Pursuing a Chemotherapy-free Regimen in Philadelphia Chromosome-Positive ALL

Study Title: A Phase III, Randomized Trial of Steroids and Tyrosine Kinase Inhibitor Induction with Chemotherapy or Blinatumomab for Newly Diagnosed BCR-ABL-positive Acute Lymphoblastic Leukemia in Adults (EA9181)

ClinicalTrials.gov Identifier: NCT04530565

Sponsor: Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) in collaboration with the National Cancer Institute National Clinical Trials Network

Accrual Goal: 330 patients to be randomized over six years

Participating Centers: All ECOG-ACRIN sites (lead organization) and National Clinical Trials Network (NCTN) organizations: Alliance for Clinical Trials in Oncology, Southwest Oncology Group (SWOG), Canadian Cancer Trials Group, and NRG Oncology. The study is open at both academic centers as well as at larger community oncology practices in the United States.

Study Design: EA9181 is a randomized, phase III international clinical trial designed to examine the efficacy of combining a tyrosine kinase inhibitor (TKI) with blinatumomab or with the chemotherapy backbone of alternating hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone (hyper-CVAD) with high-dose cytarabine and methotrexate as the initial treatment for adult patients (age ≥ 18-75 years) with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL).

Patients receive a prephase treatment with glucocorticoids and TKI for a one- to three-week period. The specific TKI (either dasatinib or ponatinib) can be selected by the treating physician. Patients are then randomized to induction therapy with TKI and two cycles of blinatumomab with central nervous system prophylaxis or TKI and four cycles of the hyper-CVAD chemotherapy backbone. Minimal residual disease (MRD) analysis will be performed at week 15 following induction therapy (end of cycle 2 for blinatumomab + TKI arm; end of cycle 4 for chemotherapy + TKI arm). The BCR-ABL1 transcript level will be determined by quantitative reverse-transcription polymerase chain reaction, and a level of at least 0.01 percent must be achieved to be considered a molecular remission. Patients who achieve an MRD-negative remission may proceed to allogeneic hematopoietic stem cell transplantation (HSCT) or continue with defined protocol consolidation and maintenance therapy based on the treating investigator’s discretion. Patients with MRD-positive remissions following induction therapy will be offered crossover to the alternate induction therapy arm.

The primary endpoint of the study is to compare overall survival (OS) in patients with newly diagnosed Ph⁺ ALL randomized to receive induction/consolidation therapy with TKI, glucocorticoids, and blinatumomab versus a chemotherapy and TKI combination induction/consolidation therapy. Secondary endpoints include the end-of-induction MRD response rates (week 15 of therapy), event-free survival, and the toxicities of the blinatumomab arm as compared to the chemotherapy arm. Another key secondary endpoint will observe the outcome of patients who proceed to allogeneic HSCT after treatment with blinatumomab and TKI as compared to patients who do not undergo allogeneic HSCT after treatment with blinatumomab and TKI.

Rationale: Ph⁺ ALL is characterized as a high-risk subtype due to the substantial risk of relapse. The major breakthrough in the past 20 years that has improved the outcome for this disease has been the incorporation of TKIs into the frontline chemotherapy regimen.^1-3  Prior to the introduction of TKIs into chemotherapy regimens for Ph+ ALL, the complete remission rates were 50 to 70 percent, but the duration of remission was short, with a median event free survival of eight months. The five-year OS rate with chemotherapy alone was less than 20 percent.^4-7  For those patients able to undergo a myeloablative allogeneic HSCT in the pre-TKI era, the five-year OS was 44 percent (sibling donor) and 36 percent (unrelated donor).⁸  Today, for adult patients with Ph⁺ ALL treated with contemporary high-dose chemotherapy regimens combined with TKI and allogeneic HSCT, the long-term cure rate is estimated at 60 percent.⁹ 

