50 years of the Polish Adult Leukemia Treatment Group (PALG).

The Polish Adult Leukemia Treatment Group (Polish Adult Leukemia Group - PALG) has been in existence for 50 years. It sets standards for the management of leukemia in adults and carries out research projects that have influenced the fate of patients. What was the treatment of leukemia in Poland like when PALG was founded?

I know from stories about what treatment was like back then. Treatment was much less intensive and less effective than it is today, and in Poland and countries in our region, it differed significantly from the standards that were then in place in Europe or the United States. The cure rate was low, the very diagnosis of acute leukemia was almost a sentence.

The activities of PALG were initiated at a congress in Gdansk in 1975 on the initiative of several leading experts in the field of hematology, representing academic centers. They had, on the one hand, the need to coordinate activities in the treatment of acute leukemia (initially, the group dealt only with acute leukemia), and, on the other hand, they wanted to introduce in Poland the experience of countries more advanced in this regard and ensure that patients had access to more effective treatment.

The founding group was a few people representing the largest hematology centers in Poland. Over time, the group grew, and now we bring together hematologists from 36 centers. The first years of activity were an attempt to implement foreign standards in Poland. It was not easy, but the results of treatment of our patients improved significantly already during the first 10 years of the Polish Leukemia Treatment Group. Later, the goals became more ambitious: PALG members began planning prospective clinical trials to verify hypotheses for optimizing treatment. Initially, the research was conducted under government programs.

How did it happen that you joined PALG?

When I started working in hematology, one of the first clinical trials on acute lymphoblastic leukemia was underway: PALG4-96, which looked at the use of granulocyte colony growth factor to reduce the hematologic toxicity of chemotherapy in this group of patients. This study showed that if such treatment is used, the depth of neutropenia is reduced, and in certain subgroups of patients this also translates into efficacy. The treatment allows the intensity of chemotherapy, and thus the efficacy of treatment increases. This was the first study I took part in as a young doctor, a hematologist.

Many of the clinical trials initiated and conducted by PALG have changed the standards of treatment for patients - and not only in Poland....

By the end of the 20th century, the scale of clinical trials conducted by PALG was becoming larger and larger, and most notably we conducted a very significant trial in acute myeloid leukemia that compared the standard that had been in place for years: daunarubicin with cytarabine in induction treatment with two experimental protocols, namely daunarubicin with cytarabine in combination with fluderabine or cladribine. Cladribine was a relatively readily available drug in Poland at the time, produced in Poland based on the original line. We had evidence from preclinical studies that adding cladribine could increase the efficacy of traditional chemotherapy regimens. We demonstrated this in our study - it was a phase III trial, and we found that adding cladribine increased the chance of complete remission and the possibility of curing patients.

The results of this study were published in 2012 in the Journal of Clinical Oncology, and were included in the US NCCN recommendations. Our regimen was indicated as one of the recommended by international scientific societies.

We have conducted a whole series of clinical trials to optimize leukemia treatment. We are active and recognized worldwide.

PALG has also conducted clinical trials in other types of leukemia?

Regarding acute lymphoblastic leukemia, we were one of the first research groups in the world to show that assessing response at the level of minimal residual disease, i.e. using highly sensitive laboratory techniques, has the greatest impact on the long-term outcome of patients. We have shown (PALG 4-2002 study) that if residual disease is detected after induction treatment, the chance of cure is much lower. This has insanely important implications, it is the most important prognostic factor that determines whether or not we will qualify a given patient for allogeneic hematopoietic cell transplantation.

As for chronic leukemia, Prof. Tadeusz Robak was the leading researcher; he tested the efficacy of cladribine in various configurations in this group of patients. He showed that this drug is relevant and its use is justified. Later, treatment standards changed, but at some stage we left our mark in the history of medicine.

In the case of chronic myeloid leukemia, it is worth mentioning an analysis comparing the safety and efficacy of generics of imatinib, the first targeted drug in oncology. Initially, we were not convinced that replacing the original drug with a generic would not negatively affect the prognosis of patients; this turned out not to be the case. We were the first group in the world to provide such proof. The analysis was conducted by Prof. Tomasz Sacha of Krakow.

In many cases, scientific findings have translated into clinical practice?

Yes, this is the essence of what we do as doctors and as scientists: we verify hypotheses that allow us to optimize our post-treatment.

How is the Polish Adult Leukemia Treatment Group structured today: do you work in teams?

We are divided into thematic sections, related to the types of diagnoses: acute leukemia (myeloid, lymphoblastic); chronic leukemia (lymphocytic, myeloid), myelodysplastic syndromes, but also by therapeutic techniques: we have a section dealing with hematopoietic cell transplants, as well as supportive care (a section dealing with infectious complications). Each section has its own leader, who forms a team drawn from various centers in Poland, discusses with the team the possibility of implementing new protocols, and tries to raise funds for new projects. Each of the new projects has its own value and potential in terms of improving treatment options for patients.

