Chronic Myeloid (Myelogenous)Leukemia (CML)                                                                                  33

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5.   Chronic Myeloid (Myelogenous) Leukemia(CML)

5.1             General considerations

Chronic myeloid (myelogenous) leukemia (CML) is a clonal disorder characterized in 95% of cases by the Philadelphia chromosome. The Philadelphia chromosome is formed by a reciprocal translo –cation between chromosomes 9 and 22 , replacing the first exon of c-abl with sequences from the bcr gene. This bcr-able gene codes for a constitutively activated tyrosine kinase that alters multiple signal transduction pathways and induces malignant transformation.

The course of CML is generally triphasic. The disease is usually diagnosed in Chronic phase, changes spontaneously after a rariable interval to an accelerated phase,  and then proceeds to a phase of blastic transformation or blast crisis. Disease progression is associated with characteristic non- random cytogenetic and molecular events which are still poorly understood.

For long time, therapeutic options for patients in chronic phase CML consisted of interferon- and/or hydroxyurea- based treatment (for patients not responding to or with contraindications against interferon alpha and hydroxyurea also busulphan). For  most patients, interferon alpha prolongs life in comparison with hydroxyurea, but it is associated with considerable toxicity. Allogeneic stem cell transplantation has the potential to cure selected patients with CML but also carries the risk for inducing death or protracted illness. More recently, imatinib mesylate, an oral Bcr Abl kinase inhibitor  has demonstrated activity in all phases of CML. It is, therefore, not only usad as salvage therapy and in the accelerated and blastic phase but also has started to enter into the initial therapy.

Lietature: for review e.g.

            BRUNSTEIN and McGLAVE, Oncology 15 (2001): 23 – 31

            DRUKER, Eur. J. Cancer 38 (Suppl 5) (2002): 70 0 76 (review on

            imatinib mesylate)

            FADERL et al, Semin, Oncol. 27 (2000): 578 – 586 (new treatment

            approaches)

            GARCIA-MANERO et al, Intern. Med. 41 (2002): 254 – 264

            GOLDMAN and DRUKER, Blood 98 (2001): 2039 – 2042

            O’DWYER et al, Annu. Rev. Med. 53 (2002): 369 – 381

            TALPAZ et al, Oncology 14 (2001): 229 – 240

            VERWEIJ et al, Eur. J. Cancer 37 (2001): 1816 – 1819 (review on imatinib mesylate)

5.2             Chronic phase

5.2.1      Initial therapy

5.2.1.1                       Interferon alpha

Initial therapy especially for patients > 55 – 60 years, lower – risk patients and patients not suitable for an allogeneic transplantation

5.2.1.2                       Hydroxyurea

Initial therapy especially for patients not tolerating interferon alpha

34                                                                                      Chronic Myeloid (Myelogenous)Leukemia (CML) ______________________________________________________________________________________

5.2.1.3                       Busulphan

            For patients not responding to or with contraindications against interferon alpha

            and hydroxyurea

            Literature : for  5. 2. 1. 1-5. 2. 1. 3

                        CHRONIC MYELOID LEUKEMIA TRIALISTS’ COLLABORATIVE

                        GROUP, J. Natl.

                        Cancer Inst. 89 (1997): 1616 – 1620 and Brit. J. Haematol. 110 (2000):

                        573 – 576

                        ITALIAN COOPERATIVE STUDY GROUP ON CHRONOC

                        MYELOID LEUKEMIA,

                        Blood 92 (1998): 1541 – 1548

                        OHNISHI et al, Cancer Chemother. Pharmacol. 48 (Suppl 1) (2001): 59 –

                        64

                        SILVER et al, Blood 94 (1999): 1517 – 1536

5.2.1.4                       Imatinib mesylate (STI 571)

Treatment should be continued as long as the patient continues to benefit

Literature:

            CUILHOT, Ann. Oncol. 13 (Suppl 5) (2002): abstr. 27 (randomized

            comparison of imatinib vs interferon + cytarabine as initial therapy)

5.2.1.5                       Combination therapy

The combination of interferon alpha and cytarabine with or without hydroxyurea was shown to increase the rate of major cytogenetic response but not always to prolong survival.

