Regimen: All Trial: MRC UKALL XII/ECOG E2993
Rowe JM et al. Blood 2005;106:3760–3767
Induction therapy
Induction—Phase 1 (weeks 1–4)
Daunorubicin 60 mg/m2 per dose; administer by intravenous injection over 3–5 minutes for 4 doses on days 1, 8, 15, and 22 (total dosage/4-week course = 240 mg/m2)
Vincristine 1.4 mg/m2 per dose; administer by intravenous injection over 1–2 minutes for 4 doses on days 1, 8, 15, and 22 (total dosage/4-week course = 5.6 mg/m2)
Prednisone 60 mg/m2 per day; administer orally, continually, for 28 consecutive days on days 1 to 28 (total dosage/4-week course = 1680 mg/m2)
Methotrexate 12.5 mg; administer intrathecally in 3–12 mL preservative-free 0.9% sodium chloride injection on day 15 (total dose/4-week course = 12.5 mg)
Asparaginase 10,000 IU/dose; administer intramuscularly, or intravenously in 10–50 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) for 12 consecutive days, on days 17 to 28 (total dose/4-week course = 120,000 IU)
Induction—Phase 2 (weeks 5–8)
(Regardless of whether residual leukemia is present at the end of phase 1)
Cyclophosphamide 650 mg/m2; administer intravenously in 100–1000 mL 0.9% NS or D5W over 15–60 min for 3 doses on days 1, 15, and 29 (total dosage/4-week course = 1950 mg/m2)
Cytarabine 75 mg/m2 per dose; administer intravenously in 25–250 mL 0.9% NS or D5W over 15–60 min for 16 doses on days 1–4, 8–11, 15–18, and 22–25 (total dosage/4-week course = 1200 mg/m2)
Mercaptopurine 60 mg/m2 per day; administer orally, continually, for 28 consecutive days on days 1 to 28 (total dosage/4-week course = 1680 mg/m2)
Methotrexate 12.5 mg per dose; administer intrathecally in 3–12 mL preservative-free 0.9% sodium chloride injection for 4 doses on days 1, 8, 15, and 22 (total dose/4-week course = 50 mg)
Notes: A diagnostic spinal tap was performed on all patients. If CNS leukemia was present at diagnosis, methotrexate was administered intrathecally via lumbar puncture or through a ventricular reservoir (eg, Ommaya) every week until blast cells were no longer present in the spinal fluid. In addition, 2400 cGy of cranial irradiation and 1200 cGy to the spinal cord were administered concurrently during induction, phase 2. For patients with CNS leukemia at presentation, intrathecal methotrexate was not administered during phase 2
Intensification therapy
Hydration for methotrexate: 6–18 hours before the anticipated start of methotrexate, start intravenous hydration containing sodium bicarbonate (NaHCO3) to alkalinize a patient's urine to pH ≥7.0, but ≤8.0, at a rate that achieves a urine output ≥100 mL/hour
Options recommended to initially produce an alkaline urine, include:
Notes: Urine alkalinization to pH ≥7.0 to ≤8.0 and urine output ≥100 mL/hour often initially require more NaHCO3 and more rapid hydration rates than will be required to maintain either or both parameters after they are achieved
The amount of sodium bicarbonate added to intravenously administered fluids should produce a solution with sodium content not greater than the concentration of sodium in 0.9% sodium chloride injection (≤154 mEq/L)
Methotrexate 3000 mg/m2; administer intravenously in one of the solutions identified above in admixture with 25–75 mEq NaHCO3 over 4 hours after urine pH ≥7.0 to ≤8.0 and urine output >100 mL/hour are confirmed for 3 doses on days 1, 8, and 22 (total dosage/course = 9000 mg/m2)
Temporarily interrupt hydration while methotrexate is administered
Order daily serum methotrexate levels timed to start 24 hours after methotrexate administration begins and continue daily measurements until the serum methotrexate level is ≤0.05 μmol/L
Continue hydration with urine alkalinization (pH ≥7.0 to ≤8.0) until serum methotrexate level is ≤0.05 μmol/L
Leucovorin calcium 100 mg/m2 per dose (preferred), or levoleucovorin calcium 50 mg/m2 per dose; administer intravenously in 25–250 mL 0.9% NS or D5W over 10–30 minutes every 6 hours starting 24 hours after methotrexate administration began, and continue for at least 6 doses or until serum methotrexate concentrations are ≤0.5 μmol/L, whichever occurs later
