9.               Myelodysplastic Syndromes (MDS)

9.1             General considerations

Myelodysplastic syndromes (MDS) are a heterogenous group of clonal myeloid stem cell disorders characterized by myelodysplasia and an ineffective hematopoiesis.

Accelerated apoptosis and its abnormal regulation in early and mature hematopoietic cells contribute to the pathobiology of MDS. Another abnormality is an increased angiogenesis due to the production of vascular endothelial growth factor (VEGF) by MDS cells.

Patients with MDS regularly develop anemia and frequently become transfusion dependent. MDS often evolves into secondary acute leukemias. Patients are described as having primary MDS when no cause is apparent and as having secondary or therapy-related MDS (t-MDS) when prior exposure to chemotherapy has occurred . MDS typically develop in the elderly (t- MDS typically have a younger age of onset).

In 1999 a working group of the WHO published a revision of  the original French- American-British (FAB) classification, which contained five subgroups.

            The  international Prognostic Scoring System (IPSS) takes blast percentages,  

            cytogenetic abnormalities and number of cytopenic cell lines into consideration. It

            resulted in the identification of four risk group with distinct median survival and

            risk of leukemic transformation.

            There is no uniform treatment for patients with MDS and the choice of treatment options is

            influenced by age and individual clinical and prognostic factors.

            Supportive measures such as transfusion to correct anemia remains standard for patients with  low-

            and intermediate-risk MDS, especially the elderly ones.

Cytokines such as erythropoietin and /or  G-CSF might be used to alleviate anemia and granulocytopenia. A number of novel treatment approaches are under investigation: Among others, immunosuppressive therapy (e.g. cyclosporine A, antithymocyte globulin resp, antilymphocyte globulin), anticytokine therapy (e.g. antitumor necrosis factor, amifostine), and antiangiogenic therapy (e.g. thalidomide).

Some high-risk MDS categories may benefit from chemotherapy of various intensity, e,g. intensive cytotoxic treatments as applied in AML. Long-term remissions are rare, however, and further intensification of either induction or postremission therapy is not likely to improve results with current drug combinations. Allogeneic stem cell transplantation, therefore, remains the treatment of choice for younger patients (up to 65 years). Overall, approximately 40 % of such patients are likely to be cured with allogeneic transplantation. Autologous stem cell transplantation may provide an alternative as postremission strategy for those without a suitable donor or of older age. Promising results have also been achieved with new regimens using nonmyeloablative stem cell transplantation followed by donor lymphocyte infusions.

The demethylating agents 5-azacytidine and decitabine look promising for the treatment of elderly patients with high-risk MDS. Patients with  t- MDS can either be offered AML-type chemotherapy, allogeneic transplantation or investigational therapy.

Literature: for review e.g.

            ALESSANDRINO et al, Haematologica 86 (2001): 1124-1157

            BERAN, Int. J. Hematol. 72 (2000): 139 – 150 (intensive chemotherapy)

            PISANI and RAINALDI, Crit. Rev. Oncol. /Hematol. 40 (2001): 215-228

            (management of high-risk MDS)

            SABA, Cancer Control 8 (2001): 79 – 102 (elderly patients)

            VERBEEK and GANSER, Ann. Hematol. 80 (2001): 499- 509

9.2             Low-and intermediate-risk MDS

9.2.1      Erythropoietin (EPO)

Especially for patients with a pre-treatment serum EPO level below 100 U/I and a RBC transfusion need < 2 units/month.

Literature: e.g.

            HELLSTROM – LINDBERG, Br. J. Haematol. 89 (1994): 67 – 71 (meta-

            analysis) ITALIAN COOPERATIVE STUDY GROUP FOR rHuEPO IN  

            MYELODYSPLASTIC          

            SYNDROMES, Br. J. Haematol. 103 (1998): 1070-1047

            Combined treatment with EPO and G-CSF

Literature:

            KASPER et al, J. Cancer Res. Clin. Oncol. 128 (2002): 497-502 (analysis

            of published data)

9.2.2      Antithymocyte globulin (ATG)

Administered with oral prednisone ( 1 mg / kg / d [ min 40 mg / d ] for 10 days and then tapered by day 17). Before treatment, allergy to ATG has to be determined.

Literature:

            MOLLDREM et al. Ann. Intern. Med. 137 (2002): 156 – 163

9.2.3      Thalidomide

Literature:

            STRUPP et al, Leukemia 16 (2002): 1 – 6

            ZORAT et al, Br. J. Haematol. 115 (2001): 881 – 894

9.3             High-risk MDS

9.3.1      Single agent chemotherapy

For palliation in patients unsuitable for more myelosuppressive treatment because of age and/or co-morbidities: e.g. cytarabine, melphalan, idarubicin or topotecan.

9.3.2      Combination chemotherapy

Because of similarities to AML, combination chemotherapy is generally based on the use of AML-type regimens (see indication no.2 ) often including an anthracycline or mitoxantrone and cytarabine with or without thioguanine. More recently combinations including etoposide and fludarabine/ cytarabine or topotecan/ cytarabine came also into use.

Literature:

BERAN et al, Cancer 92 (2001): 1999-2015 (comparison of 5 regimens: IA, FA, FAI, TA, CAT )

            OOSTERVELD et al, Leukemia 16 (2002): 1615- 1621 (comparison of  2

            studies using

            Chemotherapy only or chemotherapy followed by transplantaion,

            respectively)

9.3.3      Hypomethylating agents

5 – Azacitidine

To be repeated every 4 weeks (4 cycles)

Literature:

SILVERMAN et al, J. Clin. Oncol. 20 (2002): 2429 – 2440 (randomized controlled trial of the Cancer and Leukemia Group B to compare azacitidine with supportive care)

5 – Aza – 2’- deoxycytidine (decitabine)

To be repeated every 6 weeks (in case of CR induction 2 more courses. When an improvement, PR or stabilization was achieved, 2 more courses were administered. With a maimum of 6 courses)

Literature:

            WIJERMANS et al, J. Clin. Oncol. 18 (2000): 956 – 962

9.3.4      Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation is currently the only therapeutic modality with a potential for cure. Overall, approx. 40% of patients will be cured and best results can be expected when stem cells originate from a fully matched related donor. An increased risk of relapse and, thereby, shorter disease-free survival is associated with increased blast percentage and poor risk karyotype, whereas longer disease duration, advanced patient age, t-MDS, male gender and use of mismatched or unrelated donors are associated with an increased risk of treatment related mortality.

The development of nonmyeloablative conditioning regimens permits successful stem cell transplantatation even in patients more than 60 years of age.

Autologous stem cell transplantation may be beneficial for selected patients in complete remission after conventional chemotherapy.

Literature:

            ANDERSON et al , Blood Rev. 14 (2000): 63 – 77 (review)

CASTRO-MALASPINA et al, Blood 99 (2002): 1943 – 1951 (outcome analysis of unrelated donor marrow transplantation)

            GUARDIOLA et al, Blood 99 (2002): 4370 – 4378 (retrospective comparison of bone

marrow or peripheral blood progenitor cells for allogeneic transplantation- Chronic Leukaemia Working Party of the E.O.R.T.C)

PARKER et al, Br. J. Haematol. 119 (2002): 144 – 154 (allogeneic stem cell transplantation     following reduced-intensity conditioning compared with standard preparative regimens)

WITHERSPOON et al , J. Clin. Oncol. 19 (2001): 2134 – 2141 (allogeneic stem cell transplantation for t-MDS)