New Generation of TKIs Challenge Standards of Care in Newly Diagnosed Ph+ ALL

Marlise R. Luskin, MD, MSCE

Tyrosine kinase inhibitors (TKIs) have been revolutionizing treatments for patients with newly diagnosed acute lymphoblastic leukemia (ALL) for decades. For those with Philadelphia chromosome (Ph)–positive disease, found in a significant number of patients with ALL, the advent of effective first-generation TKIs has allowed for improvements among those with this disease subtype, which is traditionally associated with a poor prognosis, as it generally does not respond to conventional chemotherapy options.^1,2

In adults with ALL, the incidence of Ph-positive disease increases with age, with more than half of patients over the age of 50 years having the chromosomal abnormality.² “The older age of the patient population makes delivering those conventional chemotherapy regimens difficult or impossible,” Marlise R. Luskin, MD, MSCE, said in a presentation of the landscape during a recent American Society of Clinical Oncology Plenary Session.¹ Luskin is associate program director of the Dana-Farber/Mass General Brigham Hematology/Oncology Fellowship Program, the educational director of the Adult Leukemia Program at Dana-Farber Cancer Institute, and an assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

Attempts to identify optimal frontline therapy for older patients evaluated intensive chemotherapy, such as in ECOG 2993, but only approximately 20% patients are able to achieve long-term durable remission from their disease.³ “Historically, allogeneic stem cell transplant has been needed for cure, but rarely achieved because of the poor response to initial chemotherapy and ineligibility of patients for transplantation due to age or morbidity and/or lack of unsuitable donor,” Luskin added.

However, nearly 2 decades ago, imatinib (Gleevec) changed the course of treatment and aided in an exploration to better understand the biology of the disease.² “An inhibitor of the ABL kinase, [imatinib] is administered as an oral chemotherapy is very potent,” Luskin said. The agent was eventually added into the trial protocol for ECOG 2993 and patients with Ph-positive ALL were assigned to receive the TKI. “This resulted in higher [complete remission] CR rates, which resulted in more eligibility for transplantation and better overall survival [OS].”

More work, however, remained to de-escalate the chemotherapy component of the combination therapy. Small improvements in OS were achieved in studies assessing steroid and TKI combinations as well as dose reductions of chemotherapy during induction phases of treatment regimens, according to Luskin. Despite this, OS rates were under 50% for patients in the frontline setting.² Insufficient depths of CR achieved by many patients were cited as a root cause of the lack of efficacy, as patients also presented with persistent measurable residual disease or low amounts of disease below the morphologic threshold, according to Luskin.^1,2

“Some patients have high-risk genetic abnormalities in combination with the Ph chromosome, which may result from insufficient potency of the TKI. In addition to insufficient depths of CR, patients who achieve a deep CR may relapse either systemically or in the central nervous system,” she said.

Several approaches are being pursued to try to improve the rate of cure and durable remission for patients with Ph-positive ALL, including more potent TKIs, which may serve as successors to imatinib, Luskin said (Figure).¹

Figure. Challenges and Solutions for Ph+ ALL¹

PhALLCON Regimen Shifts SOC

The most recent data to play a role in changing treatment were seen with the phase 3 PhALLCON study (NCT03589326), which met its primary end point, and were presented during the American Society of Clinical Oncology Plenary Session.¹ First-line ponatinib (Iclusig), a third-generation TKI, plus reduced-intensity chemotherapy outperformed imatinib for the treatment of patients with newly diagnosed Ph-positive ALL.

“Ponatinib, a potent third-generation TKI [has] increased potency compared with imatinib and activity against the T315 [mutation], the so-called gatekeeper mutation,” Luskin explained. “This is important because the majority of relapses in imatinib-treated patients and then second-generation TKI–treated patients occur via acquisition of this mutation. Retrospective comparisons have suggested that outcomes are improved in patients who are treated with second-generation and then third-generation TKIs, but this has not been compared in a randomized fashion.”

