Chronic Leukemias

  • Differences in the etiology, pathophysiology and prognostic factors of chronic leukemias
    • Chronic myelogenous leukemia (CML)
      • Proliferative disorder of the hematological stem cells due to a chromosomal abnormality
      • Mainly occurs in mid-aged adults (~67), incidence increases with age
      • Risk factors:  ionizing radiation, exposure to benzene, atomic bomb survivors
      • s/s: no symptoms in early CML but chronic fatigue, unexplained weight loss, fever, SOB, night sweats, abdominal pain, poor appetite are common as the disease progresses
      • Diagnosis:  leukocytosis (WBC > 100,000), anemia, thrombocytopenia, presence of blasts, presence of Ph chromosome
      • Poor prognostic factors:  old age, splenomegaly, high platelet count, high % of circulating blasts
    • Chronic lymphocytic leukemia (CLL)
      • Proliferative disorder of the hematological stem cells
      • Indolent disease
      • Most common in the elderly & although risk factors are unknown, familial factors are thought to play a role
      • s/s:  fatigue, fever, chronic infections, lymphadenopathy, spleen or liver enlargement, palpable intra-abdominal nodes
      • Lab findings:  high # of mature looking small lymphocytes, abnormal karyotypes, thrombocytopenia
  • Pathogenesis of CML, the role of bcr-abl and Philadelphia chromosome.
    • Philadelphia chromosome (Ph) is a unique abnormality found in CML patients
      • Involves the translocation of chromosomes 9 & 22
        • t (9;22)
        • This chromosome contains the fusion gene Abelson & Breakpoint cluster (bcr-abl)
          • This bcr-abl gene codes for a tyrosine kinase (increases proliferation, affects differentiation & blocks apoptosis) & escapes normal genetic control
          • This gene ultimately results in the accumulation of cloned cells with a Ph abnormality
    • The goal of CML treatment is to cure patients by eradicating the Ph chromosome
      • Hematological response:  normalization of peripheral blood count
      • Cytogenetic response (elimination of Ph cells)
      • Molecular response (absence of bcr-abl gene) by RT-PCR
  • Primary treatment strategies for each stage of CML and CLL, making sure the various drugs used in each disease state are identified and understanding how they work
    • CML
      • Hydroxyurea is used to reduce the high # of circulating WBC (no effect on survival though)
      • Chronic & accelerated phase:  imatinib mesylate, dasatinib, nilotinib
        • Imatinib is a tyrosine kinase inhibitor & is first line therapy for CML
          • Responses should be seen as CHR (3 months) & CCR (9-12 months)
          • Chronic dose = 400 mg/day
          • Monitoring:  RT-PCR every 3 months; BM every 6-12 months
          • SE:  myelosuppression, rash, GI SE, edema, arthralgias & myalgias, HA, rare cardiotoxicity/CHF
          • Take this medication w/ food & water
          • Metabolized by CYP3A4
          • Need to stress that interruptions in taking this drug will have a negative impact on outcomes, need to monitor adherence.
        • Dasatinib & Nilotinib are 2nd generation tyrosine kinase inhibitors that are also indicated as first line for chronic phase, accelerated & blast crisis
          • They help to overcome bcr-abl mutations
          • SE:  myelosuppression, n/v, edema, pleural effusions (dasatinib), bleeding (dasatinib), QT prolongation (nilotinib)
          • Both of these drugs are metabolized by CYP3A4
          • Don’t take dasatinib with PPIs or H2 blockers
          • Take nilotinib on an empty stomach
          • Pregnancy isn’t recommended with any tyrosine kinase inhibitor
      • Blast crisis: acute leukemia-like therapy, clinical trials
        • Much lower remission response to imatinib
    • CLL
      • CLL is an indolent disease so the goal is to reduce tumor burden & improve QOL
        • Can try the watch & wait approach & then start chemo if symptoms develop or can just start chemo immediately
      • Who to treat:  Patients who are at high risk, have depleted 17p (poor responders to chemo), progressive disease (autoimmune complications, symptomatic splenomegaly, bulky lymph nodes, severe lymphocytosis), & young patients
        • Treatment: Ppl < 70 should receive FCR (fludarabine + cyclophosphamide + rituximab)
          • If this doesn’t work you can try chlorambucil +/- prednisone
            • Easy to use, limited SE (good for ppl > 70)
          • Fludarabine alone is extremely immunosuppressive, better in younger patients
          • Bendamustine is an alkylating agent that’s an alternative therapy
          • Rituximab targets CD20+ cells, use higher doses than were used in Non-HL, best when used in combo with fludarabine
            • SE:  infusion-like reactions
          • Alemtuzumab targets CD52+ cells,
            • SE:  prolonged immunosuppression, infusion-like reactions, CMV reactivation
          • Ofatumumab targets CD20+ cells & is used in patients refractory to fludarabine & alemtuzumab
          • Lenalidomide is an antiangiogenesis agent used for relapsed disease
      • Supportive care:
        • Risk of infections: HSV, PCP, CMV (alemtuzumab), may need to admin IV IG
        • Vaccinations:  influenza annually, pneumococcal every 5 years, avoid live vaccines (including the zoster vaccine)
      • Stem cell transplant (allogenic preferred over autologous)
        • May be helpful in younger patients
        • Not considered curative however
  • Expected outcomes (including overall and disease-free survival) based on stage, treatment and risk factors
    • Interferon-alfa & cytarabine are alternative therapies for CML patients who’ve failed on TKIs but are generally less effective than TKIs
      • Better to use these drugs in combo with one another
      • SE:  flu-like symptoms, myalgias, arthralgias, depression
      • IFN is an immunomodulatory drug
    • Allogenic stem cell transplantation is the only cure for CML
      • Higher risk of mortality in comparison to standard treatment (TKIs)
        • Usually used if TKIs fail or there’s a mutation that makes the cancer resistant to TKIs

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