Diagnosis and Clinical Management of Acute Myeloid Leukemia

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Diagnosis and Clinical Management of Acute Myeloid Leukemia Powered By Docstoc
					ACUTE MYELOID
  LEUKEMIA
                                            Initial Workup


   Clinical                               Laboratory            Bone Marrow
   H&P                                    CBC, CMP              Aspirate and core biopsy
   ECHO/MUGA scan                         DIC panel             Immunophenotyping (flow)
   2-lumen mediport                       HLA-typing, CMV       Cytogenetics
                                          serology – IgG, IgM
   CXR                                                          Ancillary Studies
                                          ( if< 70 y)
   EKG                                                          FISH MDS panel (≥ age 60)
                                          Lumbar puncture*
   BMT Consult (< age                                           PCR (<age 70)
   70)                                                              •FLT3-ITD
                                                                    •NPM-1
* LP should be preformed if patient is
  symptomatic or if peripheral WBC > 50K at diagnosis
                                                                    •C-kit (if CBF leukemia)
                                                                Database Flow Panel (TBD)
  If asymptomatic, LP should be deferred until WBC
  < 20K or CR1 to avoid peripheral blood contamination
      Acute Myeloid Leukemia – Acute Promyelocytic Leukemia (M3)
                                                                               Consolidation Therapy
                                                                                Consolidate with at least
                           TREATMENT                                            2 cycles of
                           INDUCTION                                            anthracycline-based
                                                                   Complete     (idarubicin or
                           All-trans-retinoic                      response     daunorubicin)
                           acid (ATRA) and        Assess marrow                 chemotherapy + 2 wk
                           anthracycline-based    morphology at                 ATRA with each cycle1
  CLASSIFICATION
                           (idarubicin or         count recovery
                           daunorubicin)          from start of
       M3 morphology                              induction
       and (+) for         chemotherapy1
       t(15;17) by                                                              Arsenic trioxide
                                                                   Induction
APL    either                                                      failure
                                                                                 or
       cytogenetics or                                                          Matched sibling or
                            Or
       molecular                                                                alternative donor HSCT
       testing; consider
                           ATRA + arsenic        Assess marrow     Complete     ATRA + arsenic
       possibility of M3
                           Trioxide for          morphology at     response     Trioxide x 6 cycles
       variant
                           patients unable to    count recovery
                           tolerate              from start of
                           anthracycline-        induction                       Clinical trial
                           based therapy2                          Induction     Or
                                                                   failure       Matched sibling or
                                                                                 alternative donor HSCT
                                                                                 Or
                                                                                 Gemtuzumab
                                                                                 ozogamicin3
     Acute Myeloid Leukemia – Acute Promyelocytic Leukemia (M3)
                         Post-Consolidation


                                                                   PCR
                          Maintenance therapy x                    negative
                          1-2 y with ATRA         Monitor by PCR
               PCR                                every 3 mo for                                  PCR
                          (category 1) +
               negative                           2y                                              negative
                          6-mercaptopurine +
Document                  methotrexate1
molecular                                                                       Repeat PCR for
                                                                   PCR
remission on                                                                    confirmation
                                                                   positive
bone marrow                                                                     within 4 wks
by PCR
                                                                                                  PCR
                                                                                                  positive
                                                                   PCR
                                                                   negative
               PCR                                Repeat PCR for
               positive                           confirmation
                                                  Within 4 wks
                                                                                           Follow algorithm
                                                                     PCR                     For relapsed
                                                                     positive                    APML
     Acute Myeloid Leukemia – Acute Promyelocytic Leukemia (M3)
                         Relapsed Disease
                                                                Autologous HSCT
                                                                Or
                                                                Arsenic consolidation
                                                                (total of 6 cycles)
                                                     PCR        (if not a transplant
                                                     negative   candidate)



                                     Second                     Matched or alternative
                                     Remission                  donor HSCT
                                     (morphologic)   PCR        Or
                                                     positive   Clinical Trial
            Arsenic trioxide4                                   Or
            Or                                                  Gemtuzumab orzogamicin3
First
Relapse     Gemtuzumab
            ozogamicin3
            (If early relapse post
            arsenic therapy)                                    Clinical trial
                                                                Or
                                      No remission              Matched or alternative
                                                                donor HSCT
                                                                Or
                                                                Gemtuzumab ozogamicin3
                     Acute Myeloid Leukemia:
                    Molecular Risk Categorization
RISK STATUS                       CYTOGENETICS5                           MOLECULAR MUTATIONS6

                                          Inv(16)
                                                                          Normal cytogenetics with isolated
   Better-risk                            t(8;21)
                                                                          NPM mutation
                                         t(16;16)
                                         Normal                           C-KIT in patients with t(8;21) or
                                         +8 only                          Inv(16)
Intermediate-risk                        t(9;11)
                    Other abnormalities not listed with better-risk and
                     poor-risk cytogenetics and molecular mutations



