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🌱 來自: Huppert’s Notes
Leukemias🚧 施工中
Leukemias
• Malignant hematology overview: Within malignant hematology, there are three broad categories of disease: 1) Leukemias, 2) Lymphomas, and 3) Multiple Myeloma
• Organizational framework for leukemias and disorders of the myeloid lineage: See Table 7.2
Acute Leukemia Basics
• Definition:
- Leukemia: ≥20% blasts in the bone marrow OR periphery, OR characteristic chromosomal abnormality (e.g., 8:21)
- Note: You usually cannot tell AML vs. ALL from the smear alone; must get flow and/or cell markers (unless you see Auer rods, which only occur in myeloid cells)
• Pearls:
- Acute leukemia is an emergency at initial presentation – evaluate for leukostasis, TLS, DIC
- With aggressive, high-intensity therapy, many patients can be cured
• Epidemiology:
- AML: Most common adult acute leukemia, average age 65–70 yr
- ALL: More common in children, although can also occur in adults
• Clinical features: Fevers, headaches, weakness, bleeding, bone pain (expansion of medullary cavity), abdominal pain (splenic enlargement)
TABLE 7.2 • Classifications of Acute and Chronic Leukemias
• Diagnosis:
- Labs: CBC with differential, CMP, LFTs, Ca2+/Mg2+/Phos, PT, PTT, fibrinogen, uric acid
• Critical to look for early evidence of DIC and TLS
• APML in particular is associated with DIC
- Blood smear: See BLASTS (round blue cells with high nuclear-to-cytoplasmic ratio, open chromatin, visible nucleoli, larger than a RBC)
• Look for Auer rods (only seen in AML, see Figure 7.4)
- Peripheral flow cytometry: Can help differentiate AML, ALL, APML, etc.
- Bone marrow evaluation (aspirate, core biopsy, flow cytometry, cytogenetics, DNA extraction)
• Pre-treatment workup:
- TTE (baseline, because many of the chemotherapy agents can cause cardiotoxicity)
- HIV, hepatitis serologies, quantiferon gold, CMV IgG
- Type and screen
- UA +/– urine pregnancy (if needed)
• Evaluate for oncologic emergencies: Neutropenic fever, TLS, DIC, leukostasis
Acute Leukemia Subtypes
Acute myeloid leukemia (AML)
• Pathophysiology: Malignant transformation of myeloid precursor cells
• Epidemiology:
- Median age at diagnosis is 65 yr
- Risk factors: Radiation, toxins (benzenes, alkylating agents), Down syndrome
• Clinical features: Often patients are quite ill at the time of diagnosis. 1) Functional neutropenia (fevers, infection), 2) Thrombocytopenia (bruising), 3) Anemia (weakness), 4) Expansion of medullary cavity (bone pain), 5) Infiltration of skin, soft tissue, CNS
• Diagnosis: Requires more than 20% blasts in bone marrow or periphery, except in cases of certain chromosomal abnormalities
• Treatment: Usually a combination of chemotherapy +/- allogeneic stem cell transplant (Figure 7.5)
- Chemotherapy = induction with “7 + 3” (7 days cytarabine, 3 days anthracyclines; Figure 7.5)
• After 7+3, repeat bone marrow biopsy on day 14. If bone marrow has no blasts, continue to consolidation therapy. If not, repeat induction.
• Consolidation therapy aims to maintain remission until the patient can receive a stem cell transplant, if eligible
- Allogenic stem cell transplant: 15–25% treatment-related mortality, but possibility of cure
FIGURE 7.4: Auer rods. Auer rods (or Auer bodies) are large, crystalline cytoplasmic inclusion bodies sometimes observed in acute myeloid leukemias.
FIGURE 7.5: Induction and consolidation chemotherapy prior to allogeneic stem cell transplant. Shown is an example induction and consolidation chemotherapy plan prior to allogenic stem cell transplant. Induction and consolidation regimens vary based on the type of malignancy. Typically, a bone marrow biopsy is done prior to starting treatment (day 0) and is repeated after induction chemotherapy on day 14. If there is still evidence of residual disease on the day 14 bone marrow biopsy, then repeat induction chemotherapy is considered. Alternatively, if there is no evidence of residual disease, then patients can proceed with consolidation chemotherapy. Allogenic stem cell transplant is performed after consolidation chemotherapy is completed.
