AcuteMyeloidLeukemia(AML)                                                                                                       15

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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

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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 BÜCHNER. 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)

        LÖWENBERG, 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.

 

2.2.                             Younger adult patients ( < 60 years)

 

2.2.1                              Induction treatment

 

2.2.1.1                       “ 7+3 ” ( “ 3+7 ” )

Daunorubicin                           45 – 50 mg/m²                       i.v.                           d 1-3 

Cytarabine                                100 – 200 mg/m² /d              i.v. (cont inf)            for 7 d

 

Literature:

            BISHOP et al, Blood 75 (1990): 1-6

            MAYER et al, N. Engl. J. Med. 331 (1994): 896 – 903

            OMURA et al, Cancer 49 (1982): 1530 – 1536

            PREISLER et al, Blood 69 (1987): 1441 – 1449

 

 

18                                                                                                               Acute Myeloid Leukemia (AML) ____________________________________________________________________________________

 

2.2.1.2                       DAT/TAD ( various modifications)

Literature:

            MAYER, Semin. Oncol. 14 (1987): 384 – 396 (review)

 

E.g. TAD 9

Cytarabine                       100 mg/m²              i.v. (cont inf)                    d 1+2 and

                                         100 mg/m²              b.i.d. i.v. (30 min inf)       d 3 – 8

Thioguanine                    100 mg/m²               b.i.d. p.o. every 12 h        d 3 – 9

Daunorubicin                   60 mg/m²                i.v. (1 h inf)                       d 3 – 5

 

Literature:

            BÜCHNER et al, J.Clin. Oncol. 3 (1985): 1583 – 1589

 

2.2.1.3                       ADE

Daunorubicin                                  50 mg/m²          i.v.                             d 1 , 3 , 5

Cytarabine                                      100 mg/m²        b.i.d. i.v.                     d 1 – 10

Etoposide                                       100 mg/m²         i.v. (1 h inf)                d 1 – 5

 

                        Literature:

                                    HANN et al, Blood 89 ( 1997): 2311 – 2318

 

2.2.1.4                       ICE

Idarubicin                                        10 mg/m²           i.v.                           d 1, 3, 5

Cytarabine                                       100 mg/m²         i.v. (cont inf)           d 1 – 10

Etoposide                                        100 mg/m²          i.v.                           d 1 – 5

                       

 

                        Literature:

                                    GORIN et al, Ann. Oncol. 4 (Suppl 1) (1993) : 59 – 80

In a systematic collaborative overview of randomized trials induction regimens based on idarubicin achieved better remission rates and better overall survival than those based on daunorubicin.

 

Literature:

            THE AML COLLABORATIVE GROUP, Br. J. Haematol. 103 (1998): 100 – 109

 

2.2.1.5                       HAM

Cytarabine                         3000 mg/m²           b.i.d. i.v. (3 h inf)                  d 1 – 3

Mitoxantrone                     10 mg/m²               i.v. (30 min inf)                     d 3 – 5

 

                        Literature:

                                    HIDDEMANN et al, Blood 69 (1987): 744 – 749

                                    KERN et al, Leukemia 12 (1998): 1049 – 1055 (superiority of            

                                    high- dose over intermediate- dose cytarabine in prospective  

                                    randomized comparison)

 

2.2.1.6                       FLAG

Especially for poor prognosis AML, e.g. with multiline age dysplasia

Fludarabine                       30 mg/m²              i.v. (30 min inf)        d 1 – 5

Cytarabine                        2000 mg/m²          i.v.                            d 1- 5 (3-5 h after

                                                                                                           fludarabine)

G- CSF                             300 µg          s.c.                                    daily form d 0 to

                                                                                                      achievement of CR

 

 

 

Acute Myeloid Leukemia (AML)                                                                                                       19

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                        Literature:

                                    FERRARA et al, Eur. J. Haematol. 68 (2002): 203 – 209

 

2.2.1.7                       Double induction

As a very early intensification; e.g. TAD – TAD (see 2.2.1.2) or TAD- HAM (see 2.2.1.2 and 2.2.1.5) (especially for poor- risk patients).

 

Literature:

            BÜCHNER et al, Blood 93 (1999): 4116 – 4124

 

2.2.2                              Post remission therapy

To prevent relapses, three options of further intensive treatment are available

 

2.2.2.1                       Chemotherapy

Aggressive approaches including high- dose cytarabine are preferred over long term

maintenance  therapy of median or low intensity, but the optimal regimen, number of doses per course, and number of courses is still not defined.

 

Literature: e.g.

        BÜCHNER et al, Int. J. Hematol. 72 (2000): 285 – 289

        BYRD et al, J. Clin. Oncol. 17 (1999): 3767 – 3775

        CASSILETH et al, N. Engl. J. Med. 339 (1998): 1649 – 1656

        PALMIERI et al, Leuk. Res. 26 (2002): 539 – 543

 

2.2.2.2                       Allogeneic stem cell transplantation

Literature: e.g.

