TREATMENT OF CHRONIC MYELOID LEUKEMIA - AN UPDATE

K . Pavithran, MD,
DM Assistant Professor in Haematology,

Mathew Thomas, MD
Professor of Medicine,
Medical College Hospital, 
Trivandrum-695011, India


Introduction

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by leukocytosis with accumulation of all forms of mature and immature granulocytes.  It is the commonest type of leukemia seen in India, accounting for 30% of all leukemia cases.  The disease follows a biphasic or triphasic course - chronic phase, accelerated phase and blast crisis. Median survival is around 3-5years.  The advent of newer modalities of treatment has changed the outlook for these patients.

Molecular biology and Pathogenesis:

CML is classically associated with the presence of Philadelphia (Ph) chromosome1.  First described by Nowell and Hungerford in 1960, it results from reciprocal translocation of genetic material (containing proto-oncogene c-abl) from chromosome 9 to chromosome 22 (at the breakpoint of the bcr locus). It is the hallmark of CML and is found in 95% of patients. It is also found in 5% of children and 25% of adults with acute lymphatic leukemia  and in 20% of patients with acute myeloid leukemia. In few patientswith CML large deletions are seen adjacent to the translocation breakpointon the derivative 9 chromosome, on the additional partner chromosomein variant translocations, or on both.  Prognosis is poor in these group of patients2.  Abl proteins are non receptor tyrosine kinases that have important roles in signal transduction and the regulation of cell growth3.  Different structural abnormalities of ABL and BCR facilitate the leukemogenic transformation of Bcr-Abl. The resultant fusion product  bcr/abl encodes for a fusion protein (p210) with elevated and dysregulated tyrosine kinase activity.  The normal P145 ABL exchange between the cytoplasm and the nucleus.  The activity and intracellular localization of P145ABL is regulated by integrins.  BCR/ABL acts  1). As a mitogen by activating Ras (oncogene) signal transduction pathway leading to increase in C-myc and C-fos and subsequent increase in gene transcription4 and  activation of Cylin-D complexes5.  Cyclin dependent kinases allows the cells to move from G1 phase of the cell cycle to S phase.  2). BCR/ABL  inhibits apotosis thus leading to accumulation of cells6. 3) a4b integrins are important for the adhesion of normal progenitors to the marrow micro environment, this effects the progenitor proliferation and differentiation.  BCR/ABL blocks normal integrin function and there by reduces adhesion of progenitor cell to stromal elements.  So that the stem cells escape physiological inhibitory regulation4. Disease transformation is characterized by additional cytogenetic and molecular changes.  Most common cytogenetic changes are trisomy 8, isochromosome  17q  and double Ph' chromosome7. Molecular abnormalities include abnormalities in p53, RB1, c-MYC, RAS and AML-EVI-I. Alterations in p53 are associated  exclusively with myeloid transformation8 where as abnormalities of RB1 are associated with   lymphoid transformation.

Evolution of Treatment:

Fowler's solution (arsenicals) was the first treatment used for this condition in 1856.  Later radiotherapy was found to be useful in controlling the symptoms and signs of CML and it remained the main stay of treatment until the 1950's9.  In 1953 busulfan replaced radiotherapy10.  Hydroxyurea was introduced in CML therapy in 1972 and because of its better toxicity profile, it became the preferred agent for the treatment of CML11.  In the 1980s interferon (IFN) was shown to be effective and have now became the first line of treatment for majority of patients with CML.

Conventional Chemotherapy:

Busulfan and hydroxyurea controls the signs and symptoms of CML but they do not have any effect on the progression of the disease.  Busulfan controls cell count by acting on the stem cells.  So it takes about 3 weeks for the count starts falling.  Side effects are also many.  It is best to avoid in patients who are being prepared for bone marrow transplantation (BMT) as the incidence of veno-occlusive disease is high.  Hydroxyurea is useful in bringing down the counts rapidly as it acts on the proliferating cells and is usually well tolerated.  Hydroxyurea is preferred to busulfan because the median duration of  the chronic phase and median survival are significantly better12.

Interferon (IFN):

IFN  a2 a and a 2b, both are used in the treatment of CML. Although neutralising antibodies were detected in the blood of patient's treatment with IFN a 2a, for practical purposes both should be considered equal13.  IFN a acts by I) induction of FAS and its ligand on CML progenitors, facilitating cell death of early stem cell population.  II) IFN a restore integrin dependent adhesion and adhesion mediated proliferation inhibitor signaling III) augmentation of cellular antigen presentation leading to increased recognition of CML cells by cellular immune system14.  IFNa induced hematologic remission in 70-80% of  previously untreated patients and major complete remission in between 5-25%.  IFN a has only modest activity in late chronic phase (defined as CML diagnosed for more than one year) of CML in patients. Data on the efficacy of interferon is derived from the major randomized controlled clinical trials15. The individual patient data from these trials were pooled and analyzed by the CML trialist's collaborative group16. The 5-year survival rates for patients on chemotherapy were found to be 42% and 57% for patients on IFN a.  In those who achieve major or complete cytogenetic remission median survival is prolonged by 20 months15. IFN a prolongs survival by delaying blast crisis.