What does PALG's cooperation with international centers look like?

Leukemias are not common diseases, so it would not be possible to conduct a clinical trial within a single center; multi-center cooperation is necessary. We implement it both within Poland and in other countries. We work closely with groups like ours - both in Europe and in the United States. We carry out some studies jointly. An example is the PALG AML1-2016 study, which involved all the centers in Poland, as well as a leading center from New York.

PALG members are also authors and co-authors of international recommendations for the treatment of acute myeloid leukemia (Prof. Agnieszka Wierzbowska), acute lymphoblastic leukemia (me), chronic lymphocytic leukemia (Prof. Tadeusz Robak), various aspects of treatment with hematopoietic cell allotransplantation (Dr. Tomasz Czerw and myself).

How are ideas for more research born? Do they have the potential to change medicine and patient prognosis?

I think so - that's why we implement them. When, for example, there is a new drug, but its combinations with other previously used drugs have not yet been tested, and there are indications from biological studies that a particular combination may be more effective, we create a protocol under which we want to test the combination. Of course, this involves funding, because all clinical trials must be properly monitored, conducted to the highest standards, to guarantee the greatest safety for patients, and for the researchers, who must also be insured. This requires proper infrastructure, and there must be close coordination between centers. That's why PALG has an office, it's located at the Institute of Oncology in Gliwice, it has staff, equipment. We often meet with other researchers, including online. The exchange of ideas and concepts is very efficient today.

How do you assess leukemia treatment in Poland today, after 50 years of PALG?

I rate it very well. The treatment options for Polish patients are comparable to those of patients in other countries, and even in some areas we are in the vanguard in terms of access to new therapies that we can offer to patients.

In terms of treatment, currently the biggest challenge among leukemias is acute myeloid leukemia?

It seems to be. This is a very aggressive cancer, and a cure must be fought for at all costs. Currently, in younger patients, the chance of a cure is steadily increasing, now it can reach more than 50 percent. In older patients, there are fewer opportunities for intensive treatment, and progress is slower; there is still a lot of work to be done here.

What are the biggest challenges facing PALG and leukemia physicians today? What will be the most important topics of discussion at PALG's 50th anniversary meeting?

Certainly, our discussion will focus on what to do to make treatment even more effective. As for acute myeloid leukemia, we recently initiated the MAGIC project. It's a large clinical trial, funded by an ABM grant: we are trying to individualize therapy very much, dividing patients into subgroups, depending on the subtype of leukemia and its genetic characteristics. We are tailoring the right combination of drugs to the subtypes, and we are also testing new combinations - including adding cladribine to the regimens currently considered the current standard. This trial is ongoing, and we have high hopes for it, assuming that personalizing treatment, tailoring to individual disease characteristics, can improve treatment outcomes.

Another ABM-funded clinical trial for acute lymphoblastic leukemia is underway, in which we are comparing two types of monoclonal antibody: rituximab and obinutuzumab added to chemotherapy for first-line treatment. To date, rituximab has been the standard; obinutuzumab, on the other hand, is a newer-generation antibody; we hypothesize that its administration may contribute to treatment efficacy.

In chronic lymphocytic leukemia, on the other hand, personalization of therapy refers to assessing the response at the level of minimal residual disease; if the response is exceptionally good, treatment, which normally lasts 2 years, can be shortened to reduce the risk of possible side effects.

We also have extremely ambitious plans for myeloproliferative neoplasms, such as verrucous melanoma and spontaneous hyperplasia, where we also plan to conduct a clinical trial that could change the way things are done.

There are many plans; has the creation of the Medical Research Agency made it easier to conduct clinical trials?

Very; before, we had to try to raise funds in an unstructured way, looking for potential donors; and it was not easy. Nowadays, if a project is scientifically attractive and feasible, there is a chance to get real funds from the Medical Research Agency. We are currently conducting several studies funded by the Medical Research Agency, so we can do it in a fully professional manner.

Prof. Sebastian Giebel, MD, head of the Department of Bone Marrow Transplantation and Oncohematology at the Maria Sklodowska-Curie National Cancer Institute, Gliwice Branch. President of the Polish Adult Leukemia Treatment Group and vice president of the Polish Lymphoma Research Group. Among other things, he is the author of European recommendations for the treatment of patients with acute lymphoblastic leukemia and an international expert in hematopoietic cell transplantation.

Author: Katarzyna Pinkosz/ Hematoonkologia.pl