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INDEX INDICATIONS
AND FORMS OF HEMOPOIETIC THE
REGISTRY OF HEMOPOIETIC PROGENITOR HEMOPOIETIC
PROGENITOR CELLS PRESENTATION In recent decades we have witnessed a dramatic improvement in certain medical treatments. This improvement, however, has been accompanied by a large increase in costs, a fact which concerns most of the countries with an advanced level of health-care development. Bone marrow transplantation is a good example of the forms of treatment with a high financial cost which have arisen as a result of the boom of new technologies and which are a subject of debate among clinicians and the health administrations. The important thing, however, is that transplantation cures many patients, especially young ones, who would otherwise die. In addition to that, conventional therapy is often so expensive that in many cases it exceeds the cost of transplantation. The fact that this treatment is technically complex, very expensive and marked by highly precise indications requires that information be available to permit an assessment of results and efficacy in order to be able to plan the health-care resources. The information systems, in accordance with the lines of action of the 1993-1995 Health Plan, must permit the integration of the information relating to the population, the state of health and services in order to be a useful tool in the decision-making process. The Registry of Hemopoietic Progenitor Cells Transplantation is an example of such a tool. This registry provides a knowledge of both the clinical and epidemiological characteristics of the treated population, and the aspects relating to the territorial distribution of the treatment. The information which has been obtained highlights the high level achieved in Catalonia in the field of hematology. None of this would be possible without the close cooperation of all the professionals involved. With their dedication, they have permitted Catalonia to take a leading position in the performance of this type of treatment from both the quantitative and qualitative standpoints.
INTRODUCTION Bone marrow transplantation is a technique involving the transfusion of bone marrow from a live healthy donor to a patient (allogeneic transplantation). In recent years, however, there has been extensive development of autologous transplantation (autotransplantation), involving the transplantation of the bone marrow of the patient himself, removed when it is in good condition and preserved at low temperatures. The latest advances in this field have also permitted the use of hemopoietic progenitor cells obtained from the peripheral blood. Until the 1950's, a diagnosis of leukemia or of many other blood diseases usually had a negative prognosis. Nevertheless, intensive chemotherapy and chemo-radiotherapy followed by a transplantation of hemopoietic progenitor cells has radically changed this prognosis. Bone marrow transplantation and chemotherapy originated after the forties. Jacobson et al. and Lorenz et al. demonstrated that a mouse could be protected against lethal radiation by administering spleen cells or bone marrow cells. Later it was proven that this effect was caused by the repopulation of the marrow cells of the donor. Farber et al. found that antifolic agents could induce remission in certain acute leukemias. Since then these two treatment methods have been closely related to the good results obtained with bone marrow transplantations in patients in remission after chemotherapy and in the cure of some patients in which chemotherapy had failed. The first allogeneic transplantation in Catalonia was performed in 1976 but it was not until the eighties that this procedure became common in the treatment of different hematological and lymphatic diseases and certain cancers. At the end of 1987 the regulations governing the performance of bone marrow transplantations in Catalonia were published. These rules specify the requirements for the authorization of health centers where bone marrow may be removed and transplanted. The Advisory Commission on Bone Marrow Transplantation was also created. It is formed by experts in this field and representatives of the Health Administration. And lastly, the Registry of Bone Marrow Transplantations was instituted as an instrument for gathering information on the use of this technique and its results. Owing to the advances made in recent years in bone marrow transplantation techniques, it has been necessary to revise the Regulations in order to include the new criteria established by the international scientific societies. One of the modifications which has been made is the change of name of the technique, which is now called Hemopoietic Progenitor Cells Transplantation (HPCT) in order to encompass the transplantation of hemopoiesis progenitor cells obtained not only from the bone marrow but also from other sources (mainly the peripheral blood and the umbilical cord). These new types of transplantation are acquiring growing importance in the treatment of new diseases. The purpose of these Regulations is to guarantee that the development and application of the new techniques will take place within a framework ensuring the quality of the service provided and the respect of patients' rights.