Minimal residual disease (MRD)–negative CR at the end of induction was achieved in 34.4% of patients who received ponatinib (n = 154) vs 16.7% of patients who received imatinib (n = 78; risk ratio, 2.06; 95% CI, 1.19-3.56; P = .0021). This end point was defined as having a hematologic CR for at least 4 weeks plus MRD negativity defined as BCR::ABL1 no greater than 0.01% (MR4). Median follow-up was 20.4 months (range, 18.4-23.9) in the ponatinib arm and 18.1 months (range, 13.9-24.3) in the imatinib arm.¹

Overall, the MRD negativity rate at the end of induction was 41.6% with ponatinib vs 20.5% with imatinib (risk ratio, 1.94; 95% CI, 1.19-3.17; P = .0017). The median duration of MRD negativity—defined as time from first documented MRD negativity to first documented loss of MRD negativity—was not estimable (NE; 95% CI, 17.0-NE) in the ponatinib arm compared with 20.9 months (95% CI, 10.9-NE) in the imatinib arm. The median time to treatment failure was NE with ponatinib vs 21.9 months with imatinib.¹

“Ponatinib is a very potent BCR::ABL1 inhibitor with activity against wild-type and BCR::ABL1 [mutated disease] including T315I mutations,” Elias J. Jabbour, MD, said in a presentation of the data. “The combination of ponatinib with steroid, chemotherapy, or immunotherapy has [been shown to be] very promising [and] with propensity score matching was thought to be superior to dasatinib [Sprycel] and imatinib.” Jabbour is a professor of medicine in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston. “The PhALLCON trial shows the superior efficacy of ponatinib compared with imatinib in combination with low-dose chemotherapy in patients with Ph-positive ALL with a significantly higher and clinically meaningful MRD-negativity CR rate at the end of induction.”

He added, “The combination of TKI and chemotherapy or steroids is the SOC [standard of care] for patients with Ph-positive ALL, [and] cross-trial comparison of low-intensity chemotherapy with first- or second-generation TKIs reported a 12-week CR rate of approximately 14% to 40%. Despite the high rate of initial response, resistance is often observed and frequently driven by the acquisition of the T315I kinase domain mutation.”

The secondary end point of the study was event-free survival (EFS), which was assessed among the intention-to-treat population of 164 patients who received ponatinib and 81 patients who received imatinib. The median was NE with ponatinib vs 29.0 months with imatinib (HR, 0.65; 95% CI, 0.39-1.10). Events for this analysis included death from any cause, failure to achieve CR at the end of induction, or relapse from CR.¹

Progression-free survival (PFS) and OS also were reported. The median PFS was 20.0 months (95% CI, 11.8-NE) vs 7.9 months (95% CI, 6.2-12.4) with ponatinib and imatinib, respectively (HR, 0.58; 95% CI, 0.41-0.83). The median OS was NE is both arms but showed a trend toward a benefit with ponatinib vs imatinib (HR, 0.76; 95% CI, 0.38-1.52).¹

PhALLCON was designed to assess the primary end point after the induction phase, which was followed by consolidation, postconsolidation, and single-agent use phases per study protocol.

Adult patients with Ph-positive ALL or BCR::ABL1-positive ALL were randomly assigned to ponatinib at a starting dose of 30 mg once daily with a dose reduction to 15 mg if MRD-negative CR was achieved after the induction phase, or imatinib 600 mg once daily. Both TKIs were given in combination with low-dose vincristine plus dexamethasone during the induction phase of three 28-day cycles, followed by low-dose methotrexate plus cytarabine for six 28-day cycles, and then low-dose vincristine plus prednisone for eleven 28-day cycles during the postconsolidation stage. A single-agent TKI was administered thereafter until the end of treatment.

