Ponatinib combined with steroid first-line therapy is promising in elderly and unfit patients with Ph+ acute lymphoblastic leukemia

Philadelphia chromosome (Ph) positivity is the most common cytogenetic abnormality in adults with acute lymphoblastic leukemia (ALL), occurring in up to 40% of adults with ALL and approximately 50% in patients ≥50 years of age
.

Over the past 15 years, treatment options for patients with Ph+ ALL have expanded due to the introduction of tyrosine kinase inhibitors (TKIs)
.

TKIs have been successfully used in combination with low-dose chemotherapy or standard chemotherapy in patients who are suitable for chemotherapy (fit), and can be followed by transplantation therapy
.

Studies have shown that imatinib combined with steroid induction therapy, followed by imatinib combined with chemotherapy and stem cell transplantation (SCT), can achieve an overall survival (OS) rate of 49% and 5-year disease-free survival in adult patients with Ph+ ALL.
(DFS) rate reached 46%
.

A previous GIMEMA study explored the efficacy of TKIs combined with steroids as an alternative to systemic chemotherapy
.

These findings demonstrate that the above regimen combined with prophylactic intrathecal chemotherapy in the central nervous system (CNS) is suitable for elderly and unfit patients who are not suitable for intensive chemotherapy
.

In conclusion, the incidence of Ph+ ALL increases with age, and it is crucial to improve the survival of elderly and unfit patients with Ph+ ALL
.

BCR-ABL1 kinase domain mutation is a major mechanism of relapse in Ph+ ALL patients
.

Ponatinib is a third-generation TKI with broad-spectrum kinase inhibitory activity, active against most known BCR-ABL1 mutations, and a T315I-active TKI
.

Studies have shown that Ponatinib combined with chemotherapy as first-line treatment has shown good efficacy in patients with relapsed/refractory Ph+ ALL
.

Based on this, some researchers have carried out a clinical study of Ponatinib combined with prednisone in the first-line treatment of patients ≥ 60 years old and unfit
.

>>>>Study Methods The INCB84344-201 study (previously GIMEMA LAL 1811; NCT01641107) is a Phase II, open-label, single-arm clinical study conducted by 23 Italian research centers
.

Inclusion criteria: new-onset Ph+ ALL according to WHO classification; no history of chronic myeloid leukemia (CML); unfit patients ≥ 60 years old or ≥ 18 years old; Karnofsky functional status score > 50% or Eastern Cooperative Oncology Group (ECOG) performance status Score ≤ 2 points; all organs function well
.

Patients received 7-14 days of steroid pretreatment, specifically oral prednisone in escalating doses, 40-60 mg/m2 daily
.

The GIMEMA central laboratory detected the transcription of BCR-ABL1 fusion gene in patients
.

After preconditioning, patients received oral Ponatinib 45mg/d for a total of 8 courses (1 course of 6 weeks), which was the core phase of the study
.

Patients received 60 mg/m2 of prednisone daily from day 1 to day 21, then tapered and discontinued on day 29
.

After Cycle 8, Ponatinib was continued during the study expansion phase if the investigator believed that the patient might benefit from continued treatment
.

For patients without clinical cytological evidence of meningeal involvement, intrathecal injections of methotrexate, cytarabine, and dexamethasone were administered every 28 days
.

For patients with CNS disease, intrathecal injections were administered twice weekly until complete clearance of blasts from the CSF, then weekly intrathecal injections for 4 weeks and monthly after 4 weeks of treatment
.

When the corresponding clinical manifestations and indications appear, the researchers will give aspirin, anti-infective treatment and blood transfusion to the patients
.

The primary endpoint was complete hematologic response (CHR) rate at 6 months of treatment, defined as bone marrow blasts <5%; no blasts in peripheral blood with normal differentiation, neutrophils >1.
5x109/L, platelets > 100x109/L; no leukemia extramedullary involvement
.

Secondary endpoints were CHR rate at 6, 12, 24, 36, and 48 weeks; complete cytogenetic response (CCR) rate; CCR duration; complete molecular response (CMR) rate and major molecular response (MMR) rate; Duration of CMR; event-free survival (EFS) and overall survival (OS)
.

>>>>Research Results The study of baseline characteristics of patients included a total of 44 patients, and 27 patients completed the core phase of the study and entered the expansion phase
.

Data cutoff date is April 24, 2020
.

The median follow-up time was 34.
9 months (range 0.
19-61.
54)
.