                             Complex (≥ 3 abnormalities)
                                                                          Normal cytogenetics with isolated
                                            -5
                                                                          FLT3 mutations6
                                            -7
                                           5q-
                                           7q-
    Poor-risk
                       Abnormalities of 11q 23, excluding t(9;11)
                                      Inversion 3
                                         t(3;3)
                                         t(6;9)
                                        t(9;22)
         Acute Myeloid Leukemia – Induction (<age 60)
CLASSIFICATION                            TREATMENT INDUCTION




                 No antecedent
                 hematologic          Cytarabine 200 mg/m² continuous
                                      infusion (Cl) x 7 days) + Idarubicin 12           See Post-induction
                 disease
                                      mg/m2 x 3 days)7                                  Therapy (< age 60)

 Age
< 60 y



                                     Clinical trial (incorporating either chemotherapy or low-intensity
                                     therapy
                 Antecedent
                 hematologic         Or
                 disease or
                 treatment-related   ≤30% blasts: Azacitidine 75 mg/m2 x 7 days q 4 weeks8
                 AML
                                     >30% blasts: SWOG Regimen9
                                                  Ara-C 3 g/m2 days 1-5
                                                  Daunorubicin 45 mg/m2 CIV days 6-8
                                                  CsA CIV days 6-8
                              Acute Myeloid Leukemia –
                              Post-Induction (<age 60)
                                                                                            Complete
                                                                                            Response
                   < 50% blast     Re-induction                        Marrow to
                   reduction       Cladribine                          document
                                   Cytarabine                          remission status
                                   G-CSF (CLAG)10                      upon
                                                                       hematologic
                                                                       recovery
Follow-up
bone marrow                                                                            Induction
                                                                                         failure
(day 12-16)
                   ≥ 50% blast
                   reduction           Repeat of induction
                   without                                                           Clinical trial
                                       (5 day or 7 day)                                    Or
                   hypoplasia*
                                                                                Matched sibling HSCT or
                                                                                alternative donor HSCT
                                                                                           Or
                                                                                 Best Supportive Care
              Hypoplasia               Await recovery
              (<5% blasts)*

  *Consider repeat bone marrow biopsy 1 week later for patients
  With minimal disease (i.e. < 20% blasts) at day 12-16 prior to re-induction
                  Acute Myeloid Leukemia –
                  Post-Remission (<age 60)
                                      High-dose cytarabine, 3 g/m over 3 h every 12 h on days 1, 3,
           Better-risk                 5 x 4 courses (OUTPATIENT)11
           molecular profile          Or
                                      1 to 2 cycles of high –dose cytarabine-based consolidation
                                       followed by autologous HSCT (OUTPATIENT)
                                      Or
                                      Clinical trial

                                      Matched sibling or autologous HSCT
           Intermediate-risk          or
Age < 60   molecular profile          High-dose cytarabine, 3 g/m over 3 h every 12 h on days 1, 3,
                                       5 x 4 courses11
                                      Or
                                      Clinical trial



                                      Clinical trial
           Antecedent
                                      Or
           hematologic
                                      Matched sibling HSCT
           Disease, treatment-
                                      Or
           related disease or poor-
           risk molecular profile     Alternative donor HSCT
                 Acute Myeloid Leukemia – Induction (age 60-75)
                                                                           Clinical trial (preferred)
                                                                           Or
                              Low-intensity therapy*
                                                                           Low-intensity therapy*
                              Or
              PS > 2                                                       Or
                              Best supportive care
                                                                           Best supportive care
                                                       Complex             OR
                                                       Cytogenetics        Standard-dose cytarabine (100
Age ≥ 60-75                                                                mg/m² Cl x 7 days) with
                              Obtain
                                                                           idarubicin (“7+3”)
                              cytogenetics prior
              PS ≤ 2          to treatment when
                              possible12               Non-complex
                                                       Cytogenetics        Clinical trial (preferred)
                                                                           Or
                                                                           “7+3”




                                                                           Clinical trial
                                                                           Or
  Age ≥ 75 or significant comorbidities
                                                                           Low-intensity therapy
    which cause organ dysfunction not
                                                                           Or
           directly related to leukemia
                                                                           Best supportive care



