Acute Leukemia

AJ Winer

Background 

  • Definition of Acute Leukemia: hematological malignancy caused by clonal proliferation of blasts (WBC precursors) in the bone marrow
  • Types:
    • Acute Myeloid Leukemia (AML): neoplastic accumulation of immature myeloid cells in the bone marrow
    • AML includes subtype Acute Promyelocytic Leukemia, defined by the translocation (15;17) PML-RARA
    • Acute Lymphoblastic Leukemia (ALL): neoplastic accumulation of immature lymphoblasts in the bone marrow
      • Includes subtypes B-ALL and T-ALL
  • Exposure: radiation, chemo (alkylating agents), smoking, benzene
  • Secondary to acquired condition: MDS, MPN, HIV, aplastic anemia, Down Syndrome

Presentation

  • Symptoms - related to cytopenias:
    • Anemia: fatigue, pallor, dyspnea
    • Functional leukopenia/neutropenia: recurrent infection
    • Thrombocytopenia: gingival bleeding, epistaxis, petechiae, ecchymoses, menorrhagia
    • Leukocytosis: leukemia cutis, gingival hypertrophy, leukostasis
    • Extramedullary hematopoiesis: splenomegaly, hepatomegaly, lymphadenopathy
  • Oncologic Emergencies related to leukemia:
    • See oncologic emergencies for more in depth discussion, but can present with leukostasis (blast >50k, low SaO2, HA, blurry vision, neurologic sx), TLS (from rapid cell turnover), DIC (esp APL), differentiation syndrome (see section below)

Evaluation

  • Initial studies (peripheral blood)
    • peripheral smear, search for Auer rods and schistocytes
    • Fibrinogen, PT/PTT, haptoglobin to survey for DIC
    • If high concern for AML, can send a peripheral blood FISH for 15:17 translocation (PML-RARa), cinch APL diagnosis quickly
    • immunophenotyping by flow cytometry (assess cell-surface and cytoplasmic markers: CDxx),
  • Definitive studies (done on bone marrow biopsy):
    • immunophenotyping by flow cytometry (assess cell-surface and cytoplasmic markers: CDxx),
    • genetic and mutational analysis (assess for therapeutic targets - FLT3, IDH1, etc)
    • Cytogenetic analysis (screening for gene rearrangements - PML::RARA, BCR::ABL1, etc)
  • Diagnosis of acute leukemia requires one of the following:
    • Traditionally, required 20% blasts in peripheral blood, 20% blasts in bone marrow, any pathognomonic cytogenetic abnormality of t(8;21), inv(16), t(15;17)
    • Now, for certain recurrent genetic lesions, ≥10% blasts in bone marrow or blood now indicate AML (ie AML with recurrent genetic abnormalities, AML with mutated TP53, AML with myelodysplasia-related gene mutations, etc - see ELN guidelines)
    • Exclusions to above include AML with BCR::ABL1 which requires >/=20% blasts to avoid overlap with CML in accelerated phase, among others

Management

  • Once diagnosis is established and patient admitted to Brittingham, they will need the following:
    • Hematology admission order set
    • TLS labs q8
    • Blood product consent on admission, set RBC and Plt transfusion thresholds
    • Infectious workup if neutropenic and febrile
    • Nurse-driven electrolyte repletion
    • ECG and TTE to establish pre-chemotherapy cardiac function
    • Double lumen PICC line for chemotherapy induction if indicated
    • Daily labs: CBC, TLS, DIC
    • Bone marrow cytogenetics and flow cytometry for immunophenotype
    • LP if clinical sx suspicious of CNS involvement or if c/f ALL
  • Emergent complications of leukemia and their labs to consider:
    • DIC – check fibrinogen, PT, PTT, platelets o TLS – check uric acid, phosphate, K+
    • Neutropenic fever – check temp, neutrophil count, BCx
    • Leukostasis (see below)
  • Induction Therapy
    • General strategy: “induction” chemo to try to induce clinicopathologic (as opposed to molecular) “remission” = complete remission (CR). CR is absence of symptoms, normal CBC (ANC >10k, Plt >100), and <5% blasts in bone marrow (on day 28)
    • The choice of therapy is often affected by patient fitness, which is affected by age, presence of serious comorbidity, and functional status as measured by the ECOG scale. For instance, while a “fit” patient with AML might receive 7+3 induction therapy, patients who are older than 75, have an ECOG 4>, or patients with cardiopulmonary disease would more likely receive a regimen like azacytidine/venetoclax. - response is assessed with bone marrow biopsy, usually on Day 14
    • Patients stay in the hospital after induction, until their cytopenias recover (generally until neutrophil count >500)
    • From there, bone marrow transplant (for high-risk disease) or “consolidation” chemo for normal-risk or low-risk disease

