AcuteMyeloidLeukemia(AML)                                                                                                       15

__________________________________________________________________________________

 

 

2.   Acute Myeloid Leukemia (AML)

 

2.1                                     General considerations

Acute myeloid leukemia (AML) describes a heterogenous group of related hematologic malignancies .

 

FAB ( French – American – British) classification of AML

Subtype                                                                      % *    Comment

AML – M0          undifferentiated  AML                  5     poorer prognosis , CD – 13 positive

AML – M1            AML with minimal maturation    15  

AML – M2            AML with maturation                  25    t (8 ; 21) has a favorable prognosis;

                                                                                            seen in younger adults; associated

                                                                                            with extramedullary involvement

                                                                                             and splenomegaly

AML – M3             Promyelocytic leukemia               10    see indication no. 3

AML – M4             myelomonocytic leukemia            25   monocytic and granulocytic

                                                                                             differentiation; extramedullary

                                                                                             involvement can be seen                                                                 

AML – M4eo          myelomonocytic leukemia           < 5   good prognosis; > 5 % abnormal

                                 with  eosinophilia                                eosinophils; extramedullary

                                                                                              involvement often seen

AML – M5a            monocytic leukemia                       5    poorer prognosis; > 80 % of

                                                                                              monocytic lineage are blasts;

                                                                                              often seen in older adults;

                                                                                              extramedullary disease common

AML – M5b           monocytic leukemia                        5    as for M5a ;< 80% of

                                 with differentation                               monocytic lineage are blasts

AML – M6             erythroid leukemia                           5    poorer prognosis ; > 50 % of

                                                                                              nucleated cells are erythroid;

                                                                                              often preceded by a myelodys-

                                                                                              plastic syndrome; older patients

AML – M7              megakaryoblastic leukemia         10     poor prognosis : seen in Down

                                                                                              syndrome children < 3 years:

                                                                                              often associated with prior MDS,

                                                                                              blast crisis, or myeloproliferative

                                                                                              disorders.

                 * Incidence in percent

 

                         They can be divided into three prognostic groups – favorable ,  

                          intermediate and unfavorable- based on acquired cytogenetic changes.

 

 

16                                                                                                               Acute Myeloid Leukemia (AML) ____________________________________________________________________________________

 

 

Cytogenetic classification

                      SWOG criteria                             MRC criteria

                                                                       (as for SWOG, except…….)

Favorable        t( 15 ; 17 )- with any other abnorm-

                          ality inv (16) / t (16;16 ) / del(16q)

                          - with any other abnormality

                          t(8:21) – without del (9q) or                         t (8;21) – with any other

                          complex karyotype                                              abnormality

Intermediate    + 8, -Y, +6 , del (12p)                               abnormalities of 11 q 23 del

                           normal karyotype                                 (9q), del(7q) – without other

                                                                                         abnormalities ; complex

                                                                                         karyotypes ( 3 but < 5 ab-

                                                                                         normalities); all abnormalities

                                                                                         of unknown prognostic signi-

                                                                                           ficance

Unfavorable       -5  / del(5q). –7 / del(7q)

                              T(8;21)-with del(9q)or

                             complex karyotype

                              inv(3q). abnormalities of 11 q23,

                              20q, 21q,del (9q), t(6;9)

                              t(9;22), abnormalities of 17q

                              complex karyotypes(≥3           complex karyotypes (5

                              abnormalities)                   abnormalities)

Unknown              All other clonal chromosomal

                               aberrations with fewer than 3

                               abnormalities

According to Appelbaum et al

 

 

Current induction chemotherapy will enable > 50% ( unfavorable prognosis ) to 80 % or more ( favorable prognosis ) of AML patients aged 60 years  to enter complete remission (CR1). Several regimens which are usually based on an anthracycline plus cytarabine achieve broadly similar results. For those in CR1, major post remission therapies are consolidation chemotherapy based on high- dose cytarabine and / or autologous transplantation or allogeneic transplantation. In recent prospective collaborative group trials no overall survival advantage but a significant teduction in the risk of relapse was usually seen for each type of transplant. Analysis within risk groups suggests that autologous transplant may be added of may replace chemotherapy in patients with favorable cytogenetics , but no final answer which represents the best treatment option is possible to date. If a HLA- matched related donor is available it seems likely that early allogeneic transplantation is the recommended therapy for patients with intermediate or unfavorable cytogenetics.Those who have no donor should receive intensive postremission chemotherapy with or without an autologous transplant .

 

In relapsed (or refractory) patients, reinduction chemotherapy may produce a usually shortlived , second complete remission in 30 – 60 % . Allogeneic (either HLA – sibling matched or matched unrelated donor) or autologous stem cell transplantation offers the potential for long – term disease – free survival and cure. Only a minority of patients (especially in case of allogeneic transplantation) will be eligible for that procedure, however. More recently gemtuzumab, a conjugated anti CD33 monoclonal antibody has been introduced in the treatment of relapsed and refractory AML patients. The antigen CD33 is expressed on blast cells in 80 – 90 % of AML cases, but not on pluripotent hematopoietic stem cells or on nonhematologic cells.

 

 

Acute Myeloid Leukemia (AML)                                                                                                       17

__________________________________________________________________________________

 

Unfortunately, however , AML is a disease predominantly affecting Patients > 60 years of age (median age at diagnosis approx. 65 years). Treatment options for the majority of these elderly patients are more restricted and treatment outcome is less favorable, mainly because of a higher incidence of poor prognostic factors (poor performance status, unfavorable cytogenetics. CD34- positive phenotype, raised LDH levels, increased incidence of multidrug resistance ptotein expression) and an increased rate of therapy-limiting comorbidity, Only selected patients who are fit, with no preexisting problems and a good performance status can be treated aggressively with intensive chemotherapy. Less intensive chemotherapy or even palliative care are more suitable, however, for the majority of eldery patients not fitting these eligibility criteria.

 

Literature: for review e.g.

        APPELBAUM et al. Hematology (Am. Soc. Hematol. Educ.Program)(2001):62 – 86

        BUCHNER et al. Cancer Chemother. Pharmacol. 48 (Suppl 1) (2001): 41 – 44

        (intensive remission induction therapy) and Rev. Clin. Exp. Hematol. 6 (2002):46 –       

        59 (older patients)

        BURNETT, Rev. Clin. Exp. Hematol. 6 (2002): 26 – 45 (younger patients)

        ESTEY, Cancer 92 (2001): 1059 – 1073

        HIDDEMANN and BάCHNER. Semin. Hematol 38 (Suppl 6) (2001): 3 – 9

        JACKSON and TAYLOR, Drugs Aging 19 (2002): 571 – 581  (older patients)

        LEOPOLD and WILLEMZE, Leuk. Lymphoma 43 (2002): 1715 – 1727 (treatment  

        in first relapse)

        LΦWENBERG, Semin, Hematol. 38 ( Suppl 6) (2001): 10 – 16 (older patients)

        SEKERES and STONE, Curr. Opin. Oncol. 14 (2002): 24 – 30 (older patients)

        STONE. Semin. Hematol. 38 (Suppl 6) (2001): 17 – 23 (postremission therapy)

        VADIRMAN et al. Blood 100 (2002): 2292 – 2302 (review of the WHO  

        classification of the myeloid neoplasms)

 

Remark: The treatment preferably should be in the hands of specialized centers and cooperative groups which treat the patients according to current protocots. The therapy elements presented below are only examples which do not constitute complete therapeutic sequences.