Page 1198 - Hematology_ Basic Principles and Practice ( PDFDrive )

1046 Part VII Hematologic Malignancies

that single-agent dasatinib is not sufficient to cure this disease. In a Similar results have been reported in preliminary form by the
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subsequent trial, the GIMEMA LAL1509, if patients did not achieve MRC UKALLXII/ECOG E2993 trial group. In this study, 175 Ph
complete molecular response after a prolonged 84-day induction with ALL patients received imatinib plus chemotherapy (2003 onward).
dasatinib and steroids, they received more intensive combination The authors reported that 44% of the patients were able to receive an
chemotherapy and/or allogeneic transplantation. At day 85, 58 out aSCT per protocol, a number much higher than the 28% who were
of 60 (97%) patients achieved a complete hematologic remission; able to receive aSCT in the preimatinib era of this study (1993–2003).
however, only 11 (18.6%) patients achieved a complete molecular For the imatinib cohort, the 3-year OS for patients who received
remission (CMR) with TKI plus steroid induction, suggesting that protocol aSCT was 59% versus 28% for those who did not receive
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dasatinib and steroids are insufficient to achieve a molecular remission aSCT. In a recent update of the GMALL study, 219 of 335 (66%) Ph
in most patients and that additional postremission intensification ALL patients treated with an imatinib-based chemotherapy regimen
is needed. Using this stratified treatment approach, the DFS was underwent aSCT in CR1. For the transplanted patients, the median
62% with 18 months of follow-up and OS was 69%. Nilotinib OS was 57% after 3 years and 52% after 7 years compared with the
is also a second-generation TKI that that has been evaluated as dismal outcome of the nontransplanted group (3-year OS of only
frontline therapy. In a prospective, single arm phase II trial, induction 14%). Similarly, the GRAAPH2005 study from the GRAAL group
treatment consisted of vincristine, daunorubicin, oral prednisolone, showed that patients who received imatinib-based therapy and aSCT
and nilotinib (400 mg orally twice daily). Patients in CR received had a 4-year OS of 76%, whereas the OS was 33% for those that
either five courses of consolidation followed by 2-year maintenance received imatinib maintenance alone. These studies provide a strong
therapy or an aSCT, depending on donor availability. Nilotinib was rationale for the continued recommendation for an aSCT in CR1
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administered from day 8 of induction continuously until the end for Ph ALL patients.
of maintenance or aSCT. Patients achieved a complete hematologic While ASCTs (as described previously) have not demonstrated
remission in 45 out of 50 (90%) cases. More than 70% of patients efficacy overall in ALL, a study from the CALGB (10001) suggests
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received aSCT. Estimated DFS and OS at 2 years were 71% and 66%, that this may be an effective approach for Ph ALL. A combination
respectively, similar to rates observed with other TKIs. A subsequent of imatinib and chemotherapy induction and postremission CNS
study, EWALL-PH02, in patients greater than 55 years old evaluated intensification was followed by allogeneic or autologous transplant (if
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nilotinib as induction therapy with vincristine and dexamethasone no sibling donor available) in newly diagnosed Ph ALL. Nineteen
followed by consolidation cycles with further chemotherapy added. patients subsequently received autologous transplantation in CR1.
Patients achieved a CR with induction in 35 out of 36 (97%) cases. The OS with a median follow-up of 6 years was not reached and the
In addition, 30% of patients were in a molecular remission after median DFS was 3.5 years compared with 4.1 years (not statistically
induction. Although these results are similar to other studies with different) in the 15 patients who received allogeneic SCT in CR1.
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dasatinib, most of the current trials in Ph ALL have incorporated The authors concluded that autologous transplantation represents
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dasatinib in the frontline therapy because of its potential advantage a safe and effective alternative to allogeneic transplant in Ph ALL
over nilotinib with respect to CNS penetration. without a donor.