   * Low-intensity therapy may include: azacitidine8, decitabine13, hydroxyurea, low-dose cytarabine14
                              Acute Myeloid Leukemia –
                              Post-Induction (≥ age 60)
                                                                                               Complete
                                    Clinical Trial                                             Response
                                    OR
                   < 50% blast                                         Marrow to
                                    Re-induction
                   reduction                                           document
                                    Cladribine
                                                                       remission status
                                    Cytarabine
                                                                       upon
                                    G-CSF (CLAG)10
                                                                       hematologic
                                    OR
                                                                       recovery
Follow-up                           Best supportive care
bone marrow                                                                             Induction
                                                                                          failure
(day 12-16)
                   ≥ 50% blast
                   reduction            Repeat of induction
                   without                                                      Clinical trial or
                                        (5 day or 7 day)
                   hypoplasia*                                                  Reduced intensity HSCT
                                                                                in context of clinical trial
                                                                                or
                                                                                Best supportive care

              Hypoplasia               Await recovery
              (<5% blasts)*

  *Consider repeat bone marrow biopsy 1 week later for patients
  With minimal disease (i.e. < 20% blasts) at day 12-16 prior to re-induction
            Acute Myeloid Leukemia –
            Post-Remission (≥ age 60)

                       Clinical trial or


                       Reduced intensity HSCT
                       in context of clinical trial
                       or
Complete
Remission
                       Standard-dose cytarabine
                       (100 mg/m²/day x 5-7 d
                       x 1-2 cycles) ±
                       anthracycline (idarubicin
                       or daunorubicin) or


                       Consider cytarabine 1-1.5
                       g/m²/day x 4-6 doses x
                       1-2 cycles for patients
                       with good performance
                       status
                                Acute Myeloid Leukemia
                                   Relapsed Disease
                                                    Clinical trial (strongly preferred) or
                                       Early
                                                    Salvage chemotherapy (CLAG preferred)10 followed by
                                       ( < 6 mo)
                                                    Matched sibling HSCT or alternative donor HSCT, if
                   Age < 60                         donor previously identified

                                       Late
                                       (> 6 mo)     Clinical trial (strongly preferred) or
                                                    Salvage chemotherapy (CLAG preferred)10 followed by
                                                    Matched sibling HSCT or alternative donor HSCT, if
                                                    donor previously identified or
Relapse                                             Repeat initial successful induction regimen


                                       Early       Clinical trial (strongly preferred)
                                       ( < 6 mo)   Or Best supportive care
                                                   Or Gemtuzumab orzogamicin15


                  Age ≥ 60

                                                   Clinical trial (strongly preferred)
                                       Late        Or                                          Can
          If relapse into MDS state:   (> 6 mo)    Treatment with initial successful regimen   consider
                   Azacitdine                      Or                                          Allo-HSCT
                       OR                          Gemtuzumab ozogamicin15                     If 2nd CR
                   Decitabine                      Or                                          obtained
                                                   Best supportive care
                                       Acute Myeloid Leukemia
                                               CNS Leukemia
                                                                                       Observe and repeat LP if
                                                                      LP negative      symptoms persist

                                        Negative         Lumbar
                       CT/MRI to        Mass effect     puncture      LP positive      Intrathecal chemotherapy
 At diagnosis,         Rule out                                                        2x/wk until clear, then
 neurological          bleed or mass                                                   weekly x 4-6 wk
 symptoms              effect

                                        Positive mass
                                        effect or                                      Strongly consider RT
      Neuro-oncology                                        Consider needle            followed by intrathecal
       consultation                     increased
                                                            aspiration or biopsy       chemotherapy 2x/wk
                                        intracranial
                                        pressure                                       until clear, then weekly
                                                                                       x 4-6 wk



                                         LP negative                        Observe and repeat LP symptoms
First CR screening,                                                         present
no neurological         Lumbar
symptoms                puncture                                           Intrathecal chemotherapy 2x/wk until
                                         LP positive                       clear
                                                                           or
                                                                           If patient to receive high-dose
                                                                           cytarabine, follow-up with LP post
                                                                           completion of therapy to document
                                                                           clearance
                                      Acute Myeloid Leukemia
                                        SUPPORTIVE CARE (1 OF 4)

There are variations between institutions but the following issues are important to consider in the management of
patients with AML.
General

   Prophylactic antibiotics, including antifungals, are left to the discretion of the individual
   institutions.

   Growth factors may be considered in the elderly after chemotherapy is complete. Note that
   such use may confound interpretation of the bone marrow.

   Blood products:
        Leukocyte-depleted products used for transfusion
          Irradiated blood products for patients receiving immunosuppressive therapy
        (fludarabine, HSCT).
          Transfusion thresholds – RBCs for Hgb ≤ 8 g/dL or symptoms of anemia; platelets for
          platelets < 10,000/mcL or with any signs of bleeding16
          CMV screening of potential HSCT candidates may be considered.
          Tumor lysis prophylaxis: hydration with diuresis, and urine alkalinization and allopurinol.
          Clinical evidence of tumor lysis syndrome and problematic hyperuricemia or inability to
          tolerate oral medication: considerrasburicase.
                              Acute Myeloid Leukemia
                                 SUPPORTIVE CARE (2 OF 4)

Saline or steroid eye drops to both eyes four times daily for all patients undergoing high-
dose cytarabine therapy until 24 h post completion of cytarabine.

