AcuteMyeloidLeukemia(AML)                                                                                                       15

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2.   Acute Myeloid Leukemia (AML)

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

            As induction and consolidation, followed by

            Low-dose cytarabine

            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

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            Complete remitters received a single course of

            Postremission intermediate-dose cytarabine

            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.

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.

            AQUINO, Curr. Probl. Pediatr. Adolesc. Health Care 32 (2002): 50-58    

            (review)

            BEHAR et al, Med pediatr. Oncol. 26 (1996): 173-179 (study EORTC-

            58872)

            BLEAKLEy et al, Bone Marrow Transplant 29 (2002): 843-852 (review  

            and  meta-analysis of bone marrow transplantation for pediatric AML)

            GREGORY and ARCECI, Cancer Invest 20 (2002): 1027-1037 ( review

            of risk factors and recent trials)

            O’BRIEN et al, Blood 100 (2002): 2708-2716 (report of consecutive  

            studies of the Australian and New Zealand Children’s Cancer Study Group

            which shows equiefficacy of daunorubicin and idarubicin for remission

            induction, but reduced toxicity for the former)

            PEREL et al, J. Clin. Oncol. 20 (2002): 2774-2782 (study LAME 89/91)

            RAVINDRANATH et al, N. Engl. J. Med. 334 (1996): 1428-1434 (study

            PCG-8821)

            RITTER, Eur. J. Cancer 34 (1998): 862-872

            STEVENS et al, Br. J. Haematol. 101 (1998): 130-140 (study MRC – 10)

Acute Myeloid Leukemia (AML)                                                                                                        23

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            In the following two representative examples of large multi-institutional studies   

            are outlined.

2.4.2        Childrens Cancer Group Study 2891

Induction treatment CDCTER

To be repeated with G-CSF support on days 10 – 14 regardless of response (in patients with Down syndrome on days 14 – 18 or later depending on response).

Consolidation treatment

Two additional courses of CDCTER as above.

Postinduction treatment

Allogeneic bone marrow transplantation: if a donor is available.

Conventional chemotherapy:  if no donor is available.

Course 1

Course 2,3

            Course 4

            Literature:

                        WELLS et al, Curr. Oncol. Rep. 2 (2000): 524 – 528

                        WOODS et al, Blood 87 (1996): 4979 – 4989 and Blood 97 (2001): 56-62

2.4.3        Study AML BFM- 87/BFM-93

Induction with either ADE or AIE

ADE

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            AIE

            Patients treated with idarubicin had better blast cell reductions in the bone marrow on day 15,

            However, probabilities of 5 – year EFS and DFS were similar.

            In high-risk patients followed by

            HAM 

            Followed by consolidation after hematologic recovery. When on day 15 ≥ 5% of blasts in the bone        marrow, consolidation is started without delay, clinical condition of the patient permitting.

            Consolidation (6 weeks)

  *  Age dependent (< 1 year 20 mg ; ≥ 1-2 years 26 mg : ≥ 2 –3 years 34 mg: ≥ 3   

      years 40 mg)

**  Age dependent (< 1 year 12 Gy ; ≥ 1-2 years 15 Gy: ≥ 2  years 18 Gy)

Late intensification (2 blocks)

      Maintenance

For a total of 18 months ( in children with continuous CR). CNS prophylaxis with cytarabine i.th ; CNS irradiation in patients with initial CNS leukemia.

Literature:

      CREUTZIG et al, J. Clin. Oncol. 11 (1993): 279 – 286 and J. Clin. Oncol. 19        

      (2001): 2705-2713