Therapy initiation17:

Initiallythe tumor load has to be reduced below 20 x 109/L with hydroxyurea. Side effects with IFN a are related to tumor load.  The CML cells contain high levels of cytokines (leukotriene 4), which may induce an inflammatory response on release following cell kill.  Initiate treatment with IFN 3 MU daily and then increase the dose gradually.  Tachyphylaxis develops in 1-2 weeks.  Initial side effects are mainly flu like symptoms (fever, myalgia, rhinitis).  This can be prevented by premeditation with paracetamol and taking the dose at bedtime.  Delayed side effects (persistent fatigue, weight loss, neurotoxicity,  insomnia and autoimmune phenomena) are dose limiting and occurs in about 10% of patients.  Tricyclic antidepressants (amitryptiline) are useful for the neurological side effects.  The actual dose of IFN a is important for achieving cytogenetic remission.  However, the best dose at which to start IFN a therapy in newly diagnosed patients is still not certain.  At present it varies from 3-5 MU/m2 daily to 3 times per week.  The Medical Research Council (MRC) study showed a survival advantage for patients receiving IFN a even without achieving a cytogenetic response18.

IFN a with Cytosine arabinoside (Ara-C):

Ara-C selectively suppresses the growth of CML cells compared to that of normal hematopoietic cells in vitro19.  IFN a when combined with Ara-C improves cytogenetic response and prolongs survival20,21.  So the current approach may consist of combination of daily IFN a and low dose Ara-C (10-20 mg/day for 10 days a month).

            The best dose of IFN a and best away to combine with chemotherapy remains to be established.  The WBC count should be maintained between 3-5X109/L.  The dose should be reduced only if the WBC count is less than 2 x 109/L or the platelet count is less than 50 x 109/L or in the presence of grade 2-4 toxicity.

Efficacy assessment:22

Patients should be monitored with blood counts and cytogenetic studies in all cases and molecular studies especially in the post transplant setting.

Criteria for response assessment:

Complete hematological remission - normalization of WBC  count to <9 x 109/L with normal differential, normal platelet count and disappearance of all symptoms and signs of disease.

Partial hematological remission:  Normalization of WBC with persistent immature peripheral cells or splenomegaly or thrombocytosis at 50% pre treatment level.

Cytogenetic remission:  Complete no evidence of Ph+ve cells; Partial 1-34% of metaphases Ph+ve; a minor 35 - 90% metaphases Ph+ve.

Minimal residual disease:  (MRD) means the disease that cannot be conventional investigations.  Methods available for detection of MRD are Cytogenetics, Fluorescence in situ hybridization (FISH), hyper metaphase FISH and reverse transcriptase PCR (RT-PCR).  Cytogenetic study has to be done every 3-6 months.  Relapse can be molecular relapse (increasing numbers of BCR/ABL transcripts while the marrow is still entirely Ph negative), cytogenetic relapse (Ph+ve) or hematological relapse.  Molecular relapse is defined as BCR/ABL transcripts >1000 transcripts/m g RNA.

Allogenic Bone marrow Transplantation: is the only curative treatment for CML23.  Unfortunately it is available to only 15-25% of these patients because of advanced age, non-availability of an HLA identical donor and lack of resources. Timing of transplantation during the chronic phase still remains controversial. Most of the centers prefer allergenic bone marrow transplantation within 1 year of diagnosis. However, Clift et al.24 And van Rhee et al.25 Reported similar outcomes among patients undergoing BMT during the early phase or late phase of CML.  Allogenic BMT is associated with significant morbidity and mortality. Even today the transplant related mortality is about 30%. Anti leukemia effect is due to the myeloablative effect of chemotherapy and graft-versus-leukemia (GVL) effect.  GVL effect is mediated through (1) by CD4+ve T lymphocytes exert cytotoxicity to CML cells and inhibits CFU- GM and BFU.E.  Cytotoxicity is mediated through the Fas/Fas ligand pathway.  (2) Cytokines  and IFN inhibit CML progenitor cells 26.

Allogenic BMT in chronic phase result in 3 years probability of leukemia free survival of 59%, 37% in accelerated phase and 17% in blastic phase27.  Adverse pre-transplant prognostic factors are

  1. advanced age (> 55 yrs). Older patients do worse mainly because of an increase in treatment related mortality28.
  2. Prior therapy with busulfan. Data from IBMTR registry showed that busulfan therapy before allogenic stem cell transplantation adversely affect pre-transplant survival29.
  3. Male recipient - female donor - risk of GVHD more.
  4. Transplant during the late chronic phase. transplantation during the advanced phases of CML results in increased rates of transplant related mortality and leukemia relapse.
  5. Donor T lymphocyte depletion30.  Causes of death in these patients are GVHD, infections, lung toxicity and relapse in decreasing order of frequency. In most of the studies, prior interferon therapy did not affect long-term prognosis after transplantation31.