Ponatinib is a third-generation ABL kinase inhibitor with the The role and duration of TKI therapy after transplant is currently
ability to inactivate the T315I mutant ABL kinase, which has been an area of active investigation. Wassmann and colleagues (GMALL)
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the most commonly occurring mutation at time of relapse in Ph treated 27 Ph ALL patients with imatinib upon detection of MRD
ALL, and is approved for relapsed disease based on data from the after SCT. Approximately 50% of patients achieved a molecular
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PACE trial. In the chronic myeloid leukemia blast phase/Ph ALL remission after a median of 1.5 months and these patients had a
cohort, 37% (11 out of 30) of patients who were resistant or intoler- significantly longer time to progression (28.6 months versus 3.6
ant to second-generation TKIs and 27% (6 out of 22) of patients with months; p < .001) and OS (2-year OS, 80% versus 23%; p < .001)
T315I mutations achieved a major hematologic remission. Recently compared with those who had persistent BCR-ABL1 transcript levels.
the MD Anderson Cancer Center has reported preliminary results The German group also reported results of a randomized study that
from a phase II study of ponatinib with hyperCVAD in newly diag- compared prophylactic (n = 26) versus preemptive (after detection
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nosed Ph ALL. Thirty five (95%) patients achieved major molecular of BCR-ABL1 transcripts, n = 29) imatinib after aSCT for Ph ALL.
remission and 26 (70%) complete molecular remission. The median Imatinib was discontinued early in more than half the patients in
time to MMR and CMR were 3 and 10 weeks, respectively. Several both groups, mostly because of gastrointestinal toxicity. Prophylactic
patients received alternative TKI therapy due to vascular toxicities. administration of imatinib significantly reduced the incidence of
Further definition of the incidence of serious vascular events with molecular relapse after the aSCT. However, the OS was similar in the
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ponatinib in the frontline treatment setting of Ph ALL is required; two arms (5-year OS: 75% to 80%), suggesting that imatinib can
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thus at this time the use of ponatinib as initial therapy in Ph ALL be effective either prophylactically after aSCT or based on molecular
remains investigational. relapse. At the present time, it appears that continuing TKI therapy
after transplant is an appropriate strategy. Studies evaluating MRD
Role of Transplantation for Philadelphia Chromosome may provide guidance with the question of duration of posttransplant
Positive Acute Lymphoblastic Leukemia in the Era of TKI therapy. The CALGB 10701 study, which includes 1 year of
maintenance dasatinib after transplant, has recently completed
Tyrosine Kinase Inhibitor-Based Therapy accrual and will provide further data to address this issue.
In summary, during the last decade the addition of TKIs to com-
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aSCT in CR1 was the only curative treatment option for Ph bination chemotherapy has resulted in significant improvement in
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ALL in the pre-TKI era. Although the addition of TKI therapy DFS and OS for both younger and older adults with Ph ALL. High
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has significantly improved the outcome of Ph ALL, many recent complete molecular remission rates can now be achieved and have
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studies have also highlighted the continued role of aSCT for Ph been demonstrated to be associated with improved outcomes. While
ALL. In an update of the hyper-CVAD-imatinib protocol, the allogeneic SCT remains the current treatment of choice for eligible
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MD Anderson Cancer Center group reported that in a subgroup patients, the next generation of studies in Ph ALL may help to define
of patients younger than 40 years of age, the 3-year OS was 90% the role of transplantation when complete molecular remissions are
with an aSCT compared with 33% without aSCT (p = .05). In the achieved with combination TKI and chemotherapy alone.
Japanese study, aSCT was performed in the CR1 in 54 of the 74
CR1 patients younger than 55 years of age. Relapse occurred in
13% (7 out of 54) of the transplanted patients compared with 90% BURKITT LYMPHOMA/LEUKEMIA
(18 out of 20) in those who were not transplanted. Similarly, OS
at 3 years was 75% for the transplanted group versus 36% for the BL is a mature B-cell lymphoma with an extremely short doubling
nontransplanted group. time that often presents in extranodal sites or as acute leukemia.