Acute myeloid leukemia: stem cell transplant or chemotherapy first?

In cases of acute myeloid leukemia (AML) with an intermediate risk prognosis and an available potential stem cell donor, carrying out a stem cell transplant immediately during the first complete remission (where all signs and symptoms of the disease have temporarily disappeared) does not lead to an improved overall survival rate compared with continued chemotherapy and stem cell transplantation only in the event of a relapse. These are the findings of a nationwide German trial led by researchers from University Hospital Dresden at the National Center for Tumor Diseases in Dresden (NCT/UCC) and from the University of Münster. The world’s first randomized trial on this topic (with random assignment of patients to groups) provides an important basis for future treatment decisions. In countries like the USA, where immediate stem cell transplants are the norm, the results could lead to a fundamental rethink of this treatment step. The paper was published in JAMA Oncology.

Joint press release by NCT/UCC Dresden and the University of Münster

The National Center for Tumor Diseases Dresden (NCT/UCC) is a joint institution of the German Cancer Research Center (DKFZ), University Hospital Carl Gustav Carus Dresden, the Faculty of Medicine Carl Gustav Carus of TU Dresden and the Helmholtz-Zentrum Dresden-Rossendorf (HZDR).

Despite advances in treatment, only around 30 percent of all adult AML patients survive for five years or more. In patients who are eligible for intensive therapy, stem cell transplantation from a healthy donor is often the method with the greatest chance of recovery. There is an urgent need for further therapy improvements.

A trial conducted at 16 hospitals in Germany has now provided an important basis for improved therapy decisions for patients with intermediate-risk AML. The key indicators for assigning patients to one of the three risk groups – favorable, intermediate and adverse – are specific genetic characteristics of the cancer cells, which provide an indication of how the disease will progress. Following initial chemotherapy and a temporary complete remission, patients with a favorable prognosis continue to receive chemotherapy, while those with an adverse prognosis and a suitable donor receive a stem cell transplant. Until now, there has been some debate about which of the two treatment methods is preferable for patients with intermediate-risk AML.

This recent trial has shown that although immediate transplantation of foreign (allogeneic) stem cells is very effective in the majority of intermediate-risk AML patients during the first complete remission, it does not increase overall survival compared with continued chemotherapy and transplantation only if needed.
The trial studied 143 adult AML patients aged between 18 and 60, for whom a suitable stem cell donor was available and who achieved a complete remission following the first intensive course of chemotherapy. Patients were randomly assigned to one of two groups: The first group received a stem cell transplantation, while the second group continued to be treated with chemotherapy. Patients in the second group who suffered a relapse were also given a stem cell transplant.

High recovery chances with both strategies

The treatment outcomes for both arms of the trial were very encouraging overall: The two-year survival rates were 74 percent and 84 percent. However, there was no statistically significant benefit from immediate stem cell transplantation. “This is an important finding, since there are now two strategies available for patients with a donor that offer similarly good outcomes,” says Professor Martin Bornhäuser, Director of Medical Clinic I of University Hospital Dresden and a member of the managing directorate of NCT/UCC Dresden. Each of these treatment options has its own advantages and disadvantages: Whereas treatment-related risks are greater for a stem cell transplantation, for instance, there is a higher risk of relapse with continued chemotherapy. “Based on the trial results, a patient may well be justified in choosing to continue with chemotherapy to start with, and to have a stem cell transplantation only if they suffer a relapse,” says Professor Bornhäuser. “It is the first time that it has been possible to research this in a randomized, i.e. particularly informative, trial. Most AML patients are not willing to leave the immediate transplantation decision to a random group assignment within a clinical trial. We are extremely grateful to all participants who have made this important research possible.”

Sixty percent of the patients in the trial who started with consolidation chemotherapy suffered a relapse in the first two years following the start of treatment and subsequently received an allogeneic stem cell transplantation. “If patients are very afraid of suffering a relapse and having to stay in hospital again, it can make sense to carry out a stem cell transplant immediately – after the physician and patient have carefully weighed up the options together,” says Professor Matthias Stelljes, Head of Bone Marrow Transplantation at University Hospital Münster, who is co-leader of the trial and last author of the research paper. “That is because this option has a much lower risk of relapse. And in some circumstances, this means patients are prepared to accept a higher treatment-related risk.”

In terms of quality of life, the trial showed no relevant difference between the two treatment paths – stem cell transplantation involving four to six weeks in hospital or consolidation chemotherapy for around six months. “During the stem cell transplantation itself, the quality of life experienced by patients was somewhat worse, but otherwise there were no identifiable significant differences between the two groups,” says Professor Stelljes. “What we are particularly interested in now is the result of long-term follow-up observations after ten years.”

A globally important basis for treatment decisions – an early donor search is key

The results of the trial form an important basis for physicians and patients to decide together on the best possible treatment. “In Europe, physicians are already using consolidation chemotherapy as an alternative to stem cell transplantation. The results of this trial will give them additional assurance when choosing between the two methods for individual patients,” says Professor Bornhäuser. “By contrast, in other countries like the USA, immediate stem cell transplantation has been the norm until now. So in these places our research could lead to a fundamental rethink.” Professor Michael Albrecht, Medical Director of University Hospital Dresden, says, “We are proud that research led by University Hospital Dresden is producing findings that can improve treatment decisions for leukemia patients worldwide.”