        APPELBAUM, Leukemia 14 (2000): 497 – 501

        BURNETT, Cancer Chemother. Pharmacol.48 (Suppl 1) (2001):53-

        58(review of the contribution of allogeneic and autologous        

        transplantation)

        BURNETT et al, Lancet 351 (1998): 700 – 708 (randomized  

        comparison of addition of autologous bone marrow transplantation to   

        intensive chemotherapy: study MRC AML 10)

                                CASSILETH et al, N. Engl. J. Med. 339 (1998): 1649 – 1656  

                                (chemotherapy Compared with autologous or allogeneic bone  

                                marrow transplantation :US Intergroup study)

                                COUBAN et al, Blood 100 (2002): 1525 – 1531 (randomized  

                                multicenter comparison of bone marrow and peripheral blood  

                                allogeneic transplantations for myeloid malignancies)

                                FOUILLARD et al, Blood 100 (2002): 3135 – 3140 (EBMT study of  

                                hematopoietic stem cell transplantation for de novo erythroleukemia)

                                RINGDEN et al, J. Clin. Oncol. 20 (2002): 4655 – 4664 (comparison

                                of peripheral blood stem cells with bone marrow)

                                TALLMAN et al, Blood 96 (2000): 1254 – 1258 (effect of  

                                postremission Chemotherapy before allogeneic transplantation)

                                ZITTOUN et al, N. Engl. J. Med. 332 (1995): 217 – 223 (autologous

                                or allogeneic bone marrow transplantation compared with intensive

                                chemotherapy: EORTC – GIMEMA study)

 

20                                                                                                               Acute Myeloid Leukemia (AML) ____________________________________________________________________________________

 

2.2.2.3                       Autologous stem cell transplantation

Literature: e.g.

            BURNETT, Cancer Chemother. Pharmacol. 48 (Suppl 1) (2001): 53 – 58 (review of

            the contribution of allogeneic and autologous transplantation)

            CASSILETH et al, N. Engl. J. Med. 339 (1998): 1644 – 1656 (chemotherapy

            compared with autologous or allogeneic bone marrow transplantation: US

            Intergroup study )

            HAROUSSEAU et al, Blood 90 (1997): 2978 – 2986 (comparison of autologous

            bone marrow transplantation and intensive chemotherapy)

            LEVI et al, Blood 98 (Suppl) (2001): 202b, abstr, 4514 (meta- analysis of autologous bone marrow transplantation vs chemotherapy)

            ROHATINER et al, Ann. Oncol. 11 (2000): 1007 – 1015

            ZITTOUN et al, N. Engl. J. Med. 332 (1995): 217 – 223 (autologous or allogeneic      bone marrow transplantation compared with intensive chemotherapy:

            EORTC – GIMEMA study)

 

2.2.3                              Salvage therapy

A number of newer agents has shown activity in recurrent AML, Including amsacrine, mitoxantrone, high–dose cytarabine, fludarabine, troxacitabine, homoharrigtonine, diaziquone, idarubicin, topotecan, and etoposide, some of these agents are being used in combination regimens, e.g.

 

2.2.3.1                       S – HAM         

Cytarabine             500*-1000 mg/m²           b.i.d. i.v. (3h inf)          d 1 , 2, 8 , 9

Mitoxantrone         10 mg/m²                        i.v. (30 min inf)           d 3 , 4 , 10 ,11

G- CSF                                                          starting                        d 14

     *   In older patients

 

      Literature

            KERN et al,  Cancer 79 (1997): 59 – 68

 

 

2.2.3.2                       FLAG       

Fludarabine              25 – 30 mg/m²                   i.v.                            d 1 – 5

Cytarabine               2000 mg/m²                       i.v.                            d 1, 2, 8, 9

G- CSF                     300 - 400µg                        s.c. until hematopoietic recovery

     

 

            Literature:

            FERRARA et al, Ann. Hematol. 78 (1999): 380 – 384

                        MONTILLO M et al, Am. J. Hematol. 58 (1998): 105 – 109

                        VISANI et al, Leukemia 8 (1994): 1842 – 1846

 

2.2.3.3.                     CAT

         

Cyclophosphamide               500 mg/m²                   b.i.d. i.v.                       d 1– 3

Topotecan                            1.25 mg/m²                  i.v. (cont inf)                 d 2- 6

Cytarabine                           2000 mg/m²                 i.v.(4 h inf)                    d 2- 6

            To be repeated every  3 – 4 weeks ( Provided there was full recovery from prior  

            toxicity)

 

             Literature:

                     CORTES et al, Leuk Lymph. 36 (2000): 479 – 489

 

 

Acute Myeloid Leukemia (AML)                                                                                                       21

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2.2.3.4                          Marrow-ablative (high-dose) cytotoxic treatment followed by hematopoietic stem cell

               transplantation (autologous or allogeneic)

               The details of these procedures are outside of the scope of this short

                compilation.

