An Effective Chemotherapy-Free Regimen of Ponatinib plus Venetoclax for Relapsed/Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

To the Editor:

Despite significant progress in the treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), a significant portion of patients relapse after allogeneic hematopoietic stem cell transplant (alloHSCT) as well as after regimens combining chemotherapy and BCR-ABL1 tyrosine kinase inhibitors (TKIs). The outcome of patients in first relapse remains poor with a 2-year overall survival of only 20%.¹ Prior studies have evaluated second- and third-generation BCR-ABL1 TKIs in this setting with limited success. For example, in the PACE study of ponatinib monotherapy, only 8% of patients with relapsed/refractory Ph+ ALL maintained continuous response for >12 months.² In an attempt to improve outcomes, chemotherapy plus TKI regimens have been attempted but result in a median survival of only 9 months.³

Disease progression and drug resistance in Ph+ ALL are due in part to enhancement of pro-survival signals such as upregulation of anti-apoptotic members of the B-cell lymphoma-2 (Bcl-2) family of proteins.⁴ The selective BCL-2 inhibitor, venetoclax, has demonstrated significant activity in a number of hematological malignancies, including chronic lymphocytic leukemia and acute myeloid leukemia, leading to its approval in these disorders. Leonard and colleagues evaluated the potential role of the oral Bcl-2 inhibitor venetoclax in Ph+ ALL.⁵ The combination of venetoclax with various TKIs resulted in synergistic in vitro inhibition of cell growth and induction of apoptosis, particularly with dasatinib or ponatinib. The enhanced synergy with these TKIs was mediated by inhibition of the LYN tyrosine kinase, which prevented upregulation of Mcl-1, a major resistance mechanism to venetoclax-based therapies.⁶

We therefore designed this phase 1/2 clinical trial to investigate the safety and preliminary efficacy of the oral, chemotherapy-free combination of ponatinib, venetoclax, and dexamethasone in patients with relapsed or refractory Ph+ ALL. Herein, we report the results of the phase 1 portion of the trial.

This is an open label, phase 1/2 study of the combination of ponatinib, venetoclax and dexamethasone for patients with relapsed or refractory Ph+ ALL. Patients had to be ≥18 years of age, have an Eastern Cooperative Oncology Group (ECOG) performance status ≤3, total serum bilirubin, alanine aminotransferase and aspartate aminotransferase ≤1.5 times the upper limit of normal, and creatinine clearance ≥30 mL/min. Patients must have received at least one prior BCR-ABL1 TKI but may not have received any prior therapy with venetoclax. Patients with uncontrolled cardiovascular disease were excluded. This study was conducted in accordance with the Declaration of Helsinki and was registered at ClinicalTrials.gov (NCT03576547)

The treatment regimen is shown in Supplemental Figure 1. Two dose levels of venetoclax were investigated (400mg and 800mg daily). In cycle 1, patients received a 7-day lead-in of ponatinib monotherapy at 45 mg daily. On day 8, they received dexamethasone 40 mg orally or intravenously x 4 days as well as venetoclax in a daily ramp-up strategy at doses of 20 mg, 50mg, 100 mg, 200 mg, up to 400 mg (dose level 1) and up to 800 mg (for dose level 2). Patients received tumor lysis prophylaxis during this period. Following the dose escalation period, patients could receive a CYP3A4 inhibitor (e.g. azole) and the venetoclax was reduced according to standard adjustments for drug-drug interactions. The 7-day lead-in of ponatinib monotherapy was omitted in patients with recent ponatinib exposure (i.e. within two weeks of enrollment). Ponatinib and venetoclax were given concomitantly for a total of 28 days. In subsequent cycles, patients received dexamethasone 40mg daily x 4 days on days 1–4 and venetoclax and ponatinib daily on days 1–28 of each 28-day cycle. Once patients achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi), the ponatinib dose was reduced to 30 mg daily and then was further reduced to 15mg daily once a complete molecular remission (CMR) was achieved. In cycles 1–4, all patients received a total of 8 doses of prophylactic intrathecal chemotherapy with alternating methotrexate and cytarabine. Eight doses of rituximab were given to all CD20+ patients.

CR and CRi were defined by standard criteria. Presence of measurable residual disease (MRD) was determined using quantitative reverse transcriptase polymerase chain reaction for BCR-ABL1 transcripts as previously described.⁷ A CMR was defined as the absent of detectable transcripts with a sensitivity of 10^-4. Relapse-free survival was defined as the time from response until relapse or death from any cause. Overall survival was defined as the time from start of therapy until death from any cause.