“In all AML cases, a search for a suitable stem cell donor should be conducted as early as possible,” explains Professor Stelljes. “Germany is extremely well placed to do this because of its large donor registers. No other country carries out donor searches as fast. Even when chemotherapy is the initial choice for a patient, the availability of a suitable donor provides reassurance that a transplant can be carried out quickly if the patient suffers a relapse.”

Cutting-edge diagnostic methods make it possible to monitor the course of AML in ever greater detail. One of the aims of future trials will therefore be to determine the optimum timing for stem cell transplants on an individual patient basis. “Ideally, we would be able to carry out a transplant when key disease parameters worsen significantly following consolidation chemotherapy, rather than waiting for a relapse, which is risky for the patient. This is the direction in which developments are moving now,” says Professor Bornhäuser.

Publication:
Bornhäuser M, Schliemann C, Schetelig J, et al. Allogeneic Hematopoietic Cell Transplantation vs Standard Consolidation Chemotherapy in Patients With Intermediate-Risk Acute Myeloid Leukemia: A Randomized Clinical Trial. JAMA Oncol. Published online February 09, 2023. doi:10.1001/jamaoncol.2022.7605

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https://www.nct-dresden.de/fileadmin/media/nct-dresden/das-nct/newsroom/pressemitteilungen/Stammzellen_Labor.jpg

Caption:
Stem cells from a donor being prepared for transplantation in the laboratory. © University Hospital Dresden/Marc Eisele

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National Center for Tumor Diseases Dresden (NCT/UCC)
The National Center for Tumor Diseases Dresden (NCT/UCC) is a joint institution of the German Cancer Research Center, the Carl Gustav Carus Faculty of Medicine at TU Dresden, the Carl Gustav Carus University Hospital Dresden and the Helmholtz-Zentrum Dresden-Rossendorf (HZDR).
The NCT has made it its duty to closely link research and patient care wherever possible. That is why cancer patients at the NCT sites can be treated based on the latest research results. At the same time, the proximity of laboratory and clinic provides researchers with important impulses for their practice-oriented research. The NCT sites share the common goal of developing the NCT into a top international center for patient-oriented cancer research. The Dresden center draws on the structures of the University Cancer Center Dresden (UCC), which was founded in 2003 as one of the first Comprehensive Cancer Centers (CCC) in Germany. Since 2007, the UCC has been honored by the German Cancer Aid e.V. (DKH) as a "Top Oncological Center" on a continuous basis.

German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer.
Jointly with partners from the university hospitals, the DKFZ operates the National Center for Tumor Diseases (NCT) in Heidelberg and Dresden, and the Hopp Children's Cancer Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. NCT and DKTK sites combine excellent university medicine with the high-profile research of the DKFZ. They contribute to the endeavor of transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients.
The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.

University Hospital Carl Gustav Carus Dresden
The University Hospital Carl Gustav Carus Dresden offers medical care at the highest level of care. As a full-service hospital, it covers the entire spectrum of modern medicine. The University Hospital combines 20 clinics and outpatient departments, four institutes and ten interdisciplinary centers that collaborate closely with the clinical and theoretical institutes of the Faculty of Medicine.
With 1,295 beds and 160 places for day-care treatment, the Dresden University Hospital is the largest hospital in the city and also the only full-service hospital in eastern Saxony. Around 860 doctors cover the entire spectrum of modern medicine. 1,860 nurses and caregivers ensure the patients' well-being. The medical care of patients suffering from cancer, metabolic and neurodegenerative diseases is an important focus of treatment at the University Hospital.
Germany's largest hospital comparison by the news magazine "Focus" confirms that the University Hospital Carl Gustav Carus Dresden provides an excellent quality of treatment. That is why Dresden's university medicine comes second in the Germany-wide ranking.

Carl Gustav Carus Faculty of Medicine at Technische Universität Dresden
The Dresden University Medicine, consisting of the Carl Gustav Carus Faculty of Medicine and the university hospital of the same name, has specialized in research in the fields of oncology, metabolic as well as neurological and psychiatric diseases. Within these focal areas, the topics of degeneration and regeneration, imaging and technology development, immunology and inflammation, as well as prevention and health care research are of particular interest. International exchange is a prerequisite for top-level research - the Dresden University Medical Center embraces this concept with employees from 73 nations and numerous collaborations with researchers and teams from all over the world.

Helmholtz-Zentrum Dresden-Rossendorf (HZDR)
The Helmholtz-Zentrum Dresden-Rossendorf (HZDR) conducts research in the fields of energy, health and matter. It focuses on the following questions:
•    How can energy and resources be used in an efficient, safe and sustainable way?
•    How can cancer be better visualized, characterized and effectively treated?
•    How do matter and materials react under the influence of strong fields and in smallest dimensions?
To answer these scientific questions, the HZDR operates large infrastructures that are also used by external measurement guests: Ion Beam Center, High Field Magnetic Laboratory Dresden and ELBE Center for High Power Radiation Sources.
The HZDR is a member of the Helmholtz Association, has five sites (Dresden, Freiberg, Grenoble, Leipzig, Schenefeld near Hamburg) and employs almost 1,200 people - about 500 of whom are researchers including 170 PhD students.