THERAPY OF PREVIOUSLY UNTREATED ALL

(Excluding patients on ECOG or other experimental protocols, or those with Burkitt's-type ALL (B-ALL)

  1. Pre-Chemotherapy
    1. Bone marrow biopsy: All patients should have pre-treatment marrow biopsy
      1. Cytogenetic analysis (Waisman cytogenetics lab)
        1. Consider FISH for t(9;22) if cytogenetics normal
      2. Flow cytometry
      3. Save portion (frozen) for possible future molecular diagnostic or other testing (this will automatically happen if sample sent for flow cytometry)
      4. PCR for BCR-ABL if cytogenetics/FISH negative for t(9;22) (can be done on specimen saved by flow lab)
    2. HLA typing
    3. CMV typing for all patients who might be BMT candidate
    4. MUGA scan to assess cardiac function if
      1. Patient over 60
      2. Any history or clinical evidence of cardiac disease
      3. Not necessary to delay start of chemotherapy awaiting MUGA result unless there is clinical suspicion of heart disease
    5. Venous access
      1. Double lumen PICC or Hickman catheter
        1. If Hickman, attending physician should specify which staff surgeon to place catheter
      2. Give low molecular weight heparin @100 U/kg/12 if no contraindications
        1. First dose immediately after insertion if Hickman catheter, immediately before insertion if PICC line
        2. Continue for 48-72 hours
    6. Sterility/Fertility issues
      1. Menstruating females
        1. Pregnancy test on admission
        2. Oral contraceptive to suppress ovulation and minimize risk of sterility
        3. Luprolide acetate (depo) 3.75 mg im q month. Give iv estrogen or oral contraceptive first two weeks
        4. If im injections contraindicated because of low platelets: Nafarelin nasal spray is alternative to Luprolide
      2. Men: cryopreservation of sperm should be offered
  2. INDUCTION CHEMOTHERAPY: See chemotherapy protocols
  3. Prophylaxis and management of CNS leukemia
    1. Perform LP as early as possible unless there are contraindications (eg, DIC)
    2. Precautions:
      1. Platelets should be > 50K. Platelets should be running during LP if
        1. Patient is refractory to platelet transfusions
        2. Patient is platelet transfusion-dependent (repeat platelet count 12 hours after LP and consider repeat platelet transfusion if count <20K
        3. Use 22 gauge spinal needle if patient thrombocytopenic
        4. If patient has DIC defer if possible until coagulopathy resolves
        5. Patient should lie prone for at least an hour after LP
    3. CSF lab tests: collect three 1-2 ml tubes
      1. Tube 1: protein, glucose
      2. Tube 2: hold for gram stain and culture. Culture only if
        1. protein high or glucose low OR
        2. Clinical suspicion of meningitis OR
        3. Patient has Ommaya reservoir
      3. Tube 3: cell count, differential, cytospin. Flag tube "bone marrow lab, attention pathologist"
    4. CSF considered positive if any blasts are found (interpret with caution if there are circulating blasts)
    5. Intrathecal chemotherapy (consider giving 30 mg IT hydrocortisone each time)
      1. First LP (day 0 if possible): 70 mg IT ara-C
      2. Subsequent LPs: 12 mg IT methotrexate
    6. CNS treatment strategies:
      1. Prophylaxis (CSF negative)
        1. All patients receive IT chemotherapy per protocol
        2. Patients at high risk of CNS disease (LDH >600, T-ALL/lymphoblastic lymphoma) should be considered for cranial XRT
      2. Treatment (CSF positive)
        1. IT chemotherapy: repeat LP with IT chemotherapy every 2-4 days until CSF clear x 3 consecutive taps
        2. Monthly IT chemotherapy thereafter until maintenance chemotherapy begins, then q 3 mo (or until marrow/stem cell transplant)
        3. Radiotherapy:
          1. If patient not expected to have marrow/stem cell transplant, 24 Gy cranial XRT in 12 fractions over 14-16 days during phase 2 of chemotherapy
          2. If patient expected to have marrow/stem cell transplant, dose should be 12 Gy.
      3. CNS relapse: Treat CNS disease as above and begin re-induction chemotherapy, since CNS relapse heralds marrow relapse
  4. Patient management during induction phase
    1. Laboratory monitoring
      1. All standing orders reviewed at least weekly
      2. If evidence of or risk for tumor lysis:
        1. electrolytes, phosphate, creatinine, Ca++ q 12
        2. Uric acid, LDH q day
        3. Continue monitoring until stable and past period of maximal cell kill
      3. If evidence of DIC
        1. daily PT/INR, fibrinogen, 2-antiplasmin, D-dimer
        2. aPTT, antithrombin, plasminogen, fibrin monomer q 3days
        3. continue monitoring until DIC subsides and past period of maximal cell kill. Renew lab orders q 3days after first week.
      4. Transfusion management
        1. Hgb daily
        2. Daily platelet count when prior count <50,000; qod platelet count otherwise
        3. Platelet count 1 hour post transfusion of HLA-matched platelets or if poor response (<10K increase in count) to transfusion
      5. Monitoring response to treatment and marrow recovery:
        1. WBC > 1000 and falling: WBC and ANC (differential optional) qod after chemotherapy until WBC < 1000
        2. WBC 400-1000: WBC and ANC and scan for blasts (no differential) q day
        3. WBC <400: WBC q day, ANC q 2-3 days
        4. WBC rising: WBC and ANC qd (differential optional) until ANC > 1000
        5. Fluid and electrolyte management:
          1. Electrolytes, creatinine, Mg, glucose daily
          2. LDH, AST, alk phos, GGT, total bilirubin, albumin, Ca++ phosphate q 3-4 days
          3. PA/lateral CXR (in radiology dept, not bedside) at least weekly when ANC < 500.
      6. Transfusions
        1. All blood products irradiated and filtered
        2. Patients < 60 years get CMV-negative products unless they are known to be CMV antibody-positive or they are not a candidate for marrow/stem cell transplant
        3. RBC transfusions to keep Hgb >8.5
          1. may transfuse to higher level for symptoms of anemia or comorbid anemia
        4. Platelets: 1U/10kg/day (maximum 6 units) random donor platelets OR one pack of single donor/HLA matched platelets if:
          1. platelet count < 10K
          2. platelet count 30-50K plus
            1. active bleeding
            2. invasive procedure (including LP)
            3. history of significant bleeding at similar platelet count
            4. sepsis or DIC
  5. ASSESSMENT OF RESPONSE: Post-treatment marrow aspirates/biopsies on days 14 and 28 (first day of treatment = day 0; indicate when chemo started on bone marrow lab form). Subsequent treatment is based on results of day 28 bone marrow:

