Time to tune the treatment of Ph+ ALL

In this issue of Blood, Chalandon et al report the results of a prospective randomized study comparing standard vs less-intensive chemotherapy, both combined with imatinib, for patients with newly diagnosed Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). They show that the less-intensive therapy reduces early mortality without impairing efficacy, resulting in a significantly higher hematologic complete remission (CR) rate and an equivalent major molecular response (MMolR) rate.¹ 

The advent of tyrosine kinase inhibitors (TKIs) has completely changed the therapeutic landscape of Ph+ ALL.²  A TKI combined with chemotherapy is now used as the treatment of choice for newly diagnosed Ph+ ALL patients; however, many unresolved issues are still present. Indeed, it is more correct to say that only a few clinical questions are addressed by currently available evidence, and even fair to say that all we know is that this therapy should be used. This equivocal situation is primarily attributable to the lack of prospective randomized controlled studies, and the rarity of the disease makes it difficult to conduct a large-scale trial. To my knowledge, there are only a couple of published prospective studies that enrolled a 100 or more patients,^3,4  all of which were nonrandomized phase 2 trials.

By overcoming such practical difficulties, Chalandon et al from the Group for Research on Adult Acute Lymphoblastic Leukemia successfully completed the largest trial ever, containing 270 newly diagnosed Ph+ ALL patients aged 18 to 59 years, and attempted to address the important question of whether intensive chemotherapy is really necessary for induction therapy incorporating imatinib.¹  After enrollment, patients were randomized to receive imatinib combined with either less-intensive chemotherapy consisting of vincristine and steroids (investigational arm) or a more intesnse regimen of fractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone (control arm). For the second course, patients in both arms received a similar chemotherapy consisting of methotrexate, cytarabine, and imatinib, followed by allogeneic hematopoietic cell transplantation (HCT), if eligible. In the absence of a suitable donor, those who achieved MMolR after the second course proceeded to autologous HCT. The primary end point of the study was the MMolR rate after the second course, which was 66.1% for the investigational arm and 64.5% for the control arm (P = .88), meeting the predefined criteria for noninferiority of the investigational arm. The hematologic CR rate was significantly higher in the investigational arm than that in the control arm (98.5% vs 91.0%, P = .006) because of reduced early mortality for the former. Other secondary end points, including event-free survival (EFS), relapse-free survival, cumulative incidence of relapse, cumulative incidence of nonrelapse mortality, and overall survival (OS), did not differ between arms.

Since the initial reports of imatinib used in conjunction with chemotherapy for Ph+ ALL, imatinib has been preferentially incorporated into standard ALL-type chemotherapy. Although this combination is able to raise CR rates to around 95%, early deaths occur in up to 5% of patients, which represents the primary reason for failure to achieve CR.^3-7  The strategy to combine imatinib with standard chemotherapy has been challenged by subsequent studies that investigated the use of a TKI alone or in combination with steroids.^8-10  Ottmann et al evaluated imatinib monotherapy in 27 patients older than 55 years of age, and observed CR in 26 patients and partial remission in the remaining patient.⁸  Vignetti et al conducted a study of imatinib and steroids in 29 patients older than 60 years of age, in which all of them achieved CR.⁹  Foà et al reported that all of their 53 patients over the age of 18 years treated with dasatinib and steroids achieved CR.¹⁰  These findings raise a concern that intensive chemotherapy during induction may not be beneficial and even harmful, although this notion has been inconclusive till now. The present study reported by Chalandon et al provides robust insights into this issue.¹  Compared with the control arm, the less-intensive arm yielded a significantly higher hematologic CR rate and a similar MMolR rate after the second course. Somewhat unexpectedly, both arms showed similar MMolR rates even after the first course (43.1% vs 45.5%, P = .78). This study also reports several significant findings with respect to postremission therapy that upfront allogeneic HCT leads to an improvement in long-term outcomes and that autologous HCT is effective in patients achieving MMolR at an early stage of treatment. However, despite these achievements, the overall prognosis for their patients is not satisfactory enough because the 5-year EFS and OS rates remained at 37.1% and 45.6%, respectively. This confronts us with the fact that there is much room for improvement, particularly in postremission therapy.

In conclusion, this study represents a big step forward in the treatment of newly diagnosed Ph+ ALL, and induction therapy has moved toward a more refined way. Future clinical research needs to focus on preventing a relapse for these patients.