Acute Leukemia

Background 

• Definition of Acute Leukemia: hematological malignancy caused by clonal proliferation
  immature white WBC orecursors (blasts) in the bone marrow.
• Types:
  • Acute Myeloid Leukemia (AML): clonal proliferation of immature myeloid blasts in the
    bone marrow.
  • AML includes subtype Acute Promyelocytic Leukemia (APL), defined by the t(15;17)
    resulting in the PML-RARA fusion.
  • Acute Lymphoblastic Leukemia (ALL): clonal proliferation of immature lymphoblasts in
    the bone marrow.
  • Includes subtypes B-ALL and T-ALL.
• Risk factor exposures: radiation, chemo (alkylating agents), smoking, benzene.
• Associated conditions 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:
  • Leukostasis (blast >50k, low SaO2, HA, blurry vision, neurologic sx, renal failure, chest pain).
  • TLS (from rapid cell turnover)
  • DIC (esp in APL)
  • Differentiation syndrome (see section below)
• (See oncological emergencies section for detailed management)

Evaluation

• Initial studies (peripheral blood).
• Peripheral smear (evaluate blasts, Auer rods, and schistocytes).
• Fibrinogen, PT/PTT, haptoglobin to (evaluate for DIC).
• If high concern for AML, can send a peripheral blood FISH for 15:17 t(PML-RARa), to expedite APL diagnosis quickly.
• Immunophenotyping by flow cytometry (assess cell-surface and cytoplasmic markers: CDxx).
• Definitive studies (done on bone marrow biopsy):
  • 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, or any pathognomonic cytogenetic abnormality of t(8;21), inv(16), t(15;17), t(6;9), etc.)
  • Now, for certain recurrent genetic lesions, according to ICC classification ≥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

• Upon admission to Brittingham, they will need the following:
• Place Hematology admission order set.
• Blood product consent on admission.
• Establish RBC and Plt transfusion thresholds.
• TLS labs q8h.
• Daily labs: CBC, TLS, DIC labs.
• Bone marrow cytogenetics and flow cytometry for immunophenotype.
• Infectious workup if neutropenic and febrile.
• Supportive care.
• Nurse-driven electrolyte repletion.
• ECG and TTE to establish baseline cardiac function prior to chemotherapy.
• Double lumen PICC line for chemotherapy induction (if indicated).
• 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.
• 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 remission = complete remission (CR). CR has various definitions.
• The choice of therapy is often guided by disease risk and patient fitness, including: age, serious comorbidities, and functional status (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 hypomethylating agent (HMA)/venetoclax.
• Response is assessed with bone marrow biopsy, usually on Day 14 if treated with intensive therapy.
• 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 Myeloid Leukemia

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: ATRA must be initiated at first suspicion and before confirmation. All patients receive ATRA+ Aresenic Trioxide (ATO), addition of chemotherapy (i.e. idarubicin) depending on risk (risk of early death).
• Low-risk APL: WNC <10k use ATRA + ATO (Induction + 4c consolidation)
• High-risk APL: WBC >10k, ATRA + ATO+chemotherapy (Induction +4c consolidation).
• Highly curable, no indication for bone marrow transplant unless highly refractory which is rare.
• Complications that can arise: DIC and differentiation syndrome
• Differentiation syndrome: rapidly life threatening if not managed timely
• Mechanism: ATRA causes differentiation of leukemic promyelocytes resulting in increases of vasoactive cytokines, SIRS/capillary leak syndrome, organ infiltration, endothelial damage, coagulopathy.
• Manifestations: Fever 100.4F, weight gain >5kg, dyspnea, hypoxia, pulmonary infiltrates (pulmonary edema), pleural and pericardial effusions, hypotension, renal failure.
• Risk is higher with higher WBC counts before ATRA (above 10,000 especially).
• Management: dexamethasone 10mg BID for minimum 2 days after resolution of all symptoms, supportive care If WBC rising >10 consider hydroxyure4a, if critically ill may need to hold ATRA.
• Differentiation syndrome can be seen with other AML therapies:
• Menin inhibitors (Ziftomenib, revumenib): usually seen in first 2 months, can be severe and fatal.
• IDH1/2 inhibitors (Ivosidenib/Olutasidenib/Enasidenib): can be seen in up to 90 days (some reports even longer), milder than with ATRA and menin inhibitors; consider if no other explanation fits the clinical presentation.

Acute Lymphoblastic Leukemia