When the methotrexate level is <0.5 μmol/L, parenterally administered leucovorin or levoleucovorin may be replaced with leucovorin administered orally (10 mg/m2, or a fixed 25-mg dose for patients whose body surface area is <2.5 m2), until the serum methotrexate level is ≤0.05 μmol/L
Asparaginase 10,000 IU/dose; administer intramuscularly, or intravenously in 10–50 mL 0.9% NS or D5W intravenously or intramuscularly for 3 doses on days 2, 9, and 23 (total dose/course = 30,000 IU)
Consolidation therapy
Cytarabine 50 mg/dose; administer intrathecally in 3–12 mL preservative-free 0.9% sodium chloride injection weekly for 4 weeks, with:
Cranial irradiation 2400 cGy
Consolidation—Cycle 1
Cytarabine 75 mg/m2 per day; administer intravenously in 25–250 mL 0.9% NS or D5W over 15–60 minutes for 5 consecutive days on days 1–5 (total dosage/cycle = 375 mg/m2)
Etoposide 100 mg/m2 per day; administer intravenously in a volume of 0.9% NS or D5W sufficient to produce a concentration within the range, 0.2–0.4 mg/mL over at least 60 minutes for 5 consecutive days on days 1–5 (total dosage/cycle = 500 mg/m2)
Vincristine 1.4 mg/m2 per dose; administer intravenously over 1–2 minutes for 4 doses on days 1, 8, 15, and 22 (total dosage/cycle = 5.6 mg/m2)
Dexamethasone 10 mg/m2 per day; administer orally, continually, for 28 consecutive days on days 1 to 28 (total dosage/cycle = 280 mg/m2)
Consolidation—Cycle 2 (starts 4 weeks after cycle 1)
Cytarabine 75 mg/m2 per day; administer intravenously in 25–250 mL 0.9% NS or D5W over 15–60 minutes for 5 consecutive days on days 1–5 (total dosage/cycle = 375 mg/m2)
Etoposide 100 mg/m2 per day; administer intravenously in a volume of 0.9% NS or D5W sufficient to produce a concentration within the range, 0.2–0.4 mg/mL over at least 60 minutes for 5 consecutive days on days 1–5 (total dosage/cycle = 500 mg/m2)
Consolidation—Cycle 3 (starts 4 weeks after cycle 2)
Daunorubicin 25 mg/m2 per dose; administer by intravenous injection over 3–5 minutes for 4 doses on days 1, 8, 15, and 22 (total dosage/4-week course = 100 mg/m2)
Cyclophosphamide 650 mg/m2; administer intravenously in 100–1000 mL 0.9% NS or D5W over 15–60 min on day 29 (total dosage/4-week course = 650 mg/m2)
Cytarabine 75 mg/m2 per dose; administer intravenously in 25–250 mL 0.9% NS or D5W over 15–60 minutes for 8 doses on days 31–34 and 38–41 (total dosage/4-week course = 600 mg/m2)
Thioguanine 60 mg/m2 per day; administer orally, continually, for 14 consecutive days on days 29–42 (total dosage/4-week course = 840 mg/m2)
Consolidation—Cycle 4 (8 weeks after the conclusion of cycle 3)
Cytarabine 75 mg/m2 per day; administer intravenously in 25–250 mL 0.9% NS or D5W over 15–60 minutes for 5 consecutive days on days 1–5 (total dosage/cycle = 375 mg/m2)
Etoposide 100 mg/m2 per day; administer intravenously in a volume of 0.9% NS or D5W sufficient to produce a concentration within the range, 0.2–0.4 mg/mL over at least 60 minutes for 5 consecutive days on days 1–5 (total dosage/cycle = 500 mg/m2)
Maintenance therapy (continues for a total of 2.5 years after the start of intensification therapy)
Cytarabine 50 mg/dose; administer intrathecally in 3–12 mL preservative-free 0.9% sodium chloride injection on 4 occasions 3 months apart during maintenance therapy (total of 4 doses = 200 mg)
Vincristine 1.4 mg/m2; administer by intravenous injection over 1–2 minutes every 3 months (total dosage/3-month period = 1.4 mg/m2)
Prednisone 60 mg/m2; administer orally for 5 consecutive days every 3 months (total dosage/3-month period = 300 mg/m2)
Mercaptopurine 75 mg/m2; administer orally, continually each day (total dosage/week = 525 mg/m2)
Methotrexate 20 mg/m2; administer orally or intravenously once a week (total dosage/week = 20 mg/m2)
Supportive Care
Antiemetic Prophylaxis During Induction–Phase 1
Emetogenic potential on days 1, 8, and 15 is MODERATE
Emetogenic potential on days with asparaginase (days 17–28) is MINIMAL
Antiemetic Prophylaxis During Induction–Phase 2
Emetogenic potential on days with cyclophosphamide (days 1, 15, and 29) is MODERATE
Emetogenic potential on days with cytarabine without cyclophosphamide is LOW
Emetogenic potential on days with mercaptopurine alone is MINIMAL–LOW
Antiemetic Prophylaxis During Intensification
Emetogenic potential on days with methotrexate (days 1, 8, and 22) is MODERATE