INDICATIONS
AND FORMS OF Hemopoietic progenitor cells transplantation (HPCT) is performed with one of the two following objectives: to destroy a diseased bone marrow and implant a new one from a healthy donor, or to restore the hemopoietic function following intensive chemotherapy treatments which damage the bone marrow. The indications of HPCT are given in TABLE 1.The diseases for which HPCT is most often carried out are acute leukemias and chronic myeloid leukemia. In recent years the indication in solid neoplasias (mainly breast cancer) has undergone a large increase. TABLE 1. Indications of hemopoietic progenitor cells transplantation TABLE 2 presents the HPCT modalities, which may be classified according to two criteria: the genetic and immunological relation between the donor and the recipient, and the source of the hemopoietic progenitor cells. The combination of these two classification criteria gives rise to a number of modalities. TABLE 2. Classification of hemopoietic progenitor cells transplantations From the immunological standpoint, syngeneic HPCT (between identical twins) and autotransplantation (obtainment of the hemopoietic progenitor cells from the patient himself) are relatively similar since in these cases there are no immunological differences between the donor and the recipient. Allogeneic HPCT requires complete donor-recipient human leukocyte antigens (HLA) compatibility. For many years the only donors who were used were family members. The probability of HLA identity between two siblings is 1:4 (25%) and the possibility of finding a compatible HLA donor increases with the number of siblings. It is also possible to use as donors certain family members of the first order with minor incompatibility of the HLA system. Likewise, the performance of HPCT with the use of unrelated donors has increased in recent years. The probability of HLA compatibility between a patient and an individual of the general population is much lower, ranging from 1:20,000 to 1:40,000. In order to permit the application of the latter form of HPCT, many registries of voluntary donors have been created around the world. These donors have consented to form part of the respective registry and to be typified according to their HLA system. At present there are over 2 million donors around the world. In Spain, at the initiative of the Josep Carreras International Foundation for the Fight against Leukemia, REDMO (Spanish Registry of Bone Marrow Donors) has been created. It has been included in the National Health System and is connected telematically to all the world registries. HPCT is a relatively aggressive procedure. For this reason its use is limited to patients up to a certain age limit: 55 years for allogeneic HPCT and 65 years for autotransplantations.
THE
REGISTRY OF Objectives and general characteristics The Order of 8 July 1994, creating the Advisory Commission on Hemopoietic progenitor cells transplantation, establishes that the functions of the Commission include the preparation of studies and reports and the provision of advice on this subject to the Catalan Ministry of Health and Social Security, to which it is attached. Consequently, it requires a single registry of patients who are treated by this technique, as a tool to provide it with information. This aspect is concretized in the following objectives: •
To have a knowledge
of the epidemiological characteristics of the patients who receive
a hemopoietic progenitor cells transplantation. The activity
of the registry will respond to the requirements of health planning
and of contracting of services of the Catalan Service of Health
(SCS) and of the Catalan Ministry of Health, and it will likewise
attend to the needs of the Advisory Commission.
In 1995, the following health centers of Catalonia were authorized to carry out hemopoietic progenitor cells transplantations (HPCTs): •Hospital
de la Santa Creu i Sant Pau
•Hospital
Clínic i Provincial de Barcelona
•Hospital
Duran i Reynals
•Hospital
Universitari Materno-Infantil de la Vall d'Hebron
•Hospital
General i Universitari de la Vall d'Hebron
•Hospital
de Lleida Arnau de Vilanova
•Hospital
Universitari de Tarragona Joan XXIII
•Clínica
Corachan
Institut d'Oncologia Corachan (IDOC)
•Hospital
General de Catalunya
•Clínica
Nostra Senyora del Pilar
•Institut
Universitari Dexeus
These centers are obliged to notify the Registry of Hemopoietic Progenitor Cells Transplantations of all the information necessary for its operation and updating. The management of the Registry is performed by the Health Area of SCS. Nevertheless, the Advisory Commission on Hemopoietic Progenitor Cells Transplantations, formed by experts in this field and representatives of the Health Administration, supervises the maintenance and follow-up of the Registry and provides advice on the processing of data. The data on all the HPCTs carried out during the year are gathered in January and February of the following year by means of the individual notification forms, which the centers complete and submit to the Registry. The information on the follow-up of the patients who have received an HPCT in previous years is gathered during the same period. Once all the data from all the centers have been gathered, they are subjected to an internal validation and are then processed to prepare the systematic and non-systematic reports.