The median age at diagnosis was 66.
5 years (range, 26-85 years), and 35 patients (79.
5%) were ≥60 years old
.

Thirty-eight patients (86.
4%) had an ECOG performance score of 0-2 at baseline
.

The median white blood cell count at diagnosis was 4.
3x106/mL (range 0.
33-115.
9x106/mL) in enrolled patients; one patient had a WBC of >100x106/mL
.

At baseline, 6 patients (13.
6%) developed central nervous system disease; 33 patients were negative for CNS involvement (75.
0%); data were missing in 5 patients (11.
4%)
.

Fifteen patients received intrathecal injections at baseline
.

The specific characteristics are shown in Table 1
.

Table 1 Efficacy analysis Of the 44 patients included, 42 patients (95.
5%) achieved CHR at any time during treatment; 2 patients died before CHR assessment, and 1 died of lung infection on day 6 (Day 26 of illness), 1 patient died of bilateral pneumonia on day 47 of severe neutropenia, and the 2 deaths were considered unrelated to the drug
.

For the primary endpoint, CHR was achieved in 38 patients (86.
4%) at week 24; for the secondary endpoint, CCR was achieved in 24 patients (54.
5%) and CMR in 18 patients (40.
9%) at week 24 , 14 patients (31.
8%) achieved MMR; the specific end point event results are shown in Table 2
.

Table 2 The median duration of CHR was not reached (95% CI 20.
7 - not evaluable [NE]), as shown in Figure 1A
.

Thirty-four patients (77.
3%) achieved at least one CCR and 36 (81.
8%) achieved at least one CMR during treatment
.

The median duration of CCR and CMR was not reached (95%CI 21.
91-NE) and 11.
6 months (95%CI 4.
53-20.
90), respectively, as shown in Figure 1B-C
.

Six patients (14.
3%) experienced a relapse within 30 days before or after the last dose of ponatinib
.

Figure 1 At the time of data cutoff, the median EFS was 14.
31 months (95%CI 9.
30-22.
31), and the median OS was not reached (95%CI 25.
82-NE), as shown in Figure 2
.

Figure 2 Safety Analysis The most common adverse events (TEAEs) of any grade during treatment included: rash (n = 16; 36.
4%), asthenia (n = 10; 22.
7%), increased alanine aminotransferase ( n=7; 15.
9%), erythema (n=7; 15.
9%), and increased γ-glutamyltransferase (n=7; 15.
9%), as shown in Table 3
.

Twenty patients (45.
5%) experienced serious adverse events (SAEs)
.

The most common SAEs were acute coronary syndrome (n=3; 6.
8%), arterial occlusive disease (n=2; 4.
5%), atrial fibrillation (n=2; 4.
5%), heart failure (n=2; 4.
5%) and pneumonia (n=2; 4.
5%)
.

The incidence of cardiac-related and vascular-related TEAEs was 29.
5% (≥grade 3, 18.
2%) and 27.
3% (≥grade 3, 15.
9%), respectively
.

TEAE resulted in dose reduction in 19 patients (43.
2%), dose interruption in 19 patients (43.
2%), and discontinuation in 12 patients (27.
3%)
.

Fatal TEAEs occurred in 5 patients
.

Twenty patients (45.
5%) died from the following causes: ALL progression (n=8); pneumonia (n=2); cardiovascular disease (n=2); pulmonary infection (n=1); Bronchopulmonary aspergillosis (n=1); septic shock (n=1) and sudden death (n=1)
.

The primary cause of death in 1 patient could not be identified, and the cause of death was not recorded in 3 patients
.

Table 3>>>>Study Conclusions Previous studies in young fit patients combined with the results of this study indicate that Ponatinib is a TKI suitable for different Ph+ ALL new-onset patient populations
.

The combination of ponatinib and prednisone appears to be a good treatment option for elderly and unfit patients, although lower doses of ponatinib need to be considered to reduce toxicity
.

From the results of the safety analysis, the specific use of Ponatinib needs to be adjusted according to the individual patient's cardiovascular risk
.

In conclusion, the Ponatinib plus prednisone regimen is promising in elderly and unfit patients with few alternatives
.

Reference: Giovanni Martinelli, Cristina Papayannidis, Alfonso Piciocchi, et al.
INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia.
Blood Adv.
2022 Mar 22;6(6):1742-1753.
doi: 10.
1182/bloodadvances.
2021004821.
Reviewer: Quinta Typesetting: Quinta Execution: Quinta pokes "read the original text", we make progress together