from Leadership Medica n. 2/2001
Leadership Medica and Leader for Chemist have always been in the front line in following the developments of scientific research in the oncological field, starting from the first studies on the various forms of leukaemia, on the advances in bone marrow transplantation up to the use of stem cells. The articles, covering every single stage of the research, were written by the very people who conducted these studies, and among the authors we mention Prof. Freireich, Prof. Gale and Prof. Lambertenghi Deliliers. And now, in line with out past contributions, we are offering as an advance news to the international scientific world the results achieved by Prof. Pier Mario Biava in a research which represents a crucial turning point in the treatment of oncological pathologies. In order to document our work over the last decade, we are quoting here the salient passages from the various articles published. Upon the release of this issue, there will be a round-table conference with the participation of Prof. Lambertenghi Deliliers and his team and of Prof. Biava, in order to publicise, also through widely circulated papers, the latest developments in oncological research, as well as its possible applications.
Emil J. Freireich
History of a Life and of a Discovery (Leadership Medica 1990)
Through his long professional experience, the author retraces the most significant steps in his research work on leukaemia, particularly for those forms whose discovery he has contributed to, also testing new therapeutic solutions.
Observations on the Natural History of Acute Leukemia
“The first major observation made by us relates to the description of what we called the “Ball” disease. Indeed, we found that some patients suffered sudden and dramatic death from cerebral haemorrhage. In these patients, there was a strict correlation between the survival of a blastic crisis and the haemorrhagic event. We were also able to prove that the survival of these “balls” was due to the sludging of leukaemic cells within the smaller intracerebral vessels. This syndrome offers the foundation for the concept that a blastic crisis represents an actual medical emergency. Up to now, this concept of medical emergency has been resorted to worldwide. In addition to the intracranic haemorrhage syndrome, we have acknowledged, defined and treated childhood meningeal leukaemia.” Studies on Chemotherapy of Adult Acute Leukemia “In 1965 the therapeutic schemes employed for the treatment of acute leukaemia in the paediatric age had a 50% therapeutic effectiveness. The therapeutic schemes led to a complete remission for adult acute leukaemia only in 9% of cases. The first major step forward in our understanding of the therapy for adult acute leukaemia was the description of the therapeutic effectiveness of the substance named arabinosyl-cytosine in conjunction with other drugs.” Research Work on Clinical Trial Techniques “Although I was the chief organiser of the first clinical trial employing placebo-controlled randomisation for the therapeutic evaluation of tumours, in the late 60s it became clear that this research method displayed serious limitations. We acknowledged that the analysis of the prognostic factors allowed the distinction of the patients responding to chemotherapy from those who were not expected to respond. For the first time we employed the multiple-variable statistical method, and in particular the one devised by Prof. Cox, to evaluate the probability of each patient’s response before the therapy. These techniques have allowed the development of logistic regression equations. In addition, we designed statistical models aimed at predicting the remission length. It was therefore possible to prospectively evaluate these models with a view to assessing the possibility that they may offer a guideline for therapy prescription based on response expectancy. Research Work Carried out on other Neoplasias and on the Biology of Tumours “During the research work conducted to identify new therapies for leukaemia, we have identified new mechanisms which have contributed to our understanding of the biology of this disease. It is not possible to grow in vitro myelopoietic colonies from patients affected by acute leukaemia in its active phase. We were the first to demonstrate that, once the remission of the disease had been achieved, it was possible to grow the above cells. This discovery has confirmed the hypothesis that complete remission represents a return to normal haematopoiesis. We also demonstrated that the non-specific immune function represents an important prediction factor as regards the response to chemotherapy in leukaemia and in other neoplasias. Furthermore, we were the first to apply Adriamycin, Fluoroacil and Citoxan (FAC) in the therapy of metastasis of breast neoplasia. We were also the first to employ Adriamycin in conjunction with other agents for the therapy of lymphoma.”
Robert Peter Gale
Bone Marrow Transplantation (Leadership Medica 1990)
“Major progress has been made in bone marrow transplantation therapy in cases of leukaemia, lymphomas and other neoplasias. With this article, we would like to take stock of the situation as regards current therapies, recent progress and future prospects.”