HEMOPOIETIC
PROGENITOR Description of the population In the period 1988-1994, 1,256 HPCTs (1,218 patients) were performed; of this total, 441 (35.1%) corresponded to children (0 to 16 years) and 815 (64.9%) to adults (over 16 years). As from 1990, there was an increase in the number of HPCTs in adults, while the figures remained relatively constant for the child population (FIGURE 1). The transplantation rate rose from 1.74/100,000 inhabitants in 1988 to 4.95 in 1994. FIGURE 1. Evolution of the number of HPCTs according to the patients' age. New cases in the period 1988-1994. A study of the distribution of the HPCTs by age groups and transplantation year corroborates the increase in recent years observed in FIGURE 1, above all for the age groups of over 25 years (TABLE 3). TABLE 3. Evolution of the number of HPCTs by age group. New cases in the period 1988-1994 FIGURE 2 shows the distribution of the HPCTs by age groups and sex. A clear predominance of transplantations in men (59.9%) may be seen. While the age group with the largest number of cases in men is from 17 to 24 years, in women it is from 35 to 44 years. The average age is 24 years for men and 27 years for women. FIGURE 2. Distribution of patients who have received an HPCT by age group and sex. New cases in the period 1988-1994 The fact that Catalonia has been a leader in the performance of HPCTs explains why the authorized Catalan centers have attracted a large number of patients resident in other autonomous regions where this treatment is not available. Although the number of hospitals qualified to treat this type of diseases has increased in the rest of Spain in recent years, Catalonia is still today an important focus of attraction for the application of this form of treatment. FIGURE 3 shows the distribution of HPCTs according to the geographic area of residence of patients. Despite the fact that the number of transplantations in patients residing outside Catalonia has increased over the course of the years, the percentage that they represent with respect to the total annual transplantations has been progressively decreasing.
FIGURE 3. Distrubution of HPCTs according to patients' place of
residence. Number of cases in the period 1988-1994 The largest number of HPCTs performed on patients residing outside Catalonia corresponds to patients from Andalusia, the Valencia region, Galicia and Aragon (FIGURE 4). FIGURE 4. Distribution of the HPCTs performed in Catalonia by autonomous regions. New cases in the period 1988-1994 FIGURE 5 shows the distribution of the HPCTs carried out in the period 1988-1994 by age groups and type of transplantation.
FIGURE 5. Distribution of HPCTs by age group and type of transplantation.
Period 1988-1994
The HPCTs performed in the period 1988-1994 correspond to a wide variety of diagnoses, which have been grouped into categories in this case (FIGURE 6 and TABLE 4) according to their clinical meaning. FIGURE 6. Distribution of HPCTs by diseases. New cases in the period 1988-1994 TABLE 4. Distribution of HPCTs by diseases. New cases in the period 1988-1994 Since the frequency of diseases in which HPCT is indicated varies between the child population and the adult population (except in the case of acute leukemia), the diseases are studied separately for each of these groups. The most frequent category is the leukemias, which represent 59.8% in overall terms. In the case of children this percentage is 71.0% and in that of adults it is 53.7%. In both age groups, but especially in children, there is a clear predominance of acute leukemias with respect to chronic leukemias, and among the acute leukemias the most frequently observed disease is lymphoblastic acute leukemia (53.6%) (FIGURE 7). FIGURE 7. Distribution of HPCTs by year and type of leukemia. New cases in the period 1988-1994 Lymphomas represent 17.2% of the total diseases, and solid tumors represent 10.7%. TABLE 4 shows the distribution of the HPCTs by diseases and transplantation year. The most notable fact is the increase of HPCTs for solid tumors in the last two years of the period. The HPCTs for solid tumors represented 5.8% in the period 1988-1992, while the percentage was 17.7% in the last two years of that period. This increase was due to the incorporation of HPCT in the treatment of certain breast cancers. TABLE 5 shows the distribution of the HPCTs by years and by types of tumor. TABLE
5. Distribution of HPCTs by year and type of solid tumor. New
