Philadelphia chromosome

Ponatinib vs Imatinib in Frontline Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia:A Randomized Clinical Trial

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

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Key Points

Question  Is frontline ponatinib superior to imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL)?

Findings  In this randomized clinical trial, ponatinib demonstrated a significantly higher minimal residual disease–negative complete remission rate at the end of induction (34.4% vs 16.7% with imatinib) and a comparable safety profile vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL.

Meaning  These efficacy and safety results support consideration of ponatinib as a frontline tyrosine kinase inhibitor in combination with chemotherapy for adults with newly diagnosed Ph+ ALL.

Abstract

Importance  In 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.

Objective  To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL.

Design, Setting, and Participants  Global 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.

Intervention  Patients 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 Measures  The 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.

Results  Of 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 Relevance  Ponatinib 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.

A Phase 2 Trial of Ponatinib in Philadelphia Chromosome–Positive Leukemias.

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BACKGROUND

Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor–refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-positive ALL).

METHODS

We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months.

RESULTS

Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event.

CONCLUSIONS

Ponatinib had significant antileukemic activity across categories of disease stage and mutation status.

 

Source: NEJM

 

FDA Approves New Drug to Treat Chronic Myelogenous Leukemia.

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The Food and Drug Administration has approved bosutinib (Bosulif) to treat chronic myelogenous leukemia (CML), a blood and bone marrow disease that usually affects older adults. Bosutinib is intended for patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive CML who are resistant to or who cannot tolerate other therapies, including imatinib (Gleevec).

Most people with CML have a chromosomal aberration called the Philadelphia chromosome, which causes the bone marrow to make an abnormal tyrosine kinase enzyme called Bcr-Abl. This enzyme promotes the proliferation of abnormal and unhealthy infection-fighting white blood cells called granulocytes. Bosutinib is a tyrosine kinase inhibitor (TKI) that works by blocking Bcr-Abl signaling.

Bosutinib’s safety and effectiveness were evaluated in a clinical trial involving 546 adults with chronic, accelerated, or blast phase CML. All of the patients had been previously treated with at least one TKI, either imatinib or imatinib followed by dasatinib (Sprycel) and/or nilotinib (Tasigna).

Among patients with chronic phase CML, 34 percent of patients who had been treated previously with imatinib and 27 percent of those who received more than one prior TKI achieved a major cytogenetic response within 24 weeks.

Among patients with accelerated phase CML who had received at least one prior TKI, 30 percent had their blood counts return to the normal range (a complete hematologic response) by week 48, and 55 percent achieved a complete hematologic response, no evidence of leukemia, or return to chronic phase (an overall hematologic response) by week 48. Among patients with blast phase CML who had received at least one prior TKI, 15 percent had a complete hematologic response and 28 percent an overall hematologic response by week 48.

The most common side effects observed in those receiving bosutinib were diarrhea, nausea, a low level of platelets in the blood, vomiting, abdominal pain, rash, anemia, fever, and fatigue.

Source: NCI

 

Genome Study Points to Treatments for High-Risk Form of Childhood Leukemia.

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Using genomic tools, researchers have uncovered genetic changes associated with a form of leukemia that recurs in some children. The findings, reported last month in Cancer Cell, suggest that some of these young patients may benefit from targeted drugs that are available but currently not used to treat this particular form of the disease.

The study focused on a subtype of acute lymphoblastic leukemia (ALL) known as Philadelphia chromosome-like ALL. Children with this subtype have a higher risk of a recurrence after standard chemotherapy and lower rates of long-term survival than other children with high-risk ALL.

Since the subtype was first described in 2009 (here and here), researchers have identified genetic changes that could explain about half of these cases. Building on this work, a team led by Dr. Charles Mullighan of the St. Jude Children’s Research Hospital analyzed RNA from 15 patients with the subtype and sequenced the genomes of two of these patients.