Acute Myelogenous Leukemia

Background 

  • Definition: abnormal proliferation of myeloblasts in BM or peripheral smear
  • 80% of acute leukemias in adults are AML
  • Classification:
    • Features used to confirm myeloid lineage and subclassify AML to guide treatment: morphology: blasts, granules, auer rods
    • Immunophenotype:
      • precursor: CD34, CD45, HLA-DR
      • Myeloid: CD13, CD33, CD117
      • Monocyte: CD11b, CD64, CD14, CD15
    • Prognosis: age, prior antecedent MPN/MDS, and genetics (cytogenetics + molecular mutation status) are independent risk factors of poor prognosis

European Leukemia Net (ELN) Genetic Risk classification

Risk Category

Genetic Abnormality
Favorable APL: t(15;17); PML-RARa; t(8;21): RUNX1-RUNX1T1; inv(16): CBFB-MYH1; mutated NPM1 w/o FLT3-ITD or w/ FLT3-ITDlow*; biallelic mutation in CEBPA
Intermediate FLT3-ITDlow*; mutated NPM1 & FLT3-ITDhigh*; t(9;11): MLLMLLT3; cytogenetic abnl not classified as favorable or adverse, including normal karyotype w/o mutations in FLT3-ITD & NPM1
Adverse -5 or del(5q); -7; -17/abn(17p); complex or monosomal karyotype; t(6;9): DEK-NUP214; t(9;22) BCR-ABL1; inv(3): GATA2- MECOM; wildtype NPM1 & FLT-ITD high*; mutated TP53, RUNX1, ASXL

Treatment

  • Induction chemotherapy:
    • Based on patient fitness:
    • Typical is “7+3”: idarubicin on days 1-3 + cytarabine on days 1-7
    • Patients with poor fitness often receive hypomethylating agent (HMA) therapy with azacytidine or decitabine with Venetoclax.
    • If therapy-related AML, MDS-related AML, or AML with cytogenetics similar to MDS, use “Vyxeos” which is liposomal daunorubicin and cytarabine on days 1, 3, and 5
    • If favorable-risk dz (t(8;21) or inv(16)), use cytarabine on days 1-7, and 3 days of low-dose daunorubicin + gemtuzumab-ozogamicin

Acute Promyelocytic Leukemia (APL)

  • Definition: translocation of retinoic acid receptor: t(15;17) PML-RARA
  • Specific findings: promyelocytes on differential or Auer rods on smear Treatment: depends on whether pt is high risk or non-high-risk, but for both, give ATRA + Arsenic Trioxide (ATO) to induce differentiation of blasts
    • Non-high-risk APL: ATRA + ATO (Induction + 4c consolidation)
    • High-risk APL: WBC >10k. Often chemo along with ATRA + ATO

Complications that can arise: DIC and differentiation syndrome 

  • Differentiation syndrome:
    • Mechanism: promyelocytes will differentiate from ATRA resulting in a constellation of life-threatening complications o Complications include Pulmonary edema, subarachnoid hemorrhage, hypotension
    • Risk is higher with higher WBC counts before ATRA (above 20,000 especially)
    • Management: dexamethasone 10mg BID, supportive care. If critically ill, hold ATRA and ATO and consider hydroxyurea

Acute lymphogenous Leukemia

Classification

  • Lymphoblastic neoplasms may present as:
    • ALL with >20% BM blasts
    • Lymphoblastic lymphoma with mass lesion and <20% BM blast
  • No granules seen - +TdT seen in 95% of ALL
  • Lumbar puncture is performed, with co-administration of intrathecal chemo

Treatment

  • Induction:
    • Typical induction is “HyperCVAD” (hyper-fractionated cyclophosphamide, vincristine, doxorubicin (“A” due to trade name Adriamycin), and dexamethasone
    • If t(9;22) (known as Philadelphia chromosome), use tyrosine kinase inhibitor (TKI) o If CD20+, use rituximab
  • Sometimes will do CNS ppx, especially if prior to BMBx
  • Note that many of these regimens are adapted from Pediatric treatment protocols
  • Post-remission choice of chemo depends on risk of recurrence and monitor for relapse/refractory

Overview of Common Chemotherapy Regimens

Regimen

Components

Use
7+3 Cytarabine (Ara-C) x 7 d and anthracycline (e.g. idarubicin x3 d) AML Induction
Vyxeos Cytarabine + liposomal daunorubicin AML-MRC or t-AML
CLAG-M Cladribine, cytarabine (Ara-C), Filgrastim (G-CSF), mitoxantrone AML induction (relapsed/refractory)
ATRA All-trans retinoic acid given with arsenic trioxide (ATO) APML
HyperCVAD/MA CVAD = Cyclophosphamide, vincristine, doxorubicin, dexamethasone
MA = methotrexate/cytarabine
(Given as alternating cycles)		 ALL
R-CHOP rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone NHL
R-EPOCH etoposide + rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone NHL
ABVD doxorubicin, bleomycin, vinblastine, dacarbazine HL
Last updated on