cases in the period 1988-1994 In recent years there has been a rise in the number of autotransplantations, above all in the adult population (FIGURES 8 and 9). In 1994 there was a 75% increase in autotransplantations in patients over 16 years of age with respect to the previous year. FIGURE 8. Distribution of HPCTs by year and type of transplantation. New cases in the period 1988-1994 (0-16 years) FIGURE 9. Distribution of HPCTs by year and type of transplantation. New cases in the period 1988-1994 (> 16 years) The distribution of HPCTs according to the type of transplantation in patients with acute lymphoblastic leukemia (ALL) remained relatively stable over the course of the years, except in 1991 and 1992, when autotransplantations increased to the detriment of allogeneic transplantations (FIGURE 10). FIGURE 10. Distribution of HPCT for ALL, by year and type of transplantation. New cases in the period 1988-1994 On the other hand, the increase of autotransplantations in the case of ANLLs has followed an upward trend from the year 1990 to the present, while allogeneic transplantations showed a slight decrease in 1992, which has remained stable in recent years (FIGURE 11). FIGURE 11. Distribution of HPCTs for ANLL, by year and type of transplantation. New cases in the period 1988-1994 FIGURE 12 shows the distribution of HPCTs in the population from 0 to 16 years for acute leukemias, according to the number of remissions of the disease. Whereas 32.4% of the transplantations were performed in the first remission in the cases of ALLs, this percentage was 92.2% in the case of ANLLs. FIGURE 13 shows the same data referred to the adult population. In this case the difference between the transplantations which were performed in the first remission, according to the type of acute leukemia, was not as large (66.7% for ALLs and 84.9% for ANLLs). FIGURE 12. Distribution of the number of HPCTs for ALL and ANLL, according to the phase of the disease. Period 1988-1994 (0-16 years) FIGURE
13. Distribution of the number of HPCTs for ALL and ANLL, according
to the phase of the disease. Period 1988-1994 (> 16 years) In general, the survival rate of children is higher than that of adults (FIGURE 14). Until the second year after transplantation, the difference (5%) remains constant, but by the fifth year this difference is 14%. In the group from 0 to 16 years, the survival rate in the first, third and fifth years was 62%, 49% and 49%, respectively. In adults, these figures were 57%, 41% and 35%, respectively. FIGURE 14. Survival of patients by age group. Period 1988-1994 In order to study the influence of the introduction of new indications and of the improvement in technique, the survival for the various types of HPCTs has been analyzed on the basis of whether the transplantation was performed in the period 1988-1990 or the period 1991-1994. Survival is higher in the latter period in the case of autotransplantation (FIGURE 15). On the other hand, in the case of allogeneic HPCTs, no statistically significant differences are observed with respect to the year in which the transplantations were performed (FIGURE 16). FIGURE 15. Survival of autotransplantations. Period 1988-1990 and 1991-1994 FIGURE
16. Survival of allogeneic transplantations. Periods 1988-1990
and 1991-1994 Of the total number of patients who received an HPCT (1,218) according to the data of the Registry, 590 (48.4%) died. The largest number of deaths took place in the first year after transplantation. The mortality rate during the first year after transplantation decreased progressively in the latter years of the period, diminishing from 53% in 1988 to 31% in 1993. FIGURE 17 provides a comparison of the mortality arising in the first year of the HPCT for the different age groups, with the overall mortality of the population of Catalonia for the same age groups in 1992. The specific rates (expressed per 1,000 patients) corresponding to the patients who have received an HPCT, have been calculated on the basis of the mortality in the first year of treatment for the patients who received a transplantation between the years 1988-1994. This figure shows that the mortality rates of the population of Catalonia increase with age, while the mortality rates of the patients who have received an HPCT remain stable. FIGURE 17. Mortality during the first year of patients who received an HPCT, and of the general population of Catalonia, by age group The standard mortality index (SMI) has been used to permit a comparison of these two mortality rates. The SMI is based on the number of expected deaths in the study population (patients who have received an HPCT, taking the mortality rate of Catalonia as a reference) and on the number of deaths observed. FIGURE 18 shows the relationship between the two rates. The high mortality of the age group from 5 to 14 years stands out (1,952 times higher than the mortality rate for the same age group of the general population of Catalonia). Beginning with the age group from 15 to 24 years, this index decreases with age, reaching a level of about 50 times higher in the group from 55 to 64 years with respect to the same age group of the general population of Catalonia. In overall terms, the patients who have received an HPCT have a death risk which is 178 times higher than that of the general population of Catalonia. FIGURE 18. Relationship between the observed mortality and the expected mortality, by age group. Period 1988-1994
ANNEX 1 Abbreviations HPCT: hemopoietic progenitor cells transplantation HLA: human leukocyte antigens CML: chronic myeloid leukemia SCS: Catalan Service of Health REDMO: Spanish Registry of Bone Marrow Donors ALL: acute lymphoblastic leukemia ANLL: acute non-lymphoblastic leukemia SMI: standard mortality index |