Leukemia “Bone marrow transplantation is often resorted to in the treatment of leukaemia, also including patients affected by acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML)”. Lymphomas “There is a significant interest in the resort to bone marrow transplantation, chiefly in the form of autotransplantation, in the intermediary and in the most serious stages of lymphomas and of Hodgkin’s lymphoma. The studies carried out on the subject show that remission can be achieved with high doses of chemotherapy, with or without radiotherapy in patients affected by advanced stages of lymphoma. Autotransplantation has been recently resorted to in the treatment of initial stages of lymphoma. Results are encouraging and indicate a 20% survival rate in the absence of the disease after 3 or 5 years. Results obtained with chemotherapy display a 5% survival rate. The query to be solved is whether autotransplantation should be used as the initial part of the therapy in patients affected by Hodgkin’s lymphoma and displaying unfavourable prognostic factors. A response on this subject can only be provided through a randomised clinical study.” Problems and Prospects “Although significant progress has been made in the use of bone marrow transplantation as a therapy, certain problems continue to exist. Rejection rarely takes place when the donor is a relative with an identical HLA structure. However it is possible for the rejection rate to increase in the event of alternative donating forms. The disease arising in the donated tissue as a reaction towards the receiver (Tr. Vs. Os.) is another major problem that may take place after bone marrow transplantation. This pathology may be viewed as the opposite of rejection. Indeed, the T lymphocytes of the donated tissue react against the receiver. Tr. Vs. Os. takes place in 50% of receivers from HLS-identical subjects, in a higher rate in transplantations with alterative donors. Recent studies show that it is possible to obtain an incidence of Tr. Vs. Os. through immunosupression with Cyclosporine and Metotrexate. The removal of T lymphocytes form the marrow to be transplanted prevents the occurrence of this pathology. However, this method has resulted in an increased incidence of leukaemia recurrence and of rejection. The survival rate before recurrence has not improved. Autotransplantation does not display the above complications. The major problem we face with this method is that of establish whether increased doses of antitumour substances and radiations bring about recovery and whether the reinfused tissue contains tumorous cells. There is an ongoing animated debate regarding the possibility that reinfused malign cells may represent a major cause for neoplasia recurrence. Significant efforts are being made to identify techniques which may enable the removal of any existing neoplastic cells from the tissue to be transplanted”. Future Prospects “Bone marrow transplantation is particularly important, not only because it restores to health certain patients affected by neoplasias which would otherwise be incurable, but also because it represents a therapy model involving high doses of chemotherapy and/or radiations against tumours. Based on our current knowledge of the subject, it is not clear whether transplantation will continue to be associated with high doses of chemotherapy or radiations, or whether it will prove preferable to use the hematopoietic growth factor or the granulocite-stimulating factor or macrophage granulocites without bone marrow transplantation. In future, it will be possible to correct these pathologies by transplanting bone marrow autologous cells that have been modified through of genetic engineering. A further possibility of employing transplantation is its use in conjunction with the transplantation of other organs. Indeed bone marrow transplantation allows the replacement of the receiver’s bone marrow with that of the donor. It could therefore become possible to transplant organs such as heart, liver and lungs without the risk of rejection. This strategy has been successfully employed with animals. These future prospects may open a door to a wider resort to organ transplantation in man.
Meeting with Prof. Giorgio Lambertenghi Deliliers
New Technologies in the Fight against Leukemia (Leadership Medica 1994)
“Professor Lambertenghi, what is the future of bone marrow transplantation?” “The future lies in the separation of stem cells from the umbilical cord or from peripheral blood, and no longer from bone marrow only. These cells are grown in vitro, expanded and then employed for transplantation. We can therefore expect that in the near future we shall be freed from the need to work on bone marrow: it will be sufficient to have a limited number of totipotent stem cells, grown in vitro, expanded through haematopoietic growth factors and transplanted.” “What is today’s objective?” Today’s objective is the search of alternative sources of stem cells for patients who do not have a family donor. These people represent 70% of the patient sample requiring transplantation. In order to approach the bone marrow transplantation issue, they have three options available: 1) consulting the bone marrow donor registry and checking on the existence of an HLA-compatible donor; however the probabilities of finding a donor increase in proportion to the length of the registry itself: this is why we require international cooperation; 2) the umbilical cord may be the next resource: the blood taken form the placenta, which would otherwise be eliminated, is used to set up a blood bank as an alternative source in addition to bone marrow; 3) the third option is that of autologous transplantation; in this field, the use of stem cells from peripheral blood appears to offer numerous advantages compared to the use of medullar cells. Besides, stem cells can be grown and expanded in vitro. “As regards the preparatory phase for transplantation, have there been changes in the potential donor selection criteria, over the last few years?” “The probabilities of finding, within the patient’s family, a donor with the requested features are in any case limited to approximately 30% of cases. We are therefore left with 70% of “outstanding” cases. For these, it is necessary to make an alternative choice, since we are dealing with patients who can be treated with traditional therapies. We therefore require hematopoietic stem cells coming from other sources.”
(traduzione Interpres sas-Giussano)