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CML

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Chronic Myelogenous Leukemia

ASH 2001: abstract 3511

Combination STI-571 + Ara-C is safe
MTD: Imatinib 400 mg QD & ara-c 20 mg/m2 days 15-28.


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CHRONIC PHASE
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INTERFERON

r alpha 2bIFN at 5 x 10(6)IU/m2 subcutaneously QD

N Engl J Med 330(2):820, 1994
J Natl Cancer Inst; 89(21):1616-20 1997
Blood; 82(10):2975-84 1993
Ann Intern Med; 122(4):254-61 1995
Blood; 92(5):1541-8 1998

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INTERFERON + CYTARABIN

INTERFERON alfa-2b 5 million units per square meter of body-surface area per day
CYTARABINE 20 mg/m2 per day X 10 days Q month

3-year survival rate was 85.7% with interferon+cytarabine & 79.1% with interferon alone. The rate of hematologic response was higher in the interferon-cytarabine group than in the interferon group (P = 0.003). Major cytogenetic responses were observed 12 months after randomization in 126 of 311 patients treated with interferon+cytarabine (41%) & in 75 of 314 patients treated with interferon only (24%, P<0.001).
Ref:Guilhot F, et al. New England Journal of Medicine 337(4): 223-229, 1997.

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HYDROXYUREA

Hydroxyurea 1-3 grams /day as a single dose on an empty stomach.

Hydroxyurea is superior to busulfan in the chronic phase of CML, with significantly longer median survival & significantly fewer severe adverse effects.
The median survival of the busulfan treated Philadelphia-positive patients is 45.4 months and of the hydroxyurea group 58.2 months (P = .008).

Ref: Hehlmann R et al. Blood; 82(2):398-407 1993

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BUSULFAN

Busulfan (Myleran), ---rarely used---, is given PO, either daily 4-8 milligrams per day or in 2-week courses.
A dose of 0.1 milligrams/kg/day is often used initially. The dose is halved as the WBC count drops by one half and is discontinued when the WBC count drops below 20,000.

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Splenectomy may be required and useful in patients having hematologic problems and physical discomfort from a massive spleen.

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ACCELERATED PHASE
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Daunorubicin 120 mg/m2 IV on DAY 1,
Cytarabine (ara-C) 1.5 g/m2/d CI over 24 hours for 4 days, Solu-Medrol (methylprednisolone) 100 mg/d for 5 days,

Followed on day 5 by GM-CSF 125 micrograms/m2/d over 6 hours until recovery of granulocyte count above 2.0 x 10(3)/microliters
Kantarjian HM, et al. J Clin Oncol; 10(3):398-405 1992

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BLAST PHASE
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Daunorubicin 120 mg/m2 IV on DAY 1,
Cytarabine (ara-C) 1.5 g/m2/d CI over 24 hours for 4 days, Solu-Medrol (methylprednisolone) 100 mg/d for 5 days,

Followed on day 5 by GM-CSF 125 micrograms/m2/d over 6 hours until recovery of granulocyte count above 2.0 x 10(3)/microliters
Kantarjian HM, et al. J Clin Oncol; 10(3):398-405 1992

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MITOXANTRONE + HIGH-DOSE ARAC


Mitoxantrone 5 mg/m2 intravenously daily for 5 days, Cytosine arabinoside 3 g/m2 IV over 2 hours every 12 hours for six doses

26% achieved complete remission, and one 4% had a partial remission for an overall response rate of 30%. The median survival was 14 weeks for the total population, and 24 weeks for patients achieving a complete remission.

Kantarjian HM et al. Cancer; 62(4):672-6 1988
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MITOXANTRONE + AZACYTIDINE

mitoxantrone, 12 mg/m2 per day for three days and 5-azacytidine 150 mg/m2 per day for 5 days

overall response rate:23%, including five complete responders, two partial responders, & two with hematologic improvement.

Dutcher JP, et al. Phase II study of mitoxantrone and 5-azacytidine for accelerated and blast crisis of chronic myelogenous leukemia: a study of the Eastern Cooperative Oncology Group. Leukemia; 6(8):770-5 1992
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*** For Philadelphia-Chromosome-positive (Ph-positive) acute lymphocytic leukemia (ALL) blast phase:

Vincristine 0.4 mg CIV X 4 days;
Doxorubicin 12 mg/m2 CIV X 4 days;
Decadron 40 mg QD on DAYS 1-4, 9-12, & 17-20 (VAD).

Course 2 was given starting on day 24 with the addition of cyclophosphamide 1 g/m2.


9 patients achieved CR (30%) and 3 attained a PR (10%), for an overall RR of 40%
Walters RS et al. Cancer; 60(8):1708-12 1987
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All patients younger than 60 years of age with an identical twin or with HLA-identical siblings should be considered for bone marrow transplantation (BMT) early in the chronic phase.

A meta-analysis of 7 trials that randomized patients to receive interferon or conventional chemotherapy(hydroxyurea
or busulfan) demonstrated a 30% reduction in the annual death rate for patients who received interferon (P<.00001). The annual death rate was reduced by 26% in the trials of interferon versus hydroxyurea (P=.001)and 36% in the trials of interferon versus busulfan (P=.00007). Median
survival was prolonged by 1 to 2 years; 5-year survival rate was 57% for patients treated with interferon, and 42% for patients treated with chemotherapy (P<.00001). Further analysis of the 2 trials included a 3-way randomization between interferon, hydroxyurea, and busulfan and
showed hydroxyurea to be superior to busulfan, decreasing the proportional odds of death by 24% (P=.02).

Chronic phase
Chronic phase: bone marrow and cytogenetic findings as described above with less than 5% blasts and promyelocytes in the peripheral blood and bone marrow.

Accelerated phase
Accelerated phase: greater than 5% in either the peripheral blood or bone marrow but less than 30% blasts in both the peripheral blood and bone marrow.

Blastic phase
Blastic phase: greater than 30% blasts in the peripheral blood or bone marrow.

When greater than 30% blasts are present in the face of fever, malaise, and progressive splenomegaly, the patient has entered blast crisis, and survival is on the order of a few months.