2.1.1. Acute myeloid leukemia

There are about 150 new AML cases/year in Finland. AML is a malignancy that occurs in all age groups and also affects many young patients. It is a potentially curable disease. The treatments of AML are very intensive, introducing much suffering for the patient and consuming a lot of health care resources. Table 1 presents current classification of acute myeloid leukemia.

Myeloid leukaemias are chemosensitive malignancies, and the current induction therapy regimens afford complete remission in 60-80% of all the patients with AML and in 75%-80% of the younger patients (Stone &Mayer 1993, Rove & Liesweld 1996, Burnett 2001). However, the disease has a tendency to relapse, and the main problem in younger population is prevention of the relapse (Hamblin 1995, Cripe & Hinton 2000, Burnett 2001). Intensification of treatment seems to yield superior results. About 30-45% of the patients in remission can expect long-term DFS of over 3 years after intensive post-remission consolidation therapy without allogeneic stem cell transplantation (SCT) (Mayer et al. 1994)Rowe & Liesweld 1996, Appelbaum et al.1998, Elonen et al. 1998). In terms of disease-free survival, the best therapeutic modality seems to be allogneic SCT in the first remission. Allogeneic SCT results in a 10-year DFS for 45-60% of the patients (Schiller et al. 1992, Appelbaum et al. 1998). This is probably due to the graft-versus- effect of the transplanted donor immune system. Along its favorable therapeutic potential, however allogeneic SCT involves serious problems, including acute and late treatment-related morbidity and mortality due mostly to the graft-versus-host effect. Despite the constantly developing modalities of palliative and supportive care, allogeneic SCT still involves a 25-40% risk of treatment-related death (Rowe & Liesweld 1996). This situation highlights the need for good prognostic and predictive markers in selecting the patients for allogeneic SCT to be performed in the first complete remission. (Stone & Mayer. 1993, Rowe & Liesweld 1996).

The elderly patients have clearly inferior treatment results compared to younger patients. This is partly explained by undertreatment of elderly patients, but also the disease seems to present with more unfavorable biology. Intensification of the treatment may offer some advantage to elderly patients also, but new innovative approaches are needed. One possibility in this group could be allogeneic SCT with reduced intensity conditioning. (Buchner et al. 2001)

Various characteristics of the disease have been suggested to be predictive for the treatment outcome in AML. As our knowledge of the biology of AML has increased, cytogenetic and molecular markers have superseded morphology as the most important prognostic indicator. The most important prognostic factors in AML are presented in table 1. Cytogenetic changes are the prognostic factors that currently have the strongest influence on survival (Table 2). However these can not detected in all of the patients.

2.1.2. Acute lymphatic leukemia

In Finland, 70-80 new cases of acute lymphatic leukemia are diagnosed annually. Over half of these patients are children, but some cases are seen in all age groups.

In childhood ALL, the chance for long-term survival has been steadily increasing and is now up to 51-79% (Pui et al. 1993). However, while the prognosis is improving and more patients end up as long-term survivors, the question of the late effects of treatment has become more and more important. The most alarming late effects are therapy-induced secondary malignancies, cardiotoxicity, growth impairment, and neuropsychological dysfunction, which are commonly attributed to the CNS-directed therapy. For these reasons, it is important to tailor the therapies in view of each individual’s risk factors. Numerous risk factors have been identified, but the agreed-upon standard low-risk categories include patients 1-9 years of age with precursor B-ALL and a WBC count lower than 50.000/ml. (Smith et al. 1996) This estimation can distinguish between patient groups with about 80% and 65% chances for 4 years’ disease-free survival.

Apart from the intensity of the treatment, the role of CNS prophylaxis is another important question. Prophylactic CNS treatment with cranial irradiation, high-dose methotrexate, and intrathecal therapy clearly reduces the risk for CNS relapse and increases the cure rates, but simultaneously exposes the children to the risk of late neurologic sequelae. This calls for better tools to predict which patients are particularly at risk of CNS invasion. The mechanisms of CNS invasion are, however, still mostly unknown.