Screening LP for occult CNS disease is a consideration for remission patients who had initial
WBC > 50,000/mcL or monocytic histology.

 Patients receiving high dose cytarabine therapy (particularly those with impaired renal
function or patients > 60 years), are at risk for cerebellar toxicity. Neurologic assessments
including tests for nystagmus, slurred speech, and dysmetria should be performed before
each dose of cytarabine.
      In patients exhibiting rapidly rising creatinine due to tumor lysis, high-dose cytarabine
     should be discontinued until creatinine normalizes.
      In patients who develop cerebellar toxicity, cytarabine should be stopped. The patient
     should not be rechallenged with high dose cytarabine in future treatment cycles. (Smith
     GA, Damon LE, Rugo HS, et al. High-dose cytarabine dose modification reduces the
     incidence of neurotoxicity in patients with renal insufficiency.
     J Clin Oncol 1997;15(2):833-839.
                                  Acute Myeloid Leukemia
                                   SUPPORTIVE CARE (3 OF 4)

APL
  Clinical coagulopathy and overt bleeding:
       Management of clinical coagulopathy and overt bleeding: Aggressive platelet
       transfusion support to maintain platelets ≥ 50,000/mcL, fibrinogen replacement with
       cryoprecipitate and fresh frozen plasma to replace clotting factors. Monitor daily until
       coagulopathy resolves.
  APL differentiation syndrome:
       Maintain a high index of suspiciaon of APL differentiation syndrome (fever, often
       associated with increasing WBC > 10,000/mcL usually at initial diagnosis or relapse,
       shortness of breath, hypoxemia, pleural or pericardial effusions). Close monitoring of
       volume overload and pulmonary status is indicated. Initiate dexamethasone at first
       signs or symptoms of respiratory compromise (hypoxia, pulmonary infiltrates,
       pericardial or pleural effusions) (10 mg BID for 3-5 days with a taper over 2 wks).
       Consider interrupting ATRA therapy until hypoxia resolves.

  Patients with relapsed APL or with hyperleukocytosis after ATRA may be at increased risk of
  CNS disease. Prophylactic intrathecal therapy (IT) is being evaluated in this group.
                               Acute Myeloid Leukemia
                                   SUPPORTIVE CARE (4 OF 4)

Leukapheresis is not recommended in the routine management of patients with a high WBC
count in APL because of the difference in leukemia biology; however, in life threatening cases
with leukostasis that is not responsive to other modalities, leukapheresis can be considered
with caution.

Arsenic trioxide monitoring

     Prior to initiating therapy

           ECG for prolonged QTc interval assessment
           Serum electrolytes (Ca, K, Mg) and creatinine

     During therapy

           Maintain K concentrations above 4 mEq/dL
           Maintain Mg concentrations above 1.8 mg/dL
           Reassess patients with absolute QTc interval > 500 millisec
             (weekly during induction therapy and before each course of post-remission therapy)
1-16



                                                              Reference List

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   (2) Estey E, Garcia-Manero G, Ferrajoli A et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to
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   (3) Lo-Coco F, Cimino G, Breccia M et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute
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   (4) Soignet SL, Frankel SR, Douer D et al. United States Multicenter Study of Arsenic Trioxide in Relapsed Acute Promyelocytic
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   (5) Slovak ML, Kopecky KJ, Cassileth PA et al. Karyotypic analysis predicts outcome of preremission and postremission therapy
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   (7) Pautas C, Thomas X, Merabet F et al. Randomized Comparison of Standard Induction with Daunorubicin (DNR) for 3 Days vs
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   (8) Silverman LR, McKenzie DR, Peterson BL et al. Response Rates in Patients with Acute Myeloid Leukemia (AML), Treated
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(10) Wrzesien-Kus A, Robak T, Lech-Maranda E et al. A multicenter, open, non-comparative, phase II study of the combination of
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(11) Mayer RJ, Davis RB, Schiffer CA et al. Intensive Postremission Chemotherapy in Adults with Acute Myeloid-Leukemia. N
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(12) Farag SS, Archer KJ, Mrozek K et al. Pretreatment cytogenetics add to other prognostic factors predicting complete remission
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(13) Lubbert M, Ruter B, Claus R et al. Continued Low-Dose Decitabine (DAC) Is an Active First-Line Treatment in All
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(14) Burnett AK, Milligan D, Prentice AG et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans
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