Acute Leukemias - Republican Scientific Medical Library

70 Chapter 4 · Relapsed and Refractory Acute Myeloid Leukemia
4.7.6 Central Nervous System (CNS) Relapse
in Acute Promyelocytic Leukemia
Extramedullary disease (EMD) occurs in approximately
5–10% of adults with AML, most commonly in the myelomonocytic,
monocytic, and possibly high-risk APL
subtypes [134–136]. Over the last few decades, the incidence
of EMD in APL appears to have been increased
possibly due to more long-term survivors. Several investigators
have attributed an increased incidence of CNS
relapse to ATRA exposure and suggested that ATRA induces
neural adhesion molecules such as CD11c, CD13,
and CD56 facilitating CNS infiltration by APL cells
[129, 137, 138]. However, the Italian cooperative group
GIMEMA found that APL patients receiving ATRA do
not have an increased risk of developing extramedullary
relapse as compared with those treated with chemotherapy
alone [139]. Since relapses in the auditory canal are
noteworthy and rarely reported previously [140] it is
quite possible that ATRA itself may contribute to these
extramedullary relapses or that the therapeutic concentration
of ATRA may not reach leukemia cells in these
sanctuaries. Whether or not ATRA plays a role in the development
of EMD remains a matter for further study.
4.7.7 Treatment of CNS Relapse
Treatment of CNS relapse likely is best treated with systemic
reinduction with arsenic trioxide or another systemic
approach along with multiple courses of intrathecal
methotrexate possibly alternating with ara-C until
the spinal fluid is free of leukemic cells. Then autologous
HSCT can be considered if molecularly negative
cells can be harvested. Mobilization with intermediatedose
ara-C or HiDAC, depending on the age of the patient,
has the advantage of providing additional treatment
of CNS disease. To date, there is no specific risk
factor identified to predict CNS relapse. However, relapse
appears to occur more frequently among younger
patients, in patients with WBC counts ³10 000/mm 3 ,
and patients with the bcr-3 (short isoform) PML-RARa
breakpoint [141]. Whether CNS prophylaxis by intrathecal
chemotherapy and/or systemic HiDAC should
be routinely performed in patients with any these risk
factors, particularly patients with a WBC ³10 000/
mm 3 remains to be established. Two recent studies have
suggested that intermediate-dose ara-C or HiDAC either
in induction or in consolidation may decrease the risk
of CNS relapse [142, 143].
4.7.8 Strategies to Detect Early Relapse in AML
Current remission criteria have low sensitivity to detect
minimal residual disease (MRD). Therefore, there is interest
in investigating more sensitive methods such as
cytogenetics, flow cytometry, and RT-PCR. These methods
when combined with morphological remission criteria
may decrease relapses, provide insight into the
clinical efficacy of different therapeutic strategies and
could improve overall prognostic stratification in AML
patients. Marcucci and colleagues [13] evaluated 118
AML patients with abnormal cytogenetics at diagnosis.
Patients converting to normal cytogenetics at CR1
(NCR1; n=103) were compared with those with abnormal
cytogenetics both at diagnosis and at CR1 (ACR1;
n=15). ACR1 patients had significantly shorter OS
(P = 0.006) and DFS (P = 0.0001), and higher cumulative
incidence of relapse (CIR) (P =0.0001). In multivariable
models, the NCR1 and ACR1 groups were predictors for
OS (P = 0.03), DFS (P = 0.02), and CIR (P = 0.05) (Fig.
4.6). The relative risk of relapse or death was 2.1 times
higher for ACR1 patients than for NCR1 patients (95%
CI, 1.1–3.9). Notably, there was no significant difference
in time of attaining CR1 between the NCR1 and ACR1
groups. At 3 years, all patients in the ACR1 group had
relapsed compared to 61% in the NCR1 group.
Fig. 4.6. Overall survival according to the presence or absence of
cytogenetic abnormalities on the first day of complete (CR) following
induction chemotherapy in acute myeloid leukemia patients
with abnormal cytogenetics at diagnosis [13].