Much of the data concerning pediatric patients with ALL also apply to adult patients. However, the prognosis for adults is much worse, as only about 30% achieve long-term remission (Liesner & Goldstone 1997). This may be partly explained by the fact that adults have a decreased ability to tolerate intensive treatments. Another explanation is that adult and childhood ALLs are biologically distinct diseases. There are also other characteristics in their biology and clinical behavior that support this hypothesis. The treatment results of adult patients are strikingly inferior compared to children, even when similar intensive regimens are applied to both. Patients with childhood ALL have more favorable cytogenetic prognostic factors, such as early pre-B cell disease and hyperdiploid karyotype. In contrast, adult patients more often present with poor prognostic factors, such as Philadelphia chromosome-positive disease, high blood cell counts, advanced age, long time to achieve CR and high-risk immunophenotypes. (Perentesis 1997)

2.1.3. Hodgkin´s lymphoma

Hodgkin´s lymphoma has two age predilections. Its incidence rises first in the thirties and forties and again after the fifties. Therefore, many patients with Hodgkin´s lymphoma are relatively young with long life expectancies if cured from their malignancies. 110-120 new cases are diagnosed annually in Finland.

According to the WHO II classification Hodgkin´s lymphoma is classified to five subclasses. Nodular sclerosis classical Hodgkin´s lymphoma, mixed cellularity classical Hodgkin´s lymphoma, lymphocyte-rich classical Hodgkin´s lymphoma and lymphocyte-depleted classical Hodgkin´s lymphoma constitute the clinically rather uniform classical Hodgkin´s lymphoma. The fifth subtype nodular lymphocyte predominance Hodgkin´s lymphoma is clinically more an indolent disease. (Jaffe et al. 2001)

For decades, Hodgkin´s lymphoma has been a highly curable malignant disease. After the introduction of modern treatment methods, e.g. extended field irradiation, MOPP (mustine, vinkristine, nitrogen mustard, prednisolone) polychemotherapy and later ABVD (adriamycin, bleomycin, vinblastine and DTIC), ABVD-MOPP hybrid, and ABVD alternating with MOPP chemotherapies, up to 70% of all patients and up to 88 % of limited-stage patients are free from disease 10 years after the treatment (Leslie et al. 1985, Longo et al. 1997). As many as 55% of the patients with stage IV disease also enjoy long-term disease-free survival. The success in disease control has not been achieved without costs. More and more attention has been drawn to the long-term side effects of the treatment. These patients show an ever increasing pattern of excess mortality due to treatment-induced factors, including secondary malignancies and cardiovascular mortality.

The risk for secondary malignancies varies, depending on the treatment modality and the patient population. After conventional treatment of Hodgkin´s lymphoma, the incidence of secondary solid malignancies starts to rise ten years after the treatment, and this rise continues for at least twenty years. For all secondary malignancies, a risk of up to 20-40% in 20 years following conventional treatment has been reported. Cardiac deaths account for 2-5% of the deaths in the patient population with Hodgkin´s lymphoma (Mauch et al. 1995, Hoppe 1997).

Most of the patients present with limited-stage disease. The question with these patients is how to minimize the treatment and the treatment-related overmortality without compromising the good chances for cure. In contrast, 45% of the patients with stage IV disease will still succumb of relapsing Hodgkin`s disease, which hence calls for more aggressive treatment. New high-dose regimens, such as baseline and escalated BEACOPP (Diehl et al. 1997), and MOPPEBVCAD (Gobbi et al. 1998) seem to offer better chances for disease control than traditional chemotherapy regimens. However, the long-term effects of these aggressive treatments are not known, and there are reasons to assume that these high-dose treatments carry a higher risk for therapy-induced AML and myelodysplastic syndrome (Diehl et al. 1997).

All of the above-mentioned factors call for better prognostic and predictive parameters that would enable individual assessment of the patients’ risk of relapse and individual tailoring of therapy to maximize the possibilities for long-term disease-free survival while minimizing the risk for long-term side effects.

