Acute Leukemias - Republican Scientific Medical Library

162 Chapter 12 · ALL Therapy: Review of the MD Anderson Program
nificant myelosuppression-associated morbidity, as well
as renal and neurotoxic complications occurred. Use of
hematopoietic growth factor support and additional
supportive care measures ameliorated some of these
problems and made the regimen adaptable to adult
ALL patients.
The Hyper-CVAD regimen follows the principles
common to other contemporary adult ALL programs:
(1) dose-intense systemic chemotherapy to induce remission
quickly followed by an intensified consolidation;
(2) prolonged maintenance therapy; (3) effective
CNS prophylaxis; and (4) accompanying supportive
care measures including hematopoietic growth factors
and prophylactic antibiotics [4]. Dose and schedule of
hyper-CVAD are summarized in Table 12.1. CNS prophylaxis
consists of intrathecal (IT) therapy with alternating
methotrexate and cytarabine, the number of IT injections
depending on the risk of CNS relapse. Mature
B-cell ALL, serum lactate dehydrogenase (LDH) levels,
and a high proportion of bone marrow cells in a proliferative
state (>14% of cells in S+G2M phase of the cell
cycle) have been associated with a higher risk of CNS
disease in adults. Those patients with low-risk of CNS
disease receive four intrathecal treatments (two IT injections
per treatment cycle), those with intermediate
risk eight, and those with high-risk disease 16 intrathecal
treatments including all patients with mature B-cell
ALL.
Maintenance consists of daily 6-mercaptopurine,
weekly methotrexate, and monthly pulses of vincristine
and prednisone, given over 2–3 years (POMP). Extension
of maintenance beyond 3 years has not shown additional
benefits, whereas omission of maintenance
therapy has been associated with shorter DFS rates [5,
6]. No maintenance therapy is given in mature B-cell
ALL; these patients respond well to short-term dose-intense
regimens, and relapses beyond the first year in remission
are rare. Patients with most other immunophenotypes
continue to receive standard POMP maintenance.
Differences of current programs for patients with
Philadelphia chromosome-positive ALL are outlined in
more detail below.
Accompanying supportive care measures include
antibiotic prophylaxis and hematopoietic growth factor
support. Granulocyte colony-stimulating factor (G-CSF)
is administered at 10 mcg/kg/day starting 24 h following
completion of chemotherapy and is continued until
neutrophil recovery to at least 1 ´10 9 /L. Antibiotic prophylaxis
during induction and intensified consolidation
consists of a combination of fluoroquinolones, antifungals,
and antivirals, and is changed to trimethoprimsulfamethoxazole
and an antiviral drug (e.g., valacyclovir,
famciclovir, acyclovir) during maintenance.
Outcome of hyper-CVAD has been reported on 204
adults with newly diagnosed ALL [7]. Median age was
39.5 years and about one third of patients were at least
50 years old. Mature B-cell ALL was diagnosed in 9%
and T-cell ALL in 17%. Philadelphia chromosome
(Ph)-positive ALL occurred in 16% of patients. CNS disease
was demonstrated at the time of diagnosis in 7%.
Of 204 patients, 185 (91%) achieved CR. Seven patients
(3%) had resistant disease and 12 patients (6%) died
during induction. The median time to CR was 21 days
with 81% of patients achieving CR following the first
course. The estimated median survival was 35 months
with a 5-year estimated survival rate of 39%. Younger
age was associated with a better outcome: 54% estimated
5-year survival for patients younger than 30 years
and 25% for those older than 60 years. Other factors
that correlated with poor outcome included Ph-positive
disease, thrombocytopenia, hepatomegaly, hyperbilirubinemia,
and hypoalbuminemia. Compared with the
earlier and less intense VAD (vincristine, adriamycin,
dexamethasone) program, CR rate (91% vs. 75%,
p>0.01) and survival (p > 0.01) have been superior with
hyper-CVAD. Hyper-CVAD has thus been established as
an active induction regimen in adult ALL demonstrating
superior outcome to previous regimens used at
MDACC [8].
12.2.2 Modifications of Hyper-CVAD
A number of issues emerged related to Hyper-CVAD,
which were addressed in subsequent modifications of
the regimen. These issues included the still higher induction
mortality in patients over age 60 years (17%
vs. 3% in younger patients), reports that suggested longer
disease-free survival with early anthracycline intensification
[9], expression of CD20 and impact on outcome,
differing CNS relapse rates between low and high
risk patients, and occurrence of late relapses following
completion of therapy.
To respond to the higher induction mortality in older
patients, patients over age 60 are offered to undergo
the induction course in a laminar airflow room in which
they will remain for the duration of the induction
(which is typically about 21 days). CNS prophylaxis re-