Acute Leukemias - DSA Flashcards
Essentials of dx for acute leukemia
o Short duration of sx – fatigue, fever, bleeding
o Cytopenias or pancytopenia
o >20% blasts in bone marrow
o Blasts in peripheral blood of 90%
Causes of acute leukemia
- Radiation and toxins (benzene) leukemogenic
- Chemotherapeutic agents – cyclophosphamide, melphalan, alkylating agents, etoposide
- After treatment for myelodysplastic prodrome – Chr 5 and 7 abnormalities
- Post etoposide – 11q23 – MLL
Acute Myeloid Leukemia (AML)
- Adult – median age 60 yo, increasing incidence with advanced age
- T(8;21) → chimeric RUNX1/RUNX1T1 protein
- Inv(16)(p13;q22) – core-binding factor leukemias
- Very poor prognosis – isolated monosomy 5 or 7
- Presence of 2 or more monosomies or 3 or more separate cytogenic abnormalities
- Internal tandem duplication in FLT3 – very poor prognosis
- Poor prognosis: TET2, ASXL1, MLL-PTD, PHF6, DNMT3A
- Favorable: lack FLT3-ITD mutations, has mutations of nucleophosmin1 (NPM1), IDH1 or IDH2
Acute promyelocytic leukemia (APL)
- T(15;17) → PML-RARa interacts with retinoic acid receptor
- blocks differentiation – overcome with retinoic acid
- highly curable – over 90% with integration of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO)
Acute Lymphoblastic Leukemia (ALL)
• 80% of childhood acute leukemias; peak incidence 3-7 ys
• 20% of adult acute leukemias
• Immunologic phenotype
• Early B lineage and T cell
• Hyperdiploidy - >50 Chr esp. Chr 4, 10, 17 and t(12;21) – TEL-AML1 = better prognosis
• Unfavorable:
o hypodiploidy - <44 Chr
o Ph+ t(9;22), t(4;11) → fusion genes involving MLL gene at 11q23
o Complex karyotype of >5 Chr abnormalities
Mixed Phenotype Acute Leukemias
- Blasts lack differentiation along lymphoid or myeloid lineage or blasts that express both lineage specific antigens
- Very high risk – poor prognosis
- Stem cell transplant advisable
- Tyrosine kinase inhibitor in patients with t(9;22) translocations
S/S of Acute Leukemia
- Ill days to weeks
- Bleeding d/t thrombocytopenia
- Skin and mucosal surfaces
- Gingival bleeding, epitaxis, menorrhagia
- Less common: widespread bleeding with DIC in APL and monocytic leukemia
- Infection due to neutropenia
- Risk rises when ANC less than 500/mcL
- Cellulitis, pneumonia, perirectal infections
- Death within few hours if abx delayed
- Fungal infections commonly seen
- Gum hypertrophy, bone and joint pain
- Hyperleukocytosis – markedly elevated circulating blast count tWBC >100,000/mcL → impaired circulation
- HA, confusion, dyspnea
- Need emergent chemo with adjunctive leukopheresis
- Mortality approaches 40% in first 48 hours
- Exam:
- Pale, have purpura and petechiae
- Signs of infection may not be present
- Stomatitis, gum hypertrophy, rectal fissures in monocytic leukemia
- Variable enlargement of liver, spleen, LN
- Bone tenderness – sternum, tibia, femur
Lab Findings of Acute Leukemia
- Pancytopenia with circulating blasts
- Blasts may be absent in peripheral smear – aleukemic leukemia
- Bone marrow hypercellular, dominated by blasts
- > 20% marrow blasts
- Hyperuricemia
- If DIC present:
- reduced fibrinogen level
- PT prolonged
- fibrin degradation products or fibrin D-dimers present
Lab findings of ALL
• especially T cell – mediastinal mass visible on CXR
o Don’t express mature T cell makers (CD3, 4, 8)
o Express combination of CD2, CD5, CD7
o Do not express surface Ig
• B cell: CD19, CD10
• All ALL express TdT – terminal deoxynucleotidyl transferase
• Lymphoma type: CD19, CD20, surface Ig, but TdT –
o Treat with aggressive lymphoma regimens
Meningeal leukemia lab findings
blasts in CSF
• Most common in monocytic types of AML, ALL
AML lab findings
- Auer Rod – eosinophilic needle-like inclusion in cytoplasm
- CD13 or CD33
- Myeloperoxidase +
Differential dx for acute leukemia
o AML must be distinguished from CML and myelodysplastic syndromes
o Acute Leukemia resembles left-shifted marrow recovery from toxic insult
• Repeat marrow study in several days to check for maturation
o ALL separated from CLL, lymphomas, hairy cell leukemia
• Maybe confused with atypical lymphocytosis of mononucleosis and pertussis
Treatment goals for acute leukemia
• Up to 60 yo – acute leukemia treated to cure
- Obtain remission:
- normal peripheral blood with resolution of cytopenias
- normal bone marrow with no excess blasts
- normal clinical status
Treatment for AML
- Anthracycline (daunorubicin or idarubicin) PLUS cytarabine alone or with other agents
- → complete remission in 80-90% under 60 yo
- 50-60% remission of older patients
- Older patients not candidates for traditional chemo: 5-azacitidine, decitabine, or clofarabine