Enrollment criteria also included ECOG performance status 0 to 2; no history or current diagnosis of chronic-phase, accelerated-phase, or blast-crisis chronic myeloid leukemia; and no clinically significant or uncontrolled cardiovascular disease. The median age in the ponatinib arm was 54 years (range, 19-82) and 52 years (range, 19-75) in the imatinib arm. Men accounted for just under half of the study population—45% and 47% of the ponatinib and imatinib arms, respectively—and most patients (96% and 94%) had an ECOG performance status of 0 or 1.¹

At enrollment the median leukocyte count was 4.4 × 10⁹/L (range, 0.4-198) in the ponatinib arm compared with a median of 3.2 × 10⁹/L (range, 0.2-81) in the imatinib arm. The median blast count was slightly higher in the ponatinib arm at baseline, Jabbour noted, with a median of 80% (range, 0%-100%) vs 75% (range, 0%-100%) in the imatinib arm.

The dominant BCR::ABL1 variants identified were p190 (70% vs 65%) and p210 (24% vs 31%) in the ponatinib arm and imatinib arm, respectively.¹

MRD negativity was assessed during treatment cycles 3, 5, 7, and 9. Using the MR4 cutoff, the MRD-negativity response rate for ponatinib during each cycle was 43% (n = 61 of 142), 63% (n = 57 of 90), 70% (n = 41 of 59), and 92% (n = 44 of 48), respectively. These rates in the imatinib arm were 22% (n = 15 of 68), 52% (n = 17 of 33), 40% (n = 8 of 20), and 47% (n = 7 of 15), respectively.

Using a threshold of BCR::ABL1 no greater than 0.0032%, ponatinib outperformed imatinib in each cycle. The rates of MRD negativity with ponatinib vs imatinib were 27% vs 15%, 40% vs 30%, 48% vs 25%, and 63% vs 27%, for cycles 3, 5, 7, and 9, respectively.¹

At the time of data cutoff more patients in the ponatinib arm were receiving study treatment compared with those in the imatinib arm (41% vs 12%, respectively). Reasons for treatment discontinuation among the 95 patients in the ponatinib arm included hematopoietic stem cell transplant (HSCT; 30%), lack of efficacy (7%), adverse effect (AE; 12%), progressive disease (4%), or other (4%). In the imatinib arm, the 70 patients who discontinued treatment cited HSCT (37%), lack of efficacy (26%), AEs (12%), progressive disease (6%), and other (5%). Twenty-one patients in the ponatinib arm died, and 13 patients in the imatinib arm died.

Subsequent anticancer treatment was received by 35% of patients available for follow-up after ponatinib (n = 163) and 57% of patients who received imatinib (n = 81). Second- or third-generation BCR::ABL1 TKIs and/or immunotherapy was received by 19% and 37% of patients, respectively. Of note, 13 patients went on to receive ponatinib-based treatment following imatinib on study.

“Ponatinib had a safety profile comparable to imatinib, which is known to be a very well-tolerated TKI,” Jabbour said. The safety-evaluable population included 163 patients in the ponatinib arm and 81 in the imatinib arm. Serious treatment-emergent AEs (TEAEs) were comparable, with 60% of patients in the ponatinib arm and 56% of patients in the imatinib arm experiencing them. Grade 3/4 TEAEs occurred in 90% and 93% of patients in each arm, respectively. Grade 5 TEAEs were reported for 5% of patients in each arm.

Of interest, treatment-emergent arterial occlusive events were reported among 4 patients in the ponatinib arm and 1 patient in the imatinib arm. Treatment-emergent venous thromboembolic events were reported in 12% of patients in each arm. Dose modifications, reductions, and interruptions due to TEAEs were reported in 10% vs 9%, 20% vs 22%, and 68% vs 40% of patients in the ponatinib vs imatinib arms, respectively.

The most common grade 3/4 nonhematologic TEAEs in the ponatinib and imatinib arms, respectively, included alanine aminotransferase level increase (19% vs 9%), lipase level increase (13% vs 19%), hypokalemia (6% vs 19%), hypertension (12% vs 6%), and nausea (3% vs 7%). The most common grade 3/4 hematologic TEAEs were decrease in platelet count (63% vs 58%), white blood cell count decrease (53% vs 49%), neutrophil count decrease (49% vs 46%), lymphocyte count decrease (38% vs 47%), anemia (31% vs 36%), and febrile neutropenia (23% vs 19%).