  6.  
    1. M1: > 95% cell kill, no evidence of leukemia.
      1. Add cytogenetic/FISH/PCR analysis if this abnormal pre-treatment
      2. Proceed to consolidation or marrow/stem cell transplant
    2. M2: 75%-95% cell kill (partial response): Repeat induction cycle or consider options for refractory disease
    3. M3: < 75% cell kill (refractory disease): see options for refractory disease
    4. If marrow result equivocal (hypocellular, regeneration vs persistent disease): Repeat marrow q 2 weeks until classifiable as M1-3
  1. Risk stratification
    1. Low risk - must have all of the following characteristics:
      1. Age < 30
      2. Presenting WBC < 30K
      3. Day 28 marrow M1 (>95% cell kill, no evidence of leukemia)
      4. Absence of unfavorable cytogenetic type
      5. CD 10 positive
    2. Intermediate risk
      1. Does not meet criteria for low risk
      2. Absence of unfavorable cytogenetic type
      3. CD10 negative
    3. High risk - any of the following present:
      1. Unfavorable cytogenetic marker: t(9;22) (or BCR-ABL found by PCR); any translocation involving 11q23; multiple cytogenetic abnormalities
      2. Day 28 marrow showing persistent leukemia.
  2. Post induction treatment is based on risk category
    1. Low risk: Chemotherapy, e.g. BFM protocol or comparable regimen
    2. Intermediate risk
      1. Patient < 50 years and no comorbid factors that mitigate against using more aggressive treatment: Augmented BFM or comparable regimen (physician choice)
      2. Patient > 50 or comorbid disease: standard chemotherapy, e.g., BFM or other regimen at discretion of attending physician
      3. If patient meets age criteria and has suitable donor: consider allogeneic BMT or stem cell transplant
    3. High risk
      1. Patient meets age criteria with suitable related donor: Allogeneic matched BMT/SCT in first remission
      2. Patient meets age criteria, no suitable related donor: matched unrelated donor BMT/SCT if suitable donor found
      3. If no marrow donor available, patient < 50 without comorbid disease: Augmented BFM or comparable chemotherapy
      4. No marrow donor, age or comorbid disease rule out augmented BFM: Standard BFM, clinical trial, or other/experimental regimen at attending's discretion

Reviewed September 2008