- Over 60 poor prognosis, standard chemo 10-20% become long term survivors
- Reduced-intensity allogenic transplant improves outcomes – up to 40% may be cured
- Favorable genetic profile: tx with chemo alone or with autologous transplant - cure 60-80%
- Don’t enter remission or high-risk genetics – cure rates of less than 10% if chemo alone; refer for allogenic stem cell transplant
- Intermediate-risk – cure rates 35-40% with chemo, 40-60% with allogenic transplant
- FLT3 +: midostaurin added to induction, consolidation, and maintenance prolongs event free and overall survival
- Prognosis poor if recurs after initial chemo
- Second remission: 20-30% chance of cure with transplantation
- Targeted tx at recurrent genetic mutations: FLT3, IDH1/IDH2
Treatment of ALL
- Adults – combination chemo – daunorubicin, vincristine, prednisone, asparaginase
- Complete remission in 90%
- Ph+ need tyrosine kinase inhibitor – dasatinib added to initial chemo
- > 60 yo – may be treated with tyrosine kinase inhibitor based regimen – 90% remission
- Less myelosuppressive than AML – does not necessarily produce marrow aplasia
- Receive CNS prophylaxis so meningeal sequestration of leukemic cells does not develop
• Tx decisions made on age and disease risk factors
• Younger than 39 yo – better outcomes under pediatric protocols
• Low risk – chemo alone with 70% chance of cure
• Intermediate risk – 30-50% cure with chemo
• High risk – rarely cured with chemo alone
o Best treated with allogeneic transplantation
• Minimal residual disease testing guides tx following induction
• Relapsed disease: bispecific Ab blinatumomab
o Bridge to transplant
o Autologous T cell engineered to express anti-CD19 antigen receptor (CART-19) for pediatric and adult relapsed B-ALL
Prognosis of acute leukemia
o 70-80% adults with AML under 60 yo complete remission, ~50% cured using risk-adapted post-remission therapy
• Older adults – 50% complete remission, cure rates very low – 10-20% even if they achieve remission and receive post remission chemo
o ALL
• Less than 39 yo – excellent outcomes after chemo followed by risk-adapted intensification and transplant – cure rates 60-80%
• Adverse cytogenetics, poor response to chemo, or older age much lower chance of cure – 20-40%
Essentials of diagnosis of CML
o Elevated WBC
o Markedly left-shifted myeloid series, low % of promyelocytes and blasts
o BCR/ABL gene – Philadelphia Chromosome (Ph+), T(9q;22q)
• 9q – Ableson murine leukemia virus homolog
Myeloproliferative general considerations
o Myeloproliferative – overproduction of myeloid cells
• Differentiate and circulate in increased numbers in peripheral blood
Early CML - chronic phase
- Normal bone marrow function
- WBC differentiate
- Neutrophils combat infection normally
o Untreated CML – unstable → accelerated → acute blast phase (acute leukemia)
S/S of CML
- Middle age – median age 55 yo
- Fatigue, night sweats, low grade fevers
- Hypermetabolic state d/t overproduction of WBCs
- Splenomegaly – abdominal fullness
- Rare: leukostasis – blurred vision, respiratory distress, priapism
- WBC >100,000/mcL but less than 500,000/mcL
- Sternal tenderness – marrow overexpansion
- Acceleration: fever in absence of infection, bone pain, splenomegaly
Lab Findings for CML
- Median WBC count 150,000/mcL, can be only modestly elevated
- Peripheral blood
- Left shifted with mature forms dominating
- Blasts less than 5%
- Basophilia, eosinophilia
- RBC morphology normal – rare nucleated RBC
- Platelet count normal or elevated
- Marrow:
- Hypercellular
- Left-shifted myelopoiesis
- Myeloblasts less than 5%
- PCR: BCR/ABL gene in peripheral blood test
Lab findings for accelerated and blast phases of CML
- Progressive anemia, thrombocytopenia
- Increasing % of blasts in blood and marrow
- Blast phase CML when blasts >20% bone marrow cells
Ddx for CML
o Early CML differentiated from reactive leukocytosis assoc. w/ infection
• WBC less than 50,000/mcL
• Splenomegaly absent
• BCR/ABL not present
o From other myeloproliferative dz:
• Hct should not be elevated
• RBC morphology normal – nucleated RBC rare or absent
• Definitive dx – BCR/ABL gene
Tx for CML
o Extreme hyperleukocytosis – emergent leukopheresis w/ myelosuppressive tx
o Chronic phase:
• Tyrosine inhibitor: imatinib, nilotinib, dasatinib targeting abl kinase
• Imatinib – 98% hematologic control of chronic phase – 400 mg/day; 30% major molecular at 1 yr
• Nilotinib 71% major molecular at 300-400mg BID for 2 yr; Dasatinib 64% major molecular at 100 mg/day for 2 yrs
o Can salvage 90% of those failing imatinib tx
• Bosutinib – dual bcr/abl tyrosine inhibitor – resistant or intolerate to other TK inhibitors