Clinical Implications of PhALLCON

In a discussion of the data, Anjali Advani, MD, provided perspective on how these data would impact clinical practice in the United States. “The strength of this trial [is that] this is the only prospective randomized trial comparing TKIs in this patient population in combination with chemotherapy,” she said. “This is a large number of patients in a relatively rare population, this was an international study, and finally, results were encouraging with no increased risk of TEAEs.”

Advani noted that the trial did have some caveats. “This was a relatively young patient population, with a median age of 54 years, and Ph-positive ALL is typically a disease of [older adults]. This population also had a low incidence of cardiovascular risk factors and so the question is whether we can generalize these results to the larger population who may be older and have comorbidities,” Advani said. Advani is a staff physician in the Department of Hematologic Oncology and Blood Disorders and director of the Inpatient Leukemia Program at the Cleveland Clinic Taussig Cancer Institute; she also is an associate professor at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in Cleveland, Ohio.

“There was a trend toward improved EFS with ponatinib; however, with the new treatments we have such as antibody-based therapies, [or] CAR chimeric antigen receptor] T cells, we are now able to salvage these patients,” Advani added. “There was no difference in OS between the 2 arms, although follow-up is short and the results are not mature yet.”

Advani added, “Although imatinib was a reasonable comparison to ponatinib in the United States, typically most clinicians are using dasatinib and so it would have been nice to have this comparison. The landscape is changing with the use of blinatumomab [Blincyto] plus TKIs either dasatinib or ponatinib in the up-front setting and there are data now published from various groups showing excellent results, although longer follow-up is needed on all of these studies.”^1,4,5

Advani noted that despite the changing landscape, the PhALLCON regimen is an exciting treatment option for patients with Ph-positive ALL.

In a discussion from the European perspective, Nicolas Boissel, MD, PhD, head of the Hematology Adolescent and Young Adult Unit at the Hôpital Saint-Louis and a professor of medicine at Université de Paris in France, noted that there may be other insights gleaned from the ongoing studies in the European Union and United States assessing ponatinib plus blinatumomab.

“It is expected that the access to ponatinib will be delayed in Europe compared to the United States, so meanwhile clinical trials remain a good option to gain access to ponatinib in the front line,” Boissel said. He also cited similar concerns as Advani, including disparities for patients with comorbidities and the role of other second-generation TKIs.

Boissel concluded by highlighting some questions to address in next steps with these investigations: “Can you get rid of chemotherapy and allogeneic HSCT in some patients [with Ph-positive ALL]? How can we identify these patients with MRD monitoring, or by identifying additional abnormalities?”

References

1. Jabbour EJ, Kantarjian HM, Aldoss I, et al. First report of PhALLCON: a phase 3 study comparing ponatinib (pon) vs imatinib (im) in newly diagnosed patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). J Clin Oncol. 2023;41(suppl 36):398868. doi:10.1200/JCO.2023.41.36_suppl.398868
2. Foà, R, Chiaretti S. Philadelphia chromosome–positive acute lymphoblastic leukemia. N Eng J Med. 2022;386(25):2399-2411. doi:10.1056/NEJMra2113347
3. Rowe JM, Buck G, Burnett AK, et al; ECOG and the MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005;106(12):3760-3767. doi:10.1182/blood-2005-04-1623
4. Foà R, Bassan R, Vitale A; GIMEMA Investigators. Dasatinib–blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N Engl J Med. 2020;383(17):1613-1623. doi:10.1056/ NEJMoa2016272
5. Advani AS, Moseley A, O’Dwyer KM, et al. Dasatinib/prednisone induction followed by blinatumomab/dasatinib in Ph+ acute lymphoblastic leukemia. Blood Adv. Published online November 2, 2022. doi:10.1182/bloodadvances.2022008216