Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia: a US, single-centre, single-arm, phase 2 trial

Jabbour, Elias; Short, Nicholas J.; Jain, Nitin; Huang, Xuelin; Montalban‐Bravo, Guillermo; Banerjee, Pinaki P.; Rezvani, Katayoun; Jiang, Xianli; Kim, Kun Hee; Kanagal‐Shamanna, Rashmi; Khoury, Joseph D.; Patel, Keyur P.; Kadia, Tapan M.; Daver, Naval; Chien, Kelly S.; Alvarado, Yesid; Issa, Ghayas C.; Haddad, Fadi; Kwari, Monica; Thankachan, Jennifer; Delumpa, Ricardo; Macaron, Walid; Garris, Rebecca; Konopleva, Marina; Ravandi, Farhad; Kantarjian, Hagop

doi:10.1016/s2352-3026(22)00319-2

Cited by 122 publications

(112 citation statements)

References 23 publications

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“…After a median follow‐up of 2.7 years, the results were similar to D‐ALBA with a 3‐year disease‐free survival (DFS) and OS estimated at 87% and 77%, respectively, while only 1 of the 24 patients enrolled proceeded to SCT 23 . Excellent DFS and OS outcomes were reported from an ongoing phase 2 trial of blinatumomab and ponatinib from MD Anderson Cancer Center in a relatively younger cohort of patients with newly diagnosed or relapsed/refractory Ph + ALL 24 . The 1‐year EFS rate was 95% in the frontline setting and 57% in the relapsed/refractory setting 24 .…”

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confidence: 67%

“…The 1‐year EFS rate was 95% in the frontline setting and 57% in the relapsed/refractory setting 24 . It is noteworthy that 68% of patients in the frontline therapy cohort achieved a CMR after 1 cycle; those results may reflect the unique MRD‐eradicating characteristics of blinatumomab 24 …”

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confidence: 99%

“…The improved outcomes with the use of the third‐generation TKI ponatinib, coupled with Hyper‐CVAD or blinatumomab, have challenged the dogma of SCT for all eligible patients in first CR 5,13,21–24 . The more effective tools in our expanded armamentarium against Ph + ALL have driven an effort to redefine the role of SCT, especially in the frontline setting.…”

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confidence: 99%

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The evolution of frontline therapy for adult Philadelphia‐positive acute lymphoblastic leukemia: Giant strides and ongoing challenges

Saliba

Foà

2022

American J Hematol

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Before the advent of BCR::ABL1 directed tyrosine kinase inhibitors (TKIs), allogeneic stem cell transplantation (SCT) was the only curative modality offering a survival advantage in adults with Philadelphiapositive acute lymphoblastic leukemia (Ph + ALL). 1 Complete remission (CR) was achieved in 60-70% of patients with overall survival (OS) rates of 10% with multiagent chemotherapy alone and 30% with SCT. 1 This SCT-centric approach excluded a large proportion of patients with Ph + ALL who were older, non-responsive to chemotherapy, or ineligible for intensive therapies. The dismal prognosis of Ph + ALL in the pre-TKI era has substantially improved by targeting the leukemiasustaining BCR::ABL1 fusion oncoprotein. [2][3][4][5] Initially introduced in the relapsed/refractory setting, TKIs targeting BCR::ABL1 now play a critical role in the frontline therapy for Ph + ALL as their incorporation into induction, consolidation, and maintenance regimens has resulted in CR rates of >90% across a wide spectrum of age and performance status. [6][7][8][9] The improved outcomes with the addition of TKIs led to revi-

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confidence: 67%

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confidence: 99%

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confidence: 99%

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The evolution of frontline therapy for adult Philadelphia‐positive acute lymphoblastic leukemia: Giant strides and ongoing challenges

Saliba

Foà

2022

American J Hematol

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“…Blinatumomab has also been evaluated in combination with ponatinib in a phase II trial among 40 patients with newly diagnosed Ph-positive ALL, with a median age of 57 years (range = 20–83 years). 33 In contrast with the D-ALBA trial, blinatumomab plus ponatinib were started concomitantly beginning in cycle 1. The CR/CRi rate was 96%, and the overall CMR rates were 87%.…”

Section: Low-intensity Therapiesmentioning

confidence: 99%

“…More recently, the combination of blinatumomab plus ponatinib showed encouraging results in the frontline setting, with a CMR rate of 87% and a 1-year OS of 95%, with only 1 of 35 patients (3%) receiving allogeneic SCT. 33 Thus, this chemotherapy-free combination may eliminate the need for both intensive chemotherapy and the need for allogeneic SCT in the frontline setting. Longer-term follow-up will be needed to confirm the durability of these responses in the absence of SCT in first remission.…”

Section: Evolving Role Of Allogeneic Sct In Ph-positive Allmentioning

confidence: 99%

Treatment de-escalation in Philadelphia chromosome–positive B-cell acute lymphoblastic leukemia: the emerging role of chemotherapy-free regimens

Haddad

Sawyers

Short

2023

Therapeutic Advances in Hematology

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The management of Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) has witnessed major progress over the past two decades. Initially, the incorporation of the first-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) imatinib into intensive chemotherapy regimens improved outcomes compared with chemotherapy alone. The combinations of chemotherapy with second- or third-generation TKIs further improved outcomes, with higher rates of complete molecular remission (CMR) and superior survival. The combination of ponatinib plus chemotherapy resulted in durable remissions and prolonged long-term survival, even in patients who did not receive allogeneic stem cell transplantation (SCT). The promising results seen with later-generation TKIs have caused many to re-evaluate the role of allogeneic SCT for patients who achieve CMR with potent TKI regimens. Recently, the chemotherapy-free combinations of blinatumomab plus TKIs were shown to be safe and effective in newly diagnosed Ph-positive ALL, sparing patients the toxicities associated with intensive chemotherapy. In particular, encouraging early results have been seen with the combination of blinatumomab plus ponatinib, suggesting that this regimen may represent a chemotherapy-free and SCT-sparing strategy for patients with Ph-positive ALL. Herein, we discuss the current evidence for frontline therapies of Ph-positive ALL, the treatment de-escalation strategies over time, and the role of allogeneic SCT in view of the emergence of newer chemotherapy-free regimens using potent TKIs.

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Ponatinib vs Imatinib in Frontline Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

Jabbour,

Kantarjian,

Aldoss

et al. 2024

JAMA

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ImportanceIn newly diagnosed Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I.ObjectiveTo compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL.Design, Setting, and ParticipantsGlobal registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022.InterventionPatients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease–(MRD) negative complete remission.Main Outcomes and MeasuresThe primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase–quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival.ResultsOf 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%).Conclusions and RelevancePonatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib.Trial RegistrationClinicalTrials.gov Identifier: NCT03589326

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Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia: a US, single-centre, single-arm, phase 2 trial

Cited by 122 publications

References 23 publications

The evolution of frontline therapy for adult Philadelphia‐positive acute lymphoblastic leukemia: Giant strides and ongoing challenges

The evolution of frontline therapy for adult Philadelphia‐positive acute lymphoblastic leukemia: Giant strides and ongoing challenges

Treatment de-escalation in Philadelphia chromosome–positive B-cell acute lymphoblastic leukemia: the emerging role of chemotherapy-free regimens

Ponatinib vs Imatinib in Frontline Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

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