Acute Leukemias - Republican Scientific Medical Library

ALL Therapy: Review of the MD Anderson Program
S. Faderl, D.A. Thomas, Hagop M. Kantarjian
Contents
12.1 Introduction ................... 161
12.2 The Hyper-CVAD Regimen in Adult ALL 161
12.2.1 Development and Treatment
Outline .................. 161
12.2.2 Modifications of Hyper-CVAD . . . 162
12.3 Subset-Specific Approaches ....... 164
12.3.1 Ph-Positive ALL ............. 164
12.3.2 Mature B ALL (Burkitt Leukemia) 164
12.4 Summary ..................... 166
References ......................... 166
12.1 Introduction
Prognosis of adult ALL has improved over the last few
decades. Following the lead from the pediatric experience,
dose-intense multiagent regimens now achieve remission
rates exceeding 80% with 5-year survival probabilities
of around 40%. In addition, ALL is more and
more recognized as a heterogeneous group of diseases.
Definition of subgroups based on cytogenetic-molecular
markers has important practical implications including
better delineation of prognostic groups, design of
risk-adapted therapies, and eventually integration of
novel agents into existing therapies that target pathways
relevant for ALL pathophysiology. The hyper-CVAD
program is one example of a regimen that has been
successfully patterned after a previous pediatric regimen
and that has developed along advances based on
better understanding of ALL biology and availability
of new drugs with activity in ALL. This article
summarizes the rationale for the development of
hyper-CVAD, experience with this regimen in adult
ALL, and recent modifications and subtype-specific
approaches.
12.2 The Hyper-CVAD Regimen in Adult ALL
12.2.1 Development and Treatment Outline
To address the problem of poor prognosis in children
with mature B-cell ALL (Burkitt’s leukemia/lymphoma),
Murphy, et al. developed a short-term dose-intense chemotherapy
regimen that consisted of a combination of
fractionated cyclophosphamide, followed by vincristine
and adriamycin in combination with CNS prophylaxis
of intrathecal methotrexate and cytarabine [1]. Following
hematologic recovery, patients would receive a second
cycle, this time with a noncross-resistant combination
of high-dose intravenous methotrexate and cytarabine.
This sequence was repeated four times for a total
of eight courses. The rationale of the combination was
based on the cell cycle characteristics of the rapidly proliferating
mature B ALL cells. Given a generation time of
the ALL cells of about 25 h and a plasma half-life of cyclophosphamide
of around 6 h, fractionation of cyclophosphamide
every 12 h would indicate that the leukemic
blasts are exposed to the active metabolite at least
twice during their doubling time and thus exert a more
powerful effect than would be possible with once daily
dosing [2, 3]. Of 29 children treated, 27 (93%) achieved
complete remission (CR) with an estimated 2-year disease-free
survival of 81%. Although highly effective, sig-