Emetogenic potential on days with asparaginase (days 2, 9, and 23) is MINIMAL
Antiemetic Prophylaxis During Consolidation, Cycle 1
Emetogenic potential on days 1–5 is LOW
Emetogenic potential on days 8 and 15 is MINIMAL
Antiemetic Prophylaxis During Consolidation, Cycle 2
Emetogenic potential on days 1–5 is LOW
Antiemetic Prophylaxis During Consolidation, Cycle 3
Emetogenic potential on days 1, 8, 15, and 29 is MODERATE
Emetogenic potential on days with cytarabine is LOW
Emetogenic potential on days with thioguanine alone is LOW
Antiemetic Prophylaxis During Consolidation, Cycle 4
Emetogenic potential on days 1–5 is LOW
Antiemetic Prophylaxis During Maintenance
Emetogenic potential on days methotrexate is given is MINIMAL–LOW
Emetogenic potential all other days is MINIMAL
See Chapter 39 for antiemetic recommendations
Hematopoietic growth factor (CSF) prophylaxis
Primary prophylaxis is NOT indicated
See Chapter 43 for more information
Antimicrobial prophylaxis
Risk of fever and neutropenia is HIGH
Antimicrobial primary prophylaxis is recommended:
Antibacterial—consider fluoroquinolone prophylaxis; Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)
See Chapter 47 for more information
Monitoring Therapy
CBC with differential daily during and after chemotherapy until recovery of ANC >500/mm3. Platelets every day while in hospital until patient no longer requires platelet transfusions
Metabolic panel and uric acid, at least daily during active treatment until the risk of tumor lysis is past
Amylase and fibrinogen levels prior to asparaginase administration. If fibrinogen level is <100 mg/dL (<1 g/L) consider prophylactic administration of cryoprecipitate
Bone marrow aspirate and biopsy after phase 1 and phase 2 of induction therapy. After a patient achieves a CR, bone marrow biopsy and aspirate should be performed at the end of each consolidation cycle (or at the very least, every other cycle), and every 3 months during maintenance therapy
Notes: A diagnostic spinal tap was performed on all patients
If CNS leukemia was present at diagnosis, methotrexate administered intrathecally via lumbar puncture or through a ventricular reservoir (eg, Ommaya) was given weekly until blast cells were no longer present in the spinal fluid. In addition, 2400 cGy of cranial irradiation and 1200 cGy to the spinal cord were administered concurrently during phase 2. For patients with CNS leukemia at presentation, intrathecal methotrexate was not administered during phase 2
In a subsequent analysis (Fielding AK et al. Blood 2007;109:944–950) of the MRC UKALL XII/ECOG E2993 study, among 1372 patients with ALL who entered remission, 609 (44%) relapsed at a median of 11 months after the start of treatment. Most (556 [91%]) patients relapsed within the bone marrow, the sole site of relapse in most (90%) of those patients. A group of 45 (8%) patients relapsed solely at extramedullary sites
Most patients (81%) relapsed within 2 years after diagnosis, although a significant minority (19%) relapsed >2 years after diagnosis. Of the 440 chemotherapy-treated patients, 349 relapsed within 2 years after diagnosis, and 87 relapsed later. Those on chemotherapy who relapsed within 2 years can be considered “relapses on therapy” because the duration of therapy was set to be 18 months from the point of initiation of the consolidation therapy (ie, 23 months)
The median survival after relapse was 24 weeks. Survival at 1 year was 22% (95% CI = 18–25%), and 7% (95% CI = 4–9%) at 5 years. Only 42 of 609 patients who relapsed remain alive without further relapse
Factors predicting a good outcome after salvage therapy were young age (OS of 12% in patients <20 years vs. OS of 3% in patients >50 years; 2P <0.001) and short duration of first remission (CR1) (OS of 11% in those with a CR1 >2 years vs. OS of 5% in those with a CR1 <2 years; 2P <0.001). Patients treated with HSCT had a superior OS (15% [95% CI = 0–35%] for autograft [n = 13], 16% [95% CI = 7–26%] for matched unrelated donor transplantation [n = 65], and 23% [95% CI = 10–36%] for sibling allograft [n = 42]) to those receiving chemotherapy alone (n = 182) whose OS was only 4% (95% CI = 1–7%) at 5 years