Acute promyelocytic leukemia (APML; subtype of AML)
• Pathophysiology: Caused by (15;17) chromosome translocation, which disturbs the retinoic acid receptor
• Clinical features: Often associated with severe DIC – must diagnose quickly because DIC can become severe. Smear: Atypical promyelocytes, +Auer rods.
• Treatment: ATRA (high-dose vitamin A) and arsenic.
- Complications of ATRA:
• Differentiation syndrome: Differentiation of blasts results in a profound inflammatory response, which causes SIRS, pulmonary edema, and AKI. Give steroid prophylaxis with ATRA; if differentiation syndrome occurs, then treat with high-dose steroids.
• Hyperleukocytosis: See oncologic emergencies above
• Pseudotumor cerebri: Hold ATRA; achieve pain control, consider steroids/diuretics
Acute lymphocytic leukemia (ALL)
• Epidemiology: Occurs in both children (2–5 yr) and adults (>60 yr). Outcomes are much better in children.
• Pathogenesis: Arises from mutations in hematopoietic progenitor cells. Some cases are BCR-ABL driven. Cases are uncommonly associated with genetic predispositions or exposure to radiation/chemotherapy.
• Clinical features: Lymphadenopathy, hepatomegaly, splenomegaly, bone pain; anterior mediastinal mass commonly occurs with T-ALL.
• Treatment:
- Tends to involve “sanctuary sites” like CNS and testicles, so prophylactic intrathecal chemotherapy administered
- If BCR-ABL present (Philadelphia chromosome-positive or Ph+ ALL), can treat with targeted agents
- Induction chemotherapy +/– allogeneic stem cell transplant:
• Common adult regimens: Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin (Adriamycin), dexamethasone)
- Chimeric antigen receptor (CAR) T cells: See treatment section. Target CD19 for B cell ALL
Chronic Leukemia Subtypes
Chronic myeloid leukemia (CML)
• Epidemiology: Common in older adults (median age 64 yr); risk factor = ionizing radiation
• Pathophysiology: Philadelphia chromosome: 9;22 chromosome translocation results in the fusion of BCR-ABL, which causes an activated tyrosine kinase
• Diagnosis: Elevated WBC, bone marrow biopsy to rule out AML/blast phase; quantitative PCR and FISH for BCR-ABL
• Clinical features:
- Chronic phase (<15% blasts): Most patients in the United States diagnosed in the chronic phase based on abnormal labs or mild symptoms (fatigue, early satiety due to hepatosplenomegaly). Tyrosine kinase inhibitors (TKIs) work well for this phase. Progression to advanced phase typically occurs after >5 yr of disease.
- Advanced phases: Accelerated phase (15–30% blasts), Blast crisis (>30% blasts – myeloid or lymphoid). These phases do not respond as well to TKIs; consider allogeneic stem cell transplant. Median survival without transplant is 6 months.
• Treatment: Tyrosine kinase inhibitors (TKIs). First approved was imatinib (Gleevec). Now multiple TKIs approved (i.e., dasatinib, nilotinib, bosutinib). Also consider allogeneic stem cell transplant if accelerated phase or blast crisis.
Chronic lymphocytic leukemia (CLL)
• Pathophysiology: Typically, elderly patients in 70s, M>F. Monoclonal proliferation of B cells (CD5/20+) that are mature but defective.
• Clinical features:
- Patients often asymptomatic (diagnosed incidentally on CBC) or they may have bulky painless lymphadenopathy, splenomegaly, respiratory or skin infection (from hypogammaglobulinemia – can’t make plasma cells)
- Richter transformation: CLL can transform into diffuse large B cell lymphoma
• Diagnosis: Elevated WBC, but kappa or lambda restricted – demonstrated on flow cytometry. Smear with smudge cells (fragile leukocytes that break on slide). If patients develop pancytopenia = poor prognosis.
• Treatment: Can often observe until progressive symptoms; targeted therapies are used when treatment is indicated (e.g., ibrutinib, venetoclax). Early vaccination is very important as these patients have progressive immunocompromise and most often die from infection.
Other Subtypes/Precursors of Leukemia
Hairy cell leukemia
• Pathophysiology: Rare, indolent B-cell leukemia. Median age of diagnosis 50–55 yr.