Literature: e.g.

            BACCARANI  et al, Blood 99 (2002): 1527 – 1535 (randomized study of  

            interferon vs Interferon + cytarabine from the Italian Cooperative Study

            Group on Chronic Myeloid Leukemia)

GUILHOT et al, N. Engl. J. Med. 337 (1997): 223 – 229

GILES et al, Leuk. Lymphoma 37 (2000): 367 – 377

SILVER et al, Leuk. Lymph. 44 (2003): 39 – 48 (results from CALGB study 9013)

5.2.2      Allogeneic transplantation

Allogeneic transplantation from either related or matched unrelated donors is the only known definitively curative therapy for patients with CML. Because a negative impact of prolonged prior interferon alpha therapy has been discussed *. allogeneic bone marrow transplantation should be considered as initial therapy option for younger patients (< 55 years for related donors, < 45 years for unrelated donors).

According to some authors interferon alpha should be stopped at least 5 months before transplantation. **

Literature: e.g.

         * BEELEN et al, Blood 93 (1999): 1779

GALE et al, Blood 91 (1998): 1810 – 1819

GRATWOHL et al, Lancet 325 (1998): 1087 -  1092

       ** HEHLMANN et al, Blood 96 (2001): 345 – 354

KISS et al, J. Clin. Oncol, 20 (2002): 2334 – 2342 (long-term outcome and quality of life ≥ 10 years after transplantation.

         * LEE et al, Blood 98 (2001): 3205 – 3211 (no evidence for an independent adverse effect of interferon pretreatment on the outcome of unrelated donor transplantation)

      McGLAVE et al, Blood 96 (2000): 2219 – 2225

      WEISDORF et al, Blood 99 (2002): 1971 – 1977 (comparison of unrelated vs   

      matched sibling donor transplantation).

Chronic Myeloid (Myelogenous)Leukemia (CML)                                                                                  35

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5.2.3      Autologous transplantation

Autologous transplantation of non- purged or purged cells may be an option for patients who cannot undergo allogeneic transplantation or who are not or poorly responding to initial therapy.

Literature: e.g.

            FRASSONI, Curr. Oncol. Rep. 2 (2000): 144 – 151

            MICHALLET et al, Leukemia 14 (2000):2064 – 2069

5.2.4      Salvage therapy

Imatinib mesylate ( STI 571)

Treatment should be continued as long as the patient continues to benefit. Higher doses (up to

1000 mg / d) were also tolerated.

Literature:

            DRUKER et al, N. Engl. J. Med. 344 (2001): 1031 – 1037 (phase I dose

            escalation study in patients failing or not tolerating interferon alpha)

            FISCHER et al, Leukemia 16 (2002): 1220 – 1228 (after autologous blood

            stem cell transplantation)

KANTARJIAN et al, Blood 100 (2002): 1590 – 1595 (after allogeneic stem cell transplantation)

5.3             Accelerated phase and blast crisis

Individualization of the therapy (e.g. dose escalation). Use of new or experimental treatment options; e.g.

Imatinib mesylate (STI 571)

Treatment should be continued as long as the patient continues to benefit

Literature:

            DRUKER et al, N. Engl. J. Med. 344 (2001): 1038 – 1042 (phase I study

            in blast crisis)

            KANTARJIAN et al, Blood 99 (2002): 3547 – 3553 (therapy in blastic

            phase)

            SAWYERS et al, Blood 99 (2002): 3530 – 3539 (therapy in blastic phase)

            TALPAZ et al, Blood 99 (2002): 1928 – 1937 (therapy in accelerated

            phase)

Also attempts with acute leukemia-directed therapy protocols (either ALL or

AML according to immunophenotype of the blasts) to restore the chronic phase.

Literature: e.g.

            AXDORPH et al, Br. J. Haematol. 118 (2002): 1048 – 1054