Blast MRD CML 1 Trial: Blockade of PD-1 Added to Standard Therapy to Target Measurable Residual Disease (MRD) in Chronic Myeloid Leukemia (CML)- a Phase II Study of Adding the Anti-PD-1 Pembrolizumab to Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia and Persistently Detectable Minimal Residual Disease: A Trial of the ECOG-ACRIN Cancer Research Group (EA9171)

Background: Chronic myeloid leukemia (CML) is driven by the activity of the oncogenic BCR-ABL tyrosine kinase, which can be effectively inhibited by tyrosine kinase inhibitors (TKIs) leading to prolonged overall and disease-free survival. Despite their effectiveness, disease can progress on TKI therapy, and lifelong treatment with TKI can have substantial negative effects on quality of life and financial health. Studies assessing the safety of TKI discontinuation in CML patients in molecular remission showed that TKIs can be discontinued in up to 45% of patients without disease recurrence.

Programmed death receptor-1 (PD-1) is an inhibitory immune checkpoint receptor expressed by T-cells that can be inhibited by the anti-PD-1 monoclonal antibody pembrolizumab. Preclinical data have shown that PD-1 is highly expressed on CML-specific cytotoxic T-cells and PD-1 ligand (PD-L1) is present on CML cells. In murine CML models, the administration of anti-PD-L1 antibodies prolonged survival. As these studies suggest that disease relapse might be due to PD-1/PD-L1 mediated immune escape by CML cells, we designed the BLAST MRD CML 1 trial to study whether adding pembrolizumab to TKI is safe, increases the rate of conversion to undetectable minimal residual disease (UMRD) and allows a higher rate of TKI discontinuation.

Methods: The primary endpoint of this ongoing national, ECOG-sponsored, single-arm pilot phase II clinical trial is to assess the proportion of CML patients on stable-dose TKI who convert to UMRD during or within 2 years of initiating pembrolizumab therapy (NCT#03516279). Secondary endpoints are (I) the proportion of CML patients who maintain UMRD for 6 months and 12 months, (II) the proportion of CML patients who discontinue TKI after achieving UMRD, (III) the proportion of patients who maintain UMRD off TKI at 2 years after first determined UMRD, and (IV) the incidence of grade 3 or 4 immune related adverse events related to pembrolizumab treatment during the first 2 years after registration. UMRD state is defined as an undetectable BCR-ABL using the central RQ-PCR assay with a sensitivity of 4.5 [MR^4.5] on 2 consecutive occasions separated by at least 4 weeks with the date of achievement of UMRD constituting the date of first test. Immune related and other adverse events will be assessed according to CTCAE v 5.0 terminology and grading.

Adult (≥18 years) patients with pathologically-confirmed CML and who have achieved major molecular response (MR³) but not UMRD at time of screening are eligible. Eligibility was recently expanded to allow third line TKI. Therefore, currently eligible patients must have been on first, second, or third line TKI therapy with either dasatinib, imatinib, nilotinib, or bosutinib for at least 2 years prior to enrolment. Patients with accelerated or blast phase CML or who have received prior allogeneic hematopoietic stem cell transplant or anti-PD-1/PD-L1 therapy are excluded.

Patients will continue a standard dose of TKI therapy and receive pembrolizumab at 200 mg IV every 21 days (Figure 1). MRD status will be assessed centrally every 4 cycles. Patients who achieve UMRD at or prior to cycle 17 will discontinue TKI and pembrolizumab. If MRD remains positive prior to cycle 17, TKI and pembrolizumab will be continued for an additional 18 cycles. If MRD is still detectable after the second year of combined therapy, patients will come off study. If patients are in an UMRD state by the end of year 1 or 2 of pembrolizumab therapy, pembrolizumab will be discontinued. Patients who remain in UMRD status for one year after the first UMRD result will discontinue TKI therapy. Once TKI is discontinued, BCR-ABL will monitored q4 weeks for the first six months post TKI discontinuation, then q8 weeks for the subsequent six months, then q12 weeks for another year.

Assuming that the addition of pembrolizumab to TKI will increase the conversion rate to UMRD from 20% to 40%, enrollment of 36 patients (40 patients to allow for 10% drop-out) would give this trial 91% power with a one-sided type-I error of 0.089. The combination therapy will be considered promising if 11 or more patients meet the criteria for TKI discontinuation. Toxicity will be monitored and reviewed every six months.

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