Acute Leukemias - Republican Scientific Medical Library

164 Chapter 12 · ALL Therapy: Review of the MD Anderson Program
Table 12.2. Modifications of hyper-CVAD
Rationale Modification
Worse prognosis of CD20-positive ALL than Addition of rituximab to hyper-CVAD in CD20-positive patients
CD20-negative disease
Anthracycline intensification reported to be Anthracycline intensification following induction course
associated with better DFS
Ph-positive ALL continues to have poor
Addition of imatinib to hyper-CVAD and change of maintenance based on
prognosis
continuous exposure to imatinib
Late relapses following completion of therapy Extension of maintenance from 2 to 3 years with 2 additional courses of
hyper-CVAD plus MTX/L-asparaginase on months 6 and 18 of maintenance
CNS prophylaxis Number of IT injections was changed from 4 for low-risk and 8 for standard-risk
patients to 6 IT injections for both groups. High-risk patients
receive 8 injections and patients with mature B ALL a total of 16
Improvement of supportive care Routine use of antibiotic prophylaxis and hematopoietic growth factors.
In addition, laminar airflow rooms for patients ³ 60 years
In a recent update, 77 patients with newly diagnosed
or primary refractory (after one course only) ALL were
treated with the modified regimen [11]. Patients with
mature B ALL were excluded. Their median age was
40 years with > 20% aged ³60 years. Overall response
rate was 98%. Mortality remained higher in patients
³60 years (6/18) compared to younger patients (2/59).
With a median follow up of 17 months, the 2-year DFS
rate was 50% overall, and 73% vs. 40% for CD20-positive
and CD20-negative ALL, respectively. Although anthracycline
intensification did not appear to improve
outcome, addition of rituximab in CD20-positive patients
may have a favorable impact on prognosis. Longer
follow up and more patients are needed to validate this
observation.
12.3 Subset-Specific Approaches
Based on cytogenetic-molecular markers and immunophenotypic
features, specific approaches are pursued in
ALL subsets such as Ph-positive disease and mature B
ALL. A summary of a subtype-specific treatment algorithm
is presented in Fig. 12.1.
12.3.1 Ph-Positive ALL
Ph-positive ALL remains a distinct poor-prognosis
group in ALL [12]. Although remission rates following
a standard hyper-CVAD induction are comparable to
Ph-negative patients, remissions are brief with median
CR durations of 16 months [13]. Imatinib mesylate, a
highly active BCR-ABL tyrosine kinase inhibitor, has
shown encouraging results in Ph-positive ALL where
the response rate was 20% when given as single agent
in patients with relapsed and refractory disease [14].
Over the last few years, several combination programs
of imatinib with dose-intensive chemotherapy to increase
response rates and improve durability of responses
in Ph-positive ALL have been investigated
[15–19]. Thomas, et al. were the first to combine imatinib
with hyper-CVAD [18, 19]. In a recent update, 25 of
26 patients (96%) with active disease at study entry
achieved CR at a median time to response of 21 days
[19]. Thirteen of the patients were able to proceed with
allogeneic stem cell transplant within a median of
3 months from start of therapy. Molecular responses
as assessed by RT-PCR for BCR-ABL occurred in 9 of
19 patients. Two-year DFS was 87% with the hyper-
CVAD imatinib combination compared with 28% with
hyper-CVAD alone. The input of next generation tyrosine
kinases (dasatinib, nilotinib) is currently evaluated.
12.3.2 Mature B ALL (Burkitt Leukemia)
Response of mature B-cell ALL to conventional ALL
therapy used to be poor, with long-term disease-free
survival rates hardly exceeding 10% [20, 21]. Use of dif-