TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA (AML M3; APML)
  1. Pre-induction
    1. Bone marrow aspirate and biopsy
      1. Cytogenetics
      2. PCR analysis for PML/RAR- transcript
      3. Flow cytometry: CD13 expression
    2. Laboratory tests
      1. CBC, differential, platelets
      2. Electrolytes, Ca, Mg, PO4, BUN, Creat, uric acid, LDH, liver panel, glucose
      3. HLA typing
      4. Coagulation
    3. Triple lumen Hickman catheter
    4. MUGA scan for patients > 60 yrs or with prior cardiac hx
    5. If WBC > 50K, treat with hydroxyurea 6-8 gm/day until WBC < 50K
    6. IV hydration, maintain urine output > 75 cc/hr
    7. Allopurinol 300 mg/day until WBC < 1K
    8. Baseline weight, monitor on same scale while on ATRA
    9. Chest X-ray (2 views, in radiology dept)
  2. Induction therapy: See chemotherapy protocols
  3. ATRA syndrome
    1. Diagnosis: consider when
      1. Unexplained fever
      2. Weight gain
      3. Serous effusions (pleural, pericardial)
      4. Peripheral edema
      5. Hypotension/orthostasis
      6. Rapidly increasing WBC
    2. When diagnosis made:
      1. Stop ATRA
      2. Give dexamethasone 10 mg iv b.i.d.
    3. When signs/symptoms disappear:
      1. Resume ATRA at 75% of initial dose. Discontinue dexamethasone.
      2. If symptoms do not recur, increase to full dose after 3-5 days
  4. Management of Coagulopathy
    1. Clinical and laboratory assessment
      1. History and Physical: document incidence and sites of bleeding (e.g., gingival bleeding, oozing from venipuncture sites, hematuria, location/size of ecchymoses, skin necrosis)
      2. Initial laboratory studies (in addition to usual tests): PT/INR, aPTT, fibrinogen, antithrombin, plasminogen, alpha2-antiplasmin, D-dimer, stool hemoccult, urinalysis, 12 hour creatinine clearance
      3. Laboratory monitoring
        1. Daily platelet count, INR, aPTT, fibrinogen, D-dimer
          1. INR q 8 hours when > 1.6 (see below)
          2. Fibrinogen q 8 hours when < 75 mg/dl
        2. Alpha2-antiplasmin, antithrombin daily for first week, then q 2-3 days
        3. Continue monitoring until coagulopathy has resolved:
          1. INR < 1.6 without FFP
          2. Fibrinogen > 150 without FFP or cryoprecipitate
          3. Alpha2-antiplasmin > 75% without FFP or Amicar
        4. Once coagulopathy has resolved, check INR, aPTT, fibrinogen, D-dimer and alpha2-antiplasmin weekly until patient is in hematologic complete remission
        5. Please inform special coagulation lab (3-5005) in advance when testing will be required on weekends.
    2. Treatment
      1. Heparin: loading dose of 2500 U/hr, followed by continuous infusion of 500 units per hour, started before initiation of cytotoxic chemotherapy. Continue until coagulopathy has resolved as defined above
      2. Vitamin K, 10 mg sq twice weekly
      3. If INR > 1.6, give 2 units FFP q 8 hours
      4. If fibrinogen < 75 mg/dl, give cryoprecipitate 1 bag/10 kg/8 hours
      5. If alpha2-antiplasmin <50%, begin epsilon amino caproic acid (Amicar)
        1. Loading dose = 6 grams i.v.
        2. Continuous i.v. infusion, 1 gram/hour
        3. Continue heparin, can mix heparin and amicar in same iv bag
        4. Continue Amicar until alpha2-antiplasmin > 50% for at least two days
      6. Contact person: Dr. Eliot Williams beeper 3472, 2-5327, home 831-3308
  5. Assessment of response
    1. Definitions:
      1. Hematologic remission
        1. ANC > 1000, platelets > 100K
        2. Marrow > 20% cellular
        3. Marrow promyelocytes < 5%, no Auer rods
        4. Normal coagulation profile
      2. Molecular remission: absence of PML/RAR- transcript by PCR
    2. Bone marrow aspirate & biopsy with PCR analysis on day 28
    3. If not in hematologic remission:
      1. Continue ATRA
      2. Repeat marrow every 2 weeks until hematologic remission or to maximum of 90 days
    4. If in hematologic and molecular remission:
      1. Proceed with consolidation therapy
      2. Repeat marrow and PCR after 3rd course of consolidation
    5. If in hematologic remission but PCR positive for PML/RAR- transcript:
      1. Proceed with consolidation therapy
      2. Repeat marrow with PCR after each course of consolidation therapy until PCR is negative
    6. If not in molecular remission after 3rd course of consolidation therapy, consider allogeneic BMT for eligible patients
    7. If in molecular remission after 3rd course of consolidation therapy, repeat marrow with PCR every 3 months for 1 year, then every 6 months for 2 years

 
 

REFERENCES

1. Vahdat et al. Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PML-RA isoform, and CD-13 expression in patients treated with all-trans-retinoic acid. Blood 1994;84:3843-9.

2. Degos et al. All-trans-retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia. Blood 1995;85:2643-53

3. Anderlini et al. Idarubicin cardiotoxicity: a retrospective study in acute myeloid leukemia and myelodysplasia. J Clin Oncol 1995;13:2827-34

4. Tallman et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997;337:1021-8

5. Mandelli et al. Molecular remission in PML-RA-positive acute promyelocytic leukemia by combined all-trans-retinoic acid and idarubicin (AIDA) therapy. Blood 1997;90:1014-21

6. Head et al. Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia. Blood 1995;86:1717-28

7. Schwartz et al. Epsilon-aminocaproic acid in the treatment of patients with acute promyelocytic leukemia and acquired alpha-2 plasmin inhibitor deficiency. Ann Intern Med 1986; 105:873
 
 

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Reviewed September 2008