-CP or CML-AP from Ph+ ALL is simple due to obvious differences in CBC and PB smear; CML presenting with lymphoid BC vs. Ph+ ALL is a more challenging distinction – molecular studies are crucial.
Slide 53-

CML: Diagnosis Demonstration of p210 BCR-ABL1 fusion (PCR) in blood in proper clinical context is likely sufficient Marrow typically included to definitively rule out accelerated phase and improve karyotyping Republished with permission of Blood: Journal of the American Society of Hematology, from Clinical Significance of Cytogenetic Abnormalities in Adult Acute Lymphoblastic Leukemia, Faderl, et al, 91, 11, 1998; permission conveyed through Copyright Clearance Center, Inc.
Slide 54-

Chronic Myeloid Leukemia Basic Science and Pathophysiology Epidemiology and Risk Assessment Diagnosis Management and Treatment
Slide 55-

CML: Treatment Know the principles of using targeted therapy (such as imatinib) in patients with chronic myeloid leukemia Plan the treatment of a blast crisis in a patient with chronic myeloid leukemia Know the indications for and timing of HSCT in a patient with chronic myeloid leukemia Know the therapeutic options for a patient who has a recurrence of chronic myeloid leukemia after HSCT
Slide 56-

CML: Impact of Tyrosine Kinase Inhibitors Pre-TKI Era The only curative long term curative therapy is allogeneic stem cell transplant, so essentially all children receive HSCT with best available donor Hydroxyurea and interferon used to control disease prior to SCT Post-TKI Era Begin TKI, continue indefinitely Consider HSCT in chronic phase only for patients with HLA-matched family donor (even then controversial) For recurrent or refractory chronic phase, try higher dose TKI and/or new TKI first (guided by mutation analysis), then HSCT for treatment failure For accelerated phase or blast crisis, attempt to induce remission with chemotherapy (AML or ALL, depending on blast phenotype) + TKI, and then take to HSCT
Slide 57-

CML: Treatment of CML-CP ABL tyrosine kinase inhibitors (TKI) Imatinib Kids: 340 mg/m2 qd (600 mg max) Adol/adult: 400 mg qd (may increase to 600 mg and 800 mg as needed for response) Dasatinib (100 mg qd) Nilotinib (400 mg bid) *Ponatinib (45 mg qd) – active against T315I mutant HSCT – controversial HSCT remains the only proven cure for CML – TKI’s achieve sustained disease control, but recurrence likely upon discontinuation Major prognostic factor for HSCT: disease phase (CP>AP>BC) CML is very sensitive to graft vs. leukemia (GVL) effect – relapses post-HSCT can be effectively treated with donor lymphocyte infusions (DLI), especially if no GVH with first HSCT When HSCT is used, TKI “maintenance” is typically added post-engraftment in effort to prevent relapse More rapid and sustained cytogenetic/molecular responses
Slide 58-

CML: Response There are three principal strategies to assess response Hematologic response (HR; determined with PB and exam) Complete (CHR): normal counts, no HSM Cytogenetic response (CyR; determined with BCR-ABL FISH on BMA) Complete (CCyR): no Ph+ Partial (PCyR): major <= 35%; minor 36-95% Molecular response (MR; determined with BCR-ABL qPCR on PB) Complete (CMR): PCR neg Major (MMR): BCR-ABL:ABL ratio <0.1% (international scale), or 3 log reduction in copy# Most recent guidelines BMA for response not needed if validated qPCR testing available Every 3 month testing until MMR, then every 3-6 months
Slide 59-

CML: Response
Slide 60-

CML: Response Response to TKI treatment is the most important prognostic factor in CML Patients with a rapid and sustained response to TKI have an excellent outcome TKI resistance Primary – treatment failure or suboptimal response with TKI Secondary - loss of response (rising qPCR, recurrence of FISH+, development of CML-AP, etc.) Both types are most commonly caused by acquired mutations in ATP-binding pocket of ABL – T315I mutations have been most problematic, since they are also resistant to 2nd and 3rd line TKI’s – recently approved ponatinib has T315I activity TKI-resistant patients generally require HSCT for cure