From 12/2018 to 1/2021, 9 patients have been treated on the phase 1 portion of the study and are the subject of this report. The median age was 37 years (range, 26 to 73 years). They had received a median of 3 (range, 2–4) prior regimens before enrollment, including a median of 2 (range, 1–3) prior BCR-ABL1 TKIs. Seven patients (78%) had received prior ponatinib, 6 patients (67%) had undergone prior alloHSCT and 5 patients (56%) had received prior blinatumomab. A T315I mutation in ABL1 was detected in 4 of 8 tested patients (50%). Other patient characteristics are summarized in Supplemental Table 1.

Three patients were treated in dose level 1 (venetoclax dose, 400 mg daily), and 6 patients were treated in dose level 2 (venetoclax dose, 800 mg daily). The median number of cycles received was 3 (range, 2–14 cycles). The regimen was overall well tolerated with most adverse events related to cytopenias and mostly grade 1 or 2 in severity (Supplemental Table 2). No dose-limiting toxicities were observed, and the maximum tolerated dose of venetoclax was not reached. One patient developed pulmonary embolism after 12 months of therapy and was managed with discontinuation of ponatinib and with appropriate anticoagulation. Ponatinib dose reductions occurred in 4 patients (44%), primarily due to elevation of transaminases (n=3). Venetoclax dose reduction occurred in 1 (11%) and was due to myelosuppression. Ponatinib dose interruptions occurred in 5 patients (55%) and was due to elevation of transaminases (n=3), deep vein thrombosis/pulmonary embolism (n=1) and myelosuppression (n=1). Venetoclax dose interruption occurred 4 patients (44%) and in all was due to myelosuppression.

Overall, 5 patients (56%) achieved CR (n=4) or CRi (n=1). No patients in dose level 1 achieved CR/CRi, whereas 5 of 6 (83%) in dose level 2 responded. Four patients (44%) achieved CMR, 3 of whom achieved CMR after the first cycle. Another patient (dose level 1) had a decrease of bone marrow blasts from 94% to 6% with normalization of ANC and platelet count reaching 97 × 10⁹/L but not meeting formal criteria for partial response. CR/CRi was achieved in 4 of 7 patients (57%) with prior ponatinib therapy, 3 of 6 (50%) with prior alloHSCT, and 3 of 5 (60%) with prior blinatumomab therapy. Two patients have died, both of whom did not respond to the regimen and died from progressive leukemia. With the median follow-up of 13.2 months, the median survival has not been reached, and the 1-year OS is 72%. Among the 5 responding patients, none has relapsed, and the estimated 6-month relapse-free survival is 100% (Figure 1). All patients who achieved CMR remain without at any detectable BCR-ABL1 transcripts at last follow-up. All patients remain in response without subsequent alloHSCT.

Figure 1 –

(A) Overall survival and (B) relapse-free survival

In this study, we have demonstrated the safety and feasibility of combining ponatinib, venetoclax and dexamethasone in patients with heavily pretreated relapsed/refractory Ph+ ALL. Five of 6 (83%) patients who received the venetoclax 800mg daily dose level achieved CR/CRi, none of whom have relapsed and all of whom remain in continuous remission without alloHSCT. These results compare favorably to the PACE trial of ponatinib monotherapy patients with relapsed/refractory Ph+ ALL in which responses were short-lived, with a median duration of response was only 3 months and a 1-year progression-free survival rate of <10%. Although our study involves a limited number of patients with a limited follow-up, the lack of any observed relapses in our cohort suggests durable clinical benefit of this novel, oral combination as compared to ponatinib monotherapy. These data are especially encouraging in the setting of the very heavily pretreated population enrolled in the present study (≥50% of patients having prior ponatinib exposure, prior blinatumomab exposure and/or prior alloHSCT).

One interesting and unexpecting finding was the very notable activity observed with the 800mg daily dose of venetoclax (CR/CRi rate 83%), whereas no patient treated at the 400mg daily dose achieved formal response. It is unclear whether the discrepant findings between these two doses is due to a true dose-dependent effect of venetoclax in Ph+ ALL or whether this is a chance observation due to the small numbers treated. Interestingly, in other leukemia (e.g. chronic lymphocytic leukemia and acute myeloid leukemia), combination therapies with 400mg daily dosing of venetoclax have been shown to be highly effective.^8–12 Future correlative studies evaluating augmentation of apoptotic proteins across various doses of venetoclax in combination with ponatinib or other TKIs may help to clarify this issue.

Overall, these results suggest that the addition of venetoclax may further increase the molecular response rates achieved with TKI-based therapies. As the therapy of Ph+ ALL continues to evolve, our findings may have significant implications for both frontline and salvage therapy. For example, blinatumomab-based combinations have recently shown promise in the treatment of Ph+ ALL, with high rates of CMR and promising survival.^13,14 Future studies combining a TKI with venetoclax and blinatumomab may provide us with a strategy to avoid all chemotherapy as well as alloHSCT for most patients with Ph+ ALL, without compromising long-term efficacy.

Data sharing statement:

The data that support the findings of this study are available from the corresponding author upon reasonable request.