o 20% complete cytologic response, not active against T315I mutation
• Hematologic complete remission within 3 mo of tx initiation
• Major cytologic response 3-6 mo – when less than 35% of metaphases Ph+
• Major molecular response within 12 mo – 3 log reduction of BCR/ABL transcript in quantitative PCR
• Excellent prognosis, 100% progression free at 8 years
• Monitor and PCR for T315I mutation if BCR/ABL transcript increasing or suboptimal response
• Mutation sensitive to 3rd generation – ponatinib
o High rate of vascular thrombotic complications
• Allogenic stem cell transplantation if cannot achieve good molecular response or progress following tx
o Advanced stage – TK inhibitor alone or with myelosuppressive chemo
• Consider for allogenic stem cell transplantation
Course and prognosis of CML
o Imatinib tx – 80% survive without progression at 9 yrs
o With good molecular responses – excellent prognosis – 100% survival at 9 years
Essentials of diagnosis of chronic lymphocytic leukemia
o B-cell lymphocytosis >5000/mcL
o Coexpression of C19, CD5 on lymphocytes
General considerations of CLL
o Clonal malignancy of B lymphocytes
o Indolent – slowly progressive accumulation of long-lived small lymphocytes
o Immunosuppression, bone marrow failure, organ infiltration with lymphocytes
o Immunodeficiency – inadequate Ab production
o Advanced dz – damage by direct tissue infiltration
S/S of CLL
- 90% after age 50 yo, median age 70 yo
- Incidental finding of lymphocytosis
- Fatigue or lymphadenopathy
- 80% lymphadenopathy, 50% hepato- or splenomegaly
- Variant – prolymphocytic leukemia – more aggressive
- Larger, more immature cells
- Complicated by autoimmune hemolytic anemia or autoimmune thrombocytopenia – 5-10%
- Richter syndrome – isolated LN transforms into aggressive large cell lymphoma
Lab findings for CLL
- Isolated lymphocytosis
- WBC >20,000/mcL, may be markedly elevated to several hundred thousand
- 75-98% circulating cells lymphocytes
- small, mature
- condensed chromatin
- Hct and platelet count normal at presentation
- Hypogammaglobinemia – 50%
- Small amount of IgM paraprotein in serum
- Immunophenotype: CD19, CD5 – also seen in mantel cell
- Distinguished by: CD23, low expression of surface Ig, CD20, absence of translocation or overexpression of cyclin D1
- IgVH somatic mutation: more indolent form – express low levels of CD38, no ZAP70
- Unmutated IgVH with high ZAP70 expression – not as well, sooner treatment required
- Del 17p (TP53)– worse prognosis
- Del 11q (ATM) inferior prognosis
- Del 13 q more favorable outcome
Ddx of CLL
o Exclude viral infections, pertussis
o Waldenstrom macroglobulinemia, hairy cell leukemia, mantle cell lymphoma – distinguished by morphology, immunophenotype, bone marrow
o Monoclonal B-cell lymphocytosis – less than 5000/mcL B-cells – precursor to B-CLL
Treatment of CLL
o Indications for tx: progressive fatigue, symptomatic lymphadenopathy, anemia, or thrombocytopenia
• Rai stage II or III/IV
o Initial tx under age 70 without significant comorbidities: fludarabine with cyclophosphamide and rituximab OR bendamustine with rituximab (better tolerated, fewer adverse effects, results shorter time to progression)
o Older patients or young patients with comorbidities: chlorambucil orally q3weeks for 6 mo
• Combine with obinutuzumab – significant responses 75% - at molecular level in 17%
• Oral ibrutinib – inhibitos Bruton tyrosine kinase – 420 mg/day – 71% response, 75% progression free at 26 mo
• Nonhematologic adverse effects – diarrhea, fatigue, nausea
• Caution with CYP3A inhibitors or inducers
• Serious bleeding if used with warfarin
o Relapsed or refractory – ibrutinib and idelalisib
• Marked lymphocytosis d/t tumor cell release from LN into blood – decreases lymphadenopathy
• Del 17q: ibrutinib – sustained duration of response – 85% at 2 yrs
• Relapsed all genetic groups– idelalisib – 150 mg BID with rituximab
o Associated autoimmune hemolytic anemia or immune thrombocytopenia – rituximab, prednisone, or splenectomy
• Avoid fludarabine – exacerbates
o Rituximab – caution in past HBV – reactivates
o Recurrent bacterial infections and hypogammaglobuinemia – prophylactic infusions of gamma globulin
o Nucleoside analogue tx need anti-infective prophylaxis for P. jirovecii pneumonia, herpes viruses, invasive fungal infections until T cell recovery
o Allogeneic transplant – curative – used only if cannot be controlled by standard therapies
• Non-myeloablastive – encouraging results
• Early transplant with Chr 17q del
Prognosis of CLL
o Stage 0-I: 10-15 yr
o Stage III or IV: 2 years
o High risk and resistant forms – allogeneic transplant overcome risk factors, long term dz control
