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As noted, Ph-positive disease is often a feature of adult ALL and increases in prevalence as patients age. Historically, patients with Ph-positive ALL eligible for alloSCT were deemed to be appropriate for this modality as a way to intensify therapy and, hopefully, achieve improved long‑term survival and cure.
The LALA-94 study was a prospective, multicenter trial that examined the role of alloSCT in patients with Ph-positive ALL before the advent of small-molecule TKIs targeting BCR‑ABL, such as imatinib and dasatinib. In this study, patients who had donors and went on to receive alloSCT had better OS outcomes than those who did not pursue transplant due to lack of a donor. This result suggested alloSCT in patients with Ph-positive B‑cell ALL to be a promising modality that improved survival in the pre-TKI era.
The advent of BCR-ABL inhibitor therapy has changed the landscape of treatment for Ph-positive ALL. A single-arm phase II study examined the TKI dasatinib plus hyper-CVAD alternating with methotrexate and cytarabine in 94 patients with newly diagnosed Ph-positive ALL. Patients received dasatinib at 100 mg or 70 mg daily in combination with chemotherapy for 8 cycles during an intensive phase, followed by dasatinib plus chemotherapy as maintenance therapy, or alloSCT for patients with an available donor. The primary endpoint was 12-month relapse-free survival.
The OS rate at 3 years was 69% across the full cohort, and the 3-year EFS rate was 55%, suggesting that patients who received dasatinib for Ph-positive B‑cell ALL in combination with chemotherapy responded well. The 12-month relapse-free survival rate in 41 patients who received a transplant was 83%.
Ponatinib, another potent TKI targeting BCR‑ABL, was evaluated in combination with hyper-CVAD in 76 adults with Ph-positive ALL in a single-center phase II trial. Ponatinib was dosed at 45 mg daily, subsequently reduced to 30 mg daily after a protocol amendment, and hyper-CVAD was alternated with methotrexate and cytarabine. All 65 evaluable patients achieved a CR, and 99% achieved MRD negativity by flow cytometry, suggesting a very deep molecular response to this combination therapy. Of more importance, an impressive proportion of patients were alive at 3 and 5 years (76% and 71%, respectively), suggesting that ponatinib in combination with chemotherapy is highly efficacious.
TKIs have also been combined with less intensive treatments for Ph-positive B‑cell ALL. For example, dasatinib has been combined with prednisone alone, or with prednisone and vincristine to achieve remission and potentially transition patients to more intensive, potentially curative treatments such as SCT. The regimen studied by Foà and colleagues in a phase II trial combined dasatinib with prednisone and intrathecal methotrexate in 53 patients with Ph-positive ALL. All patients achieved a CR, although the rate of subsequent relapse was high. This regimen is increasingly used in patients who may not tolerate intensive treatment and/or older patients who are Ph positive. Given the relatively high frequency of relapse, it may be appropriate to pursue SCT following achievement of remission with steroids plus dasatinib in patients who are eligible for alloSCT.
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