acute lymphoblastic leukemia

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.

What are car T cell therapies in cancer treatment, and why is there so much buzz about it nowadays?

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For a long time, the cancer treatment universe was restricted to 4 modalities, in particular Surgery, Radiation, Chemotherapy and Targeted Drug Treatments. Of late, we have seen the expansion of a fifth front in the fight against cancer, called Immunotherapy. Researchers have been endeavoring to create approaches to prepare the human immune system to battle cancer cells, similar to how they eliminate germs in trifling issues such as the common cold.

When we become ill with the common cold, our immune system attacks the infectious germs and executes them, viably curing us. What is at work here are a sort of cells present in our blood called T-cells. T-cells have the one of a kind capacity to recognize affected cells, lock on to them and kill them.

In a CAR T-cell treatment, a patient’s T-cells are designed, so that they attach themselves to cancer cells and destroy them. Such T-cells are extracted from the patient’s own blood, and are built in a lab to identify particular proteins (or antigens) present inside cancer cells. Then, once these cells increase in adequate numbers, they are infused once more into the patient’s circulation system. Once in the body, they start targeting cancer cells.

The utilization of Car T-cell treatments had been constrained to clinical trials till recently. In these trials, numerous patients in advanced stages of cancer have encountered positive outcomes. Numerous such trials included patients experiencing advanced ALL (Acute Lymphoblastic Leukemia) with limited treatment alternatives. Most patients experienced 100% remission, and remained this way for prolonged periods of time. Comparable promising outcomes have been seen in the case of lymphoma patients. Some of these treatments have been approved for treatment in certain leukemias and few solid tumours.

While the symptoms of such medicines can be perilous, the medical science has developed practical protections against such impacts, with supportive treatments. Car T-cell treatments appear to have immense potential, however given the dynamic nature of cancer mutations, further investigation is required to standardize it and make it accessible to patients all around. Numerous labs around the globe are right now testing these treatments not only for blood cancer but also solid tumors, such as pancreatic and brain tumours. Given the measure of intrigue the field has produced among scientists around the world, it is likely that the following decade will be transformative in characterizing the cancer treatment paradigm.

 

OncoBreak: ‘Patient-Centered’ Drugs, Unhelpful Chemo, Kinder Colonoscopy

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