The results, Dr. Mullighan said, were “striking.” His team found a diverse set of genetic abnormalities linked to cancer, including DNA mutations and chromosomal rearrangements. The biological effects of these changes, however, appeared to be concentrated primarily on two signaling pathways involved in cell growth and proliferation.

Making Use of Available Drugs 

“We found a wide range of gene fusions, but they converged on a limited number of pathways,” said Dr. Kathryn Roberts of St. Jude, a study author. These pathways included the proteins ABL1, PDGFRB, and JAK2, which all play a role in cell growth.

In the lab, several drugs that inhibit growth-promoting signals through these pathways—including imatinib (Gleevec), dasatinib (Sprycel), and ruxolitinib (Jakafi)—showed anticancer effects against models of Philadelphia chromosome-like ALL.

“These findings are important because these children frequently have very poor outcomes,” Dr. Mullighan said. Future studies could test whether patients with mutations affecting these pathways could be candidates to receive targeted drugs along with chemotherapy, he added.

Overall, children with high-risk ALL have a greater than 80 percent chance of being cured by standard treatments, but only about 60 percent of children with Philadelphia chromosome-like ALL are alive and free of cancer after 5 years. This subtype, which accounts for about 15 percent of childhood ALL cases, shows similar patterns of gene activity as Philadelphia chromosome-positive ALL, but the BCR-ABL1 fusion gene is absent.

Better Diagnostic Tests Needed

The new results are from the TARGET initiative, an NCI-supported project that brings together experts on childhood cancers and genome analysis to identify genetic alterations that could be targeted by new or existing therapies.

“These are exactly the kind of results this initiative was created to generate,” said Dr. Malcolm Smith of NCI’s Cancer Therapy Evaluation Program and an NCI leader of the TARGET initiative.

“At this point there are anecdotal examples of how these findings could be translated for broader application,” Dr. Smith continued. Future challenges include improving diagnostic tests to detect the specific molecular alterations and developing treatments appropriate for each alteration, he noted.

At St. Jude, Dr. Roberts is investigating two approaches for detecting this subtype of ALL at the time of diagnosis. One strategy is to profile the active pathways in the leukemia cells, and the other is to look for signature patterns of gene activity.

These tests could serve as an initial screen for Philadelphia chromosome-like ALL, followed by testing for specific genetic alterations associated with the disease, according to Dr. Christine Harrison of Newcastle University in the United Kingdom, who wrote an accompanying editorial.

She praised the study for providing “a comprehensive genomic definition” of Philadelphia chromosome-like ALL, showing it to be a disease with distinctive genetic alterations that affect a range of proteins involved in cell growth.

The work also illustrates one way that cancer researchers are increasingly using genomic tools, noted co-author Dr. Stephen Hunger of the University of Colorado, who is also chair of the Children’s Oncology Group ALL Disease Committee.

“The first step is to identify the abnormalities driving the development of a particular cancer,” he explained. “Then, you use therapies directed against those abnormalities—either alone or with chemotherapy—to improve the outcomes of patients with the least possible side effects.”

Dr. Smith added, “Targeted agents are already known for some of the molecular alterations in Philadelphia chromosome-like ALL, but for others they will need to be identified.”

Dr. Mullighan agreed that a more complete understanding of the Philadelphia chromosome-like ALL subtype is needed. When his team expanded their analysis to include samples from more than 400 patients, the critical lesions in about 20 percent of the cases were unknown.

“We need to know what the changes are, and no single method of analysis is going to pick up every genetic alteration,” he said.

Knowledge gained from studying Philadelphia chromosome-like ALL in children could prove useful for adolescents and young adults as well. This subtype is thought to be more common with advancing age, and the prognosis may also worsen with age.

Since the study was published, Dr. Mullighan has received inquiries from doctors who want to know whether their patients with ALL might be candidates for the new approach. For the study authors, this has underscored the importance of developing clinically accredited tests.

“We really need to develop the diagnostic tests so that we can identify these patients at the time of diagnosis and direct them to the most appropriate targeted therapy,” Dr. Roberts said.

Source: NCI.