 

             Literature :

                        BROWN et al, Blood 85 (1995): 1391-1395 (allogeneic transplantation in  

                        untreated first relapse)

                        CLIFT et al, J. Clin. Oncol. 10 (1992): 1723-1729 (allogeneic  

                        transplantation in untreated first relapse)

                        CHOPRA et al , J. Clin. Oncol. 9 (1991): 1840-1847 (autologous bone

                        marrow transplan-

                        tation beyond first remission)

                        MICHALLET et al. Bone Marrow Transplant. 26 (2000): 1157-1163

                        PETERSEN et al. J. Clin. Oncol. 11 (1993): 1353-1360 (autologous bone 

                        marrow transplantation in untreated first relapse or in second CR)

 

2.3          Older adult patients (> 60 years)

               The choice of treatment in elderly patients with AML is directed by the                  

               underlying biology of the disease as reflected e.g. by karyotype, expression of

               multidrug resistance and by contraindications against intensive therapy.

             

              Literature: for review e.g.

                        BÜCHNER et al, Rev. Clin. Exp. Hematol. 6 (2002): 46-59

                        JACKSON and TAYLOR, Drugs Aging 19 (2002): 571-581

 

2.3.1         Patient with unfavorable cytogenetics and no contraindications against induction therapy should undergo intensive treatment (e.g. “3+7” or TAD induction and cytarabine postremission therapy).

 

 Literature:

            GOLDSTONE et al, Blood 98 (2001): 1302 – 1311 (MRC AML 11 trial)

            ÖBERG et al, Eur. J. Haematol. 68 (2002): 376-381 (randomized trial of  

            aclarubicin vs daunorubicin in combination with cytarabine and   

            thioguanine of the Leukaemia Group of Middle Sweden: (LGMS)

            STONE et al, Blood 98(2001): 548-553 (randomized comparison of  

            postremission therapy with mitoxantrone + intermediate-dose cytarabine  

            or with standard-dose cytarabine)

 

2.3.2         Others may tolerate less intensive treatment or even supportive care only or may be candidates for

novel therapeutic approaches, respectively: e.g.

 

2.3.2.1 Mitoxantrone + cytarabine

Mitoxantrone                          8 mg/m²                    i.v.                          d 1 – 3

Cytarabine                             100 mg/m²                 i.v.(cont inf)           d 1 –7

            As induction and consolidation, followed by

           

            Low-dose cytarabine

Cytarabine                               10 mg/m²                 b.i.d. s.c.                  d 1 - 12

            To  be repeated every 6 weeks (x 8)

           

            Literature:

                        LÖWENBERG et al, J. Clin. Oncol. 16 (1998): 872-881

           

or

 

2.3.2.2 Mitoxantrone + eloposide

Mitoxantrone                          10 mg/m²                 i.v.                             d 1 – 5

Etoposide                                100 mg/m²               i.v. (1 h inf)               d 1 - 5

 

 

 

22                                                                                                               Acute Myeloid Leukemia (AML) ____________________________________________________________________________________

 

            Complete remitters received a single course of

 

            Postremission intermediate-dose cytarabine

Cytarabine               500 mg/m²                  i.v. (1 h inf) every 12 h              d 1- 6

            Beginning within 4 weeks of remission

           

            Literature:

                        BOW et al, J. Clin. Oncol. 14 (1996): 1354-1352

 

2.3.2.3   Aggressive salvage chemotherapy results in an actual survival advantage only for a minority of elderly patients with relapse AML, i.e. those with CR1 lasting for > 12 months.

 

Literature:

            FERRARA et al, Haematologica 86 (2001): 814-820

 

2.3.2.4 Anti-CD33-calicheamicin conjugate (gemtuzumab ozogamicin, Mylotarg )

 For the treatment of patients with CD33 + AML in first relapse who are 60 years     of age or older and who are not considered candidates for cytotoxic chemotherapy.

Gemtuzumab               9 mg/m²                i.v. (2 h inf)                      d 1 + 14 (+21)

 

Literature:

            BERGER et al, Invest. New Drugs 20 (2002): 395-406 (review)

            BROSS et al, Clin. Cancer Res. 7 (2001): 1490-1496 (approval summary)

            GILES, Expert Rev. Anticancer Ther. 2 (2002): 630-640 (review)

            SIEVERS et al, J. Clin. Oncol. 19 (2001): 3244-3254

 

2.4               Pediatric patients

 

2.4.1        General considerations

Over the past decades the cure rate in childhood AML has improved with intensification and optimized timing of induction and postremission therapy.

 

In large randomized trials of postremission therapy superior results have been found for allogeneic bone marrow transplantation over chemotherapy. Data are still insufficient to determine whether autologous bone marrow transplantation is also superior to nonmyeloablative chemotherapy. Low-dose maintenance may be of no benefit after intensive induction and consolidation.

 

Literature: for review and representative group studies e.g.