Numerous reports have been published on the clinical and biological prognostic factors of Hodgkin´s lymphoma. Table 3 shows the most important studies published in the 1990s. The following clinical disease characteristics, among others, have been shown to affect the possibilities for disease control: the number of involved nodal areas, bulky tumor, stage, sex, age, hemoglobin, and erythrocyte sedimentation rate. One of the largest studies published analyzed over 20 clinical prognostic factors in a population of over 5000 patients. In this study, the writers presented a prognostic score consisting of seven risk factors, which discriminated the patient population with 74% (score 0-2) and 55% (score 3-7) chances for tumor control in five years. The valid biological prognostic parameters seem to include the precense of follicular dendritic cells, proliferating cell nuclear antigen, p53 protein, bcl-2 protein, and the amounts of soluble CD30 protein and β -2 microglobulin (table 3).

It seems that the prognostic factors are highly treatment-dependent, Van Spronsen, for example, has shown that the prognostic importance of the grade of nodular sclerosis histology has disappeared over a period of ten years (Van Spronsen et al. 1997). Because most of the prognostic studies are based on a retrospective analysis of historical data, they must be interpreted with caution at a time when treatment modalities are changing.

On the other hand, we have no markers that would have been validated in large and controlled trials and would be able to sort out the really unfavorable patient population with less than 40% chance for long-term survival.

2.1.4. Non-Hodgkin´s lymphoma

Non-Hodgkin´s lymphomas constitute a heterogenous group of diseases, and their classification has posed a persistent challenge for pathologists. The most advanced classification is the one published in 2001 by the World Health Organization “Tumours of Haematopoietic and Lymphoid Tissues”. This classification includes 31 different non-Hodgkin lymphoma entities (Table 4).

However, it seems that even some of the present entities, including diffuse large-cell lymphoma, are in themselves heterogenous categories of different diseases, and more biological knowledge is still needed to further develop the classification (Frizzera 1997, Jaffe et al. 2001).

The basic principle of the modern classifications is that all the disease entities are different diseases with their own specific features, including the pattern of spread, etiology, treatment response, and optimal treatment. There are wide variations in the clinical behavior of lymphomas. Most of the lymphomas composed mainly of small lymphocytes, usually present with widely disseminated disease. These lymphomas cannot be cured with chemotherapeutics and aggressive treatments do not prolong the patient’s life, and these patients are usually treated with a “watch and wait” policy. Fortunately, the natural rate of progression of these tumors is long, and the mean survival of patients is up to 7 years. (Dana et al. 1993, Cameron & Leonard 1994) On the other hand, most lymphomas composed mainly of large cell histology can be cured with aggressive therapy, but if the treatment fails, these malignancies lead to the patient’s death within a short time (Bierman & Armitage 1996). This implies that more acute toxicities can be accepted during these curative treatments than during the treatment of low-grade lymphomas.

Aggressive and rapidly progressing lymphomas are treated with combination chemotherapy whenever the patient tolerates the treatment. For patients with localized disease, a short course of chemotherapy with additional involved field radiotherapy provides excellent probabilities for long-term disease-free survival. On the other hand, patients with an advanced disease and risk factors have a high risk of treatment failure. It has been suggested that these patients should be scheduled for high-dose therapy and autologous stem cell transplantation during their primary treatment already. However, the results of randomized studies dealing with this topic are contradictory (Verdonck et al. 1995, Martelli et al. 1996, Gianni et al. 1997, Fisher 2002, Kaiser et al. 2002). The value of high-dose therapy has been clearly demonstrated in the relapse of aggressive lymphomas (Philip et al. 1995).

The clinical risk factors of aggressive non-Hodgkin´s lymphomas are relatively well characterized. The most important of these factors are included in the international prognostic index (IPI). Patients with low-risk disease (IPI 0-1) have a 73% chance for five years of survival compared to 26% of the patients with high-risk disease (IPI 4-5). (Shipp et al. 1993) There are also new data dealing with the biological features implying a more aggressive disease. The most important biological features seem to include the expression of anaplastic lymphoma kinase protein in anaplastic large-cell lymphomas, p53 mutations in aggressive lymphomas, and bcl-2 and bcl-6 gene translocations in diffuse large-cell lymphomas (Offit et al. 1994, Ichikawa et al. 1997, Gascoyne et al. 1997, 1999, Moller et al. 1999).