The second significant development in the treatment of Ph⁺ ALL in the TKI era has been understanding the importance of achieving a complete molecular response (CMR). The field has reached consensus that CMR is the therapeutic benchmark that has the most prognostic significance for long-term outcomes.^10,11  How to best achieve CMR is a matter of debate, however. In the United States, the most common regimen utilized is hyper-CVAD combined with a second- (dasatinib) or third- (ponantinib) generation TKI. The investigators at MD Anderson Cancer Center have optimized the hyper-CVAD/TKI regimen. For patients at their center, this approach yields CMR rates of up to 65 percent for dasatinib and 79 percent for ponantinib as well as five-year OS of 46 percent for dasatinib and a three-year OS for ponatinib of 73 percent.^2,9,12  Nonetheless, with the use of an intensive chemotherapy backbone, deaths in remission occur in approximately 12 percent of patients, and vascular and cardiac toxicities have been reported with both the second- and third-generation TKIs.¹²  In an alternate strategy, several trials in Europe during the past 10 years have focused on deintensification of the induction regimen using glucocorticoids and TKI and little or no consolidation chemotherapy.^13-15  These lower intensity regimens have excellent hematologic remission rates (approaching 100%) and have nearly eliminated the treatment-associated deaths, even in older patients, but the CMR rate for this approach is 20 percent and either intensive consolidation chemotherapy or allogeneic HSCT is needed for long-term survival.¹⁵  Additionally, the BCR-ABL T315I mutation, which renders the disease resistant to all TKIs except ponatinib, emerges commonly at the time of relapse following a combination of dasatinib and a lower-intensity chemotherapy regimen.¹⁴  Building on this less intensive regimen, Dr. Robin Foà and colleagues of the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) recently reported the results of 63 patients enrolled on a phase II trial (LAL2116) evaluating glucocorticoid plus TKI induction therapy followed by the bispecific T-cell engager, blinatumomab, plus TKI consolidation.¹⁶  Complete remission was achieved in 98 percent of patients after induction therapy, and CMR was achieved in 60 percent of evaluable patients completing two cycles of blinatumomab consolidation. The CMR rate improved (up to 81%) with additional cycles of blinatumomab. At a median follow-up interval of 18 months, the OS was 95 percent, and the disease-free survival was 88 percent. For patients who achieved CMR, the probability of disease-free survival was 100 percent compared to 85 percent for patients with measurable residual disease. Toxicity was manageable, with one death occurring during the induction-consolidation period. Given these promising data with TKI and blinatumomab, the question for the field now is whether intensive cytotoxic chemotherapy is required to achieve the best rates of CMR or whether novel immunotherapy such as blinatumomab combined with TKI can achieve equivalent or improved rates of CMR with less toxicity, thus improving outcomes for all patients with Ph⁺ ALL and obviating the need for cytotoxic chemotherapy. EA9181 is primed to address this important clinical question.

Comment: Due to the relative rarity of Ph⁺ ALL (it accounts for approximately 25% of adult cases of ALL), there are few randomized control trials in this disease. Most clinical trials that have informed the treatment of Ph⁺ ALL have been single-arm phase II studies. Thus, additional related questions remain unanswered, specifically the therapeutic utility of allogeneic HSCT. Myeloablative allogeneic HSCT has represented the only curative option in the pre-TKI era.^8,17  In the TKI era it has been a mainstay of treatment for younger patients with suitable donors, based on several studies that suggest a survival benefit.^1,18,19  With the introduction of more potent TKIs (such as ponatinib) or novel immunotherapy (such as blinatumomab), one critical question to be answered is whether allogeneic HSCT benefits patients who meet and maintain CMR. Unfortunately, this question cannot definitively be answered by EA9181, as the sample size for a randomized comparison was prohibitive. It is likely, however, that a significant number of patients will be referred for transplant in this study, and investigators can collect descriptive data about the outcomes of patients who undergo transplantation and those who do not on the two arms of the study. Also of interest is whether there will be less transplant-related mortality in patients who received a chemotherapy-free induction and consolidation regimen followed by allogeneic HSCT. Finally, this trial may also provide significant information as to whether a chemotherapy-free approach can offer a long-term cure for older patients, unfit patients, or patients who are unwilling to undergo an allogeneic HSCT. The hope is that the addition of the combination of a potent TKI and effective immunotherapy to the current frontline regimen will further improve CMR and eliminate the need for chemotherapy and/or allogeneic transplantation.