2023-04-26 23:06:44
Cancer in children is considered a rare disease, very infrequent: barely 155 new cases per year for every million children under 14 years of age. Science manages to cure most cases, but some tumors have few outlets. Acute lymphoblastic leukemia, for example, is the most frequent pediatric cancer and, although 85% of patients outgrow the disease, there are subgroups where things get complicated: especially in smaller babies and with bad genetic alterations. forecast. A new scientific study, published this Wednesday in the journal New England Journal of Medicine (NEJM), targets those darker tumors and shows hopeful results in improving the survival of babies with KMT2A gene rearrangement acute lymphoblastic leukemia, a very aggressive subtype of blood cancer: by adding an immunotherapy to the usual chemotherapy treatment, the overall survival at two years went from 66% to 93%.
It is a first step. A sign that lights the way forward, but you have to be “cautious”, Susana Rives, head of the Leukemia and Lymphoma Unit at the SJD Pediatric Cancer Center Barcelona, adds. “These are promising results compared to what was previously available, but they must be confirmed with more follow-up time,” says the hematologist, who did not participate in the study. The published data correspond to a phase II clinical trial with about thirty patients, all babies under 12 months of age, and with a follow-up of a couple of years. The findings will have to be consolidated, but these first results are so encouraging that the authors hope to be able to incorporate this new therapeutic strategy as first-line treatment in this group of patients.
In absolute numbers, babies with this subtype of acute lymphoblastic leukemia (ALL) are few, less than a dozen a year in Spain, Rives calculates. If tumors in children are already infrequent, in babies under one year of age, even more so. It is a “rare among the rare” tumor, agrees Pablo Velasco, a pediatrician at the Vall d’Hebron Pediatric Oncology and Hematology service. The genetic alteration, however, is more frequent in babies with ALL than in older children: “80% of children under one year of age with ALL have this genetic rearrangement [del gen KMT2A], a characteristic that goes hand in hand with the poor prognosis. We have not found more effective therapies”, laments the pediatrician, who has not participated in this research either, but celebrates its “spectacular results”.
To treat ALL with KMT2A rearrangement in infants under one year of age, the therapeutic protocol so far includes intensive chemotherapy for two years and, in some cases, a bone marrow transplant afterwards. But the global results are not very rosy. Complication-free survival at three years is less than 40%, the authors emphasize in the article. “It is a very aggressive disease, more resistant to standard chemotherapy. Intensive chemotherapy works very well for half of the babies. But in the other half, the disease returns within two years, or children die from it, or sometimes from side effects of therapy. 90% of relapses occur during the course of the two years of therapy,” Inge van der Sluis, a pediatric oncologist and clinical pharmacologist at the Princess Máxima Center for Pediatric Oncology in Utrecht (Netherlands) and first study author.
Although the approach to ALL in adults and older children has improved in recent decades, the group of babies has lagged further behind in the search for therapies with more positive results. The highly aggressive nature of KMT2A-rearranged ALL makes relapses very frequent—two-thirds of recurrences actually occur in the first year after diagnosis, even when fully treated—and the prognosis worsens. Until now, “survival after relapse was only 20%,” explains van der Sluis.
With this dark panorama on the table, the authors of the study opted for a new therapeutic strategy: immunotherapy, which are drugs that activate the body’s own immune system to kill malignant cells. “We chose immunotherapy because chemotherapy intensification did not work and further intensification is impossible due to toxicity. We needed a new treatment modality. We chose immunotherapy with the drug blinatumomab because it has already been studied in adults and older children with ALL and it was not yet clear if this treatment was well tolerated and effective in infants”, explains the Dutch doctor. The essay would serve to clarify it.
live longer and better
Blinatumomab is a bispecific antibody that works like “a socket thief”, Rives exemplifies: on the one hand, it binds to the tumor cell and, on the other, it hooks up to T lymphocytes, which are in charge of destroying the cells malignant; and then the presents, so that the lymphocyte recognizes, attacks and destroys those leukemia cells. The researchers, who added the immunotherapy to their usual treatment, followed the patients for two years and compared their progress with data from previous studies that had only treated the children with chemotherapy. “We found that adding blinatumomab to standard chemotherapy leads to a significant improvement in survival for infants with KMT2A-rearranged acute lymphoblastic leukemia: their chance of survival increased from 66% to 93%. And the chance that his cancer would come back or that he would die from his disease was greatly reduced, from 51% to 18%,” van der Sluis summarizes. They live longer and with a better quality of life.
The short-term harmful effects of this new therapeutic approach have also been “manageable”, according to the experts consulted. In fact, there was less collateral damage than with chemotherapy alone, van der Sluis notes: “Potential side effects included fever, anemia or infection, but they were well managed.”
Rives celebrates the two great advantages that, in his opinion, this study yields: “It improves results and prevents early relapses. And the toxicity that these children have presented is less than with the intensive chemotherapy blocks, which is what they receive now. In the short term, it is not toxic. We will see what happens in the long term ”, he points out.
Patient follow-up was shorter than usual, about 26 months. But the Dutch researcher is justified: “The follow-up was relatively short, but it covers the period in which you would expect most recurrences.” In that two-year period of time is when relapses usually occur and, if in that critical period, the results improve, “that period already has value,” agrees Rives. Van der Sluis herself qualifies, however, that future relapses cannot be “excluded and longer follow-up is expected.”
It will take time —and more studies— to consolidate the data, all the voices consulted agree. In fact, the limitations of the study itself already reflect the short follow-up time and that it is not a randomized study (with a control arm that did not receive immunotherapy to refine the real impact). But the authors hope that these results will already change the standard of treatment for a cancer with such a poor prognosis. “As a result of our study, all babies with ALL with the KMT2A rearrangement will receive immunotherapy as part of standard treatment. Although it should be noted that blinatumomab is not registered as a first-line treatment in infants. As a consequence, patients can currently only receive treatment within the study protocols to gain access to blinatumomab. The vast majority of pediatric cancer patients are treated in study protocols,” explains van der Sluis. And it advances that they have already planned a larger study, with 160 patients from 27 countries (including Spain), to implement their findings.
more follow up
The experts admit that it is a study with few patients and followed up for a short time, but they justify that, being such an infrequent disease, it is more difficult to increase the number of participants. Velasco assures that, in any case, this study published in NEJM It is already “good news” and opens up an “interesting future”. The trials to come, yes, will help answer questions that now remain in the air. “We know that relapses occur, above all, at the beginning. But, is immunotherapy going to change the relapse profile? We do not know. We will have to follow up ”, she raises.
It is unknown, for now, what happens to these babies beyond the age of two, if the disease returns or undescribed side effects appear. But the results are “encouraging”, insists Pablo Menéndez, principal investigator of the Stem Cell Biology, Developmental Leukemia and Immunotherapy group at the Josep Carreras Leukemia Research Institute. “The research of many years begins to give results in childhood cancer. You have to be careful and follow them for years, but these are not mice: they are patients, and with an approved and marketed drug, ”he celebrates.
The researcher, who did not participate in this study, recalls that blinatumomab is a drug approved by regulatory agencies for adults and children with acute lymphoblastic leukemia, although in Spain it is given “in an atomized way” because it is not financed. Its price is around 100,000 euros per patient, says Menéndez, and when it is administered, Velasco agrees, it is done at the discretion of each hospital. “It has a high cost and we will see how it is administered in the early stages to these new patients, but there should be no problem paying for it because, in number, they are few,” Menéndez points out.
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