Leukemia: Certain children can be spared transplantation

(Vienna, 22.12.2022) A study in collaboration with St. Anna CCRI shows that stem cell transplantation does not provide any advantage over chemotherapy in a specific form of leukemia. “It should therefore no longer be used as standard in these patients,” says co-first author of the retrospective study published in the Journal of Clinical Oncology, Univ.-Prof. Dr. Andishe Attarbaschi of St. Anna Children’s Hospital. The next step will now be to test whether immunotherapy for this group is not only better tolerated but also more effective than chemotherapy.

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children and generally has a very good chance of cure of about 90 percent. If the disease is characterized by a specific genetic marker, namely the rearrangement of 11q23/KMT2A, then about 70 percent of children (≥1 year) remain free of relapse within five years after initial therapy. This was the conclusion of an international retrospective analysis by the Ponte-di-Legno Childhood ALL Working Group with the largest group of children ≥1 year and adolescents to date (n=629). Unlike in infants, who are known to have a very poor chance of cure in the presence of an 11q23/KMT2A rearrangement, the prognosis for children older than one year and adolescents has been completely unclear.

Furthermore, the results show that in the largest two subgroups of this study (B-ALL with translocation (4;11) and T-ALL with t(11;19)) patients with stem cell transplantation had no survival advantage over those who received chemotherapy alone. For Attarbaschi, who was the senior physician in charge of the study, this has an immediate consequence: “Based on our results, we want to withdraw transplantation for the subgroup of patients with a translocation (4;11) in our new ALL study, which will open in 2025. So this study has a direct clinical impact, which I’m very pleased about.”

Better, but not good enough
The effectiveness of treatment for leukemia is significantly better than historical results. The researchers attribute this on the one hand to the optimization of chemotherapy and adjuvant treatment measures, and on the other hand to the much more accurate assignment of patients to therapies based on treatment responses. However, the results are still not good enough, says Attarbaschi. “We need to further improve initial therapy – that is the second important message of our analysis. Which is why we are now looking at whether chemotherapy can be replaced by immunotherapy, a treatment that is also better tolerated.” A corresponding study using the bi-specific antibody blinatumumab is already underway. The results are yet to be seen.

Unique reference guidelines
About five percent of patients with ALL have an 11q23/KMT2A rearrangement. From those, five subgroups have emerged in the present work, which are described in great detail for the first time. “Previously, nothing like this existed. Our study has an extensive appendix with detailed descriptions of the disease subgroups. Physicians who have a patient with one of these rare genetic leukemia variants can now look up how prognosis and treatment response were in our patients. In clinical practice, something like this is invaluable,” continues Attarbaschi.

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Retrospective International Study of ALL with 11q23/KMT2A Rearrangement
The aim of the retrospective international study presented here was to determine prognostic factors and efficacy of allogeneic hematopoietic stem cell transplantation in first remission in acute lymphoblastic leukemia (ALL) with 11q23/KMT2A rearrangement. A total of 629 patients who received chemotherapy between 1995 and 2010 were retrospectively analyzed. The impact of clinical and biological characteristics, early response (determined by minimal residual disease at the end of induction therapy), and stem cell transplantation on treatment outcome was assessed.

At the end of induction treatment, the remission rate was 93 percent and the 5-year event-free survival (EFS) was 69 percent. The latter showed strongly varying values in the individual subgroups, ranging from 42 percent EFS in patients with translocation (9;11)-positive T-ALL and 65 percent in those with translocation (4;11)-positive B-ALL to 91 percent in patients with translocation (11;19)-positive T-ALL.

Low minimal residual disease at the end of induction treatment was associated with favorable EFS. EFS was not improved by transplantation in translocation (4;11)-positive B-ALL and translocation (11;19)-positive T-ALL.

About acute lymphoblastic leukemia (ALL) with KMT2A rearrangement
Approximately five percent of patients with childhood and adolescent acute lymphoblastic leukemia (ALL) have a so-called 11q23/KMT2A rearrangement. In infants, this genetic alteration has been associated with a very poor prognosis to date. A study testing a new form of therapy for infants is about to be published.

In children one year of age and older, and adolescents, the present work provides the first insight into the characteristics and prognosis of this very heterogeneous group. The largest identified subgroup, with 273 patients, represents those with the translocation (4;11). Translocation (11;19) is also relatively common (n=106). Further subgroups are the translocations (9;11), (6;11) and (10;11) with 76, 20 and 14 patients each. These genetic groups differ with respect to clinical features of leukemia, such as the number of leukemic cells at diagnosis, age at first onset or response to therapy, and prognosis. In addition, translocations (4;11), (6;11), and (10;11) occur only in B-ALL, whereas (11;19) and (9;11) occur in both B- and T-ALL.

Publication:
Outcomes of Childhood Noninfant Acute Lymphoblastic Leukemia With 11q23/KMT2A Rearrangements in a Modern Therapy Era: A Retrospective International Study.
Andishe Attarbaschi#; Anja Möricke#; Christine J. Harrison#; Georg Mann; André Baruchel; Barbara De Moerloose; Valentino Conter; Meenakshi Devidas; Sarah Elitzur; Gabriele Escherich; Stephen P. Hunger; Keizo Horibe; Atsushi Manabe; Mignon L. Loh; Rob Pieters; Kjeld Schmiegelow; Lewis B. Silverman; Jan Stary; Ajay Vora; Ching-Hon Pui; Martin Schrappe*; Martin Zimmermann*, on behalf of the Ponte-di-Legno Childhood Acute Lymphoblastic Leukemia Working Group.

#shared first authorship: Andishe Attarbaschi; Anja Möricke; Christine J. Harrison
*shared senior authorship: Martin Schrappe; Martin Zimmermann
Journal of Clinical Oncology, October 18, 2022 DOI: 10.1200/JCO.22.01297

Funding:
The study was supported by grants from the National Institute of Health (U10 CA98543 and U10 CA180886, U10 CA98413, and U10 CA180899) and by the St. Baldrick’s Foundation, the National Cancer Institute (CA21765.), and American Lebanese Syrian Associated Charities.