• Clinical features: Palpable splenomegaly, cytopenias, fatigue
• Diagnosis: Lymphocytes with fine, hair-like, irregular projections and +tartrate-resistant acid phosphatase (TRAP) stain. Bone marrow may become fibrotic – dry tap.
• Treatment: Cladribine
Myelodysplastic syndrome (MDS)
• Pathophysiology: Age >50 yr. Elderly marrow “fails.” Risk factors: Radiation, toxins (benzenes, alkylating agents). On spectrum of AML, but < 20% blasts. Can progress to AML, so requires monitoring.
• Clinical features: May be diagnosed incidentally on CBC or can lead to progressive anemia.
• Diagnosis:
- Myeloblasts in peripheral blood/marrow <20% and
- Dysplastic bone marrow (Pseudo-Pelger-Huet anomaly [Pince Nez], sideroblasts) and
- Anemia, thrombocytopenia
• Prognosis: Use IPSS-R scoring system (Greenberg et. al. Blood 2012). Based on blood counts, blast percentage, and cytogenetics. Correlates with survival and risk of AML progression, which can help in treatment selection.
• Treatment: Usually can monitor unless patients develop symptomatic anemia or thrombocytopenia (i.e., recurrent bleeding), or recurrent infections in the setting of ANC <500/μl
- Supportive care: Vitamin B6, B12, folate given high cell turnover. Transfuse pRBCs and platelets as needed.
- Low-intensity therapy: Hematopoietic growth factor (erythropoietin), hypomethylating agents (azacitidine or decitabine), lenalidomide if patients have an isolated deletion of chromosome 5 [del(5q)]
- High intensity therapy: Intensive combination chemotherapy + allogeneic stem cell transplant
Myeloproliferative Neoplasms
Clonal expansion of one or more myeloid lineage(s).
Polycythemia vera (PV)
• Pathophysiology: Median age of onset 60–65 yr. Abnormal hematopoietic stem cell (HSC) – constitutively active JAK2 receptor, cells proliferate without EPO stimulation:↑RBC, ↓EPO.
• Clinical features: 4 Hs:
- Hyperviscosity of blood: “Ruddy complexion,” headache, dizziness, blurry vision, thrombosis, DVT/PE, CVA, MI, hepatic or portal vein thrombosis
- Hypervolemia and hypertension
- Histamine: Pruritus particularly after bathing, peptic ulcers
- Hyperuricemia: ↑cell turnover, hepatosplenomegaly, gout
• Diagnosis: JAK2 mutation panel, consider bone marrow biopsy
- PV: ↑RBCs (Hct >50%, Hgb >16.5 g/dL in males and >16 g/dL in females), ↓Epo. Also may have ↑WBC, ↑platelets, ↑B12. Almost 100% of patients have a JAK2 mutation.
- Rule out secondary polycythemia: ↑RBCs ↑Epo (see section on polycythemia)
• Treatment: Repeated phlebotomy to lower Hct <45%, hydroxyurea, ASA, consider allopurinol if hyperuricemia; 2nd line ruxolitinib if patient has JAK2 mutation and is refractory to hydroxyurea. Must monitor for transformation to MDS/AML.
Essential thrombocythemia (ET)
• Pathophysiology: Overproduction of platelets by the megakaryocytes in the bone marrow. JAK2 mutation present in 40–50% of cases.
• Clinical features: Increased bleeding (from acquired vWF disorder) or thrombosis (CVA)
• Diagnosis: ↑Platelets (>450K/μl), leukocytosis may also be present. Rule out reactive thrombocytosis secondary to infection, inflammation, etc. Must not meet criteria for another myeloproliferative disorder (e.g., PV).
• Treatment: High risk patients (age >60 yr, >1 million plt/μl, history of thrombosis): Hydroxyurea and low-dose aspirin
Primary myelofibrosis
• Pathophysiology: Megakaryocytes make excess PDGF which causes bone marrow fibrosis. 50% of patients have a JAK2 mutation.
• Clinical features: Extramedullary hematopoiesis → splenomegaly (abdominal pain, early satiety), B symptoms. Risk of infection, thrombosis, bleeding.
• Diagnosis: ↓RBCs, +tear-drop–shaped erythrocytes. Bone marrow biopsy with reticulin or collagen fibrosis.
• Treatment: Hydroxyurea and ruxolitinib (JAK2 inhibitor). Allogeneic stem cell transplant indicated for patients <60 yr. Avoid splenectomy.