Matched unrelated or mismatched related donors:

Extended family typing will identity  one  HLA antigen mismatched related donor in about 5 - 10% of patients; without as HLA identical sibling donor.  Transplant with one antigen mismatched related donors results in survival similar to that using matched unrelated donors.  Suitable candidate for matched unrelated donor BMT are young patients (<30 yrs.) in chronic phase who have a matched donor and have exhibited resistance to IFN - a therapy17.

Relapse following BMT:

Treatment options available are supportive care, chemotherapy (hydroxyurea), IFN a. Second allogenic BMT and adoptive immunotherapy with donor lymphocyte infusion (DLI).  Donor lymphocyte infusion induces remission in more than 70% of patients with relapsed CML, following allogenic BMT. Induction of GVL with DLI is very useful for patients who relapse with chronic phase CML.  The effectors of this GVL effect are thought to be donor T cells. Treatment related mortality is about 20%.  The major toxicities are bone marrow aplasia and  GVHD32.

Investigational approaches:

1. Intensive chemotherapy:  Induced cytogenetic remission in 60-70% of patients with CML. nowadays it is more often used as a method for in vivo purging of Ph+ve  cells during autologous BMT.

2. Autologous BMT:  Rationale of autologous BMT is that hematopoiesis in CML consists of normal and Ph+ve  cells. Initially studies using unpurged marrow stem cells occasionally resulted in cytogenetic responses, which were transient.  Encouraged by these results, studies were continued with purged marrow stem cells.  The results of several studies indicate that they may prolong the survival of patients with CML as compared with conventional chemotherapy,  but it has not yet been shown to be curative for this disease33,34.

3. Chemotherapy with newer agents:

a)Pegylated  IFN-a 2b : Attachment of a 40 kDa polyethylene glycol polymer to the  IFN-a 2b molecule  results in a drug with good activity compared to IFN-a 2b with longer half life (half-life ~ 70 hours).  Blood levels are detectable for 1 week after a single injection compared to 24 hrs with IFN-a 2b. Improved  efficacy  with less adverse effects will makepeg IFN-a 2b the preferred  IFN-a 2b in the future. In a study of  21 patients (14 male, 7 female) with chronic phase CML the drug was found to be well tolerated35.

b) YNKO1 (Ocfosfate): is an oral pro-drug of ara-c36. Cytosine arabinoside (AraC) is rapidly inactivated via systemic deamination with half-lives ranging from 1 h (i.v.) to  4 h (s.c.)  and cannot be applied orally due to its hydrophilic properties. These imitations might be overcome by YNK01 - a lipophilic prodrug of AraC - that is resistant to deoxycytidine deaminase and can be applied orally. So we can reduce  the number of injections and compliance will be better.

c) Homoharringtonine (HHT): a plant alkaloid, is shown to be effective in CML. In patients with late phase CML who were resistant to IFN a therapy showed complete haematologic remission in 66% and major cytogenetic response in 17% with a combination of Ara-c and HHT treatment37.  Now the trials are going on in early phase CML.

d) Decitabine:  Hypermethylation of DNA is feature of tumor progression.  Hypermethylation is seen in about 50% of patients with chronic phase CML and 100% with blast crisis.  Decitabine is a potent hypomethylating agent and is being evaluated in patients with accelerated and blastic phase of CML with encouraging results38.

e) STI 571: is an orally active tyrosine kinase inhibitor. The half-life of this compound is 13-19hrs making single daily doses possible. It is well tolerated. Phase I studies show promising results39. Thiesing  et al. showed that combinations of STI 571 with IFN, DNR, or Ara-C may be more useful than STI 571 alone in the treatment of CML40.

Other agents under evaluation are farnesyl transferase inhibitors, azidothymidine, topotecan and all trans retinoic acid (ATRA).

3. Inhibition of BCR/ABL gene products:41 The chimericmolecules created by cancer-associated chromosomal abnormalitiesare ideal therapeutic targets because they are unique to the disease.

a) Antisense oligonucleotide (AS-ODN) therapy:  AS-ODN acts by inhibiting transcription of target genes.  Limitations - they are unstable and susceptible to nuclease digestion.  AS-ODN against the BCR/ABL breakpoint can inhibit expression of the P 210 protein.  In addition to BCR/ABL mRNA other potential targets include GRB2, Shc, p120GAP and c-myc. 

b) Ribozymes: are RNA sequences that can catalytically cleave other RNA molecules.  These molecules are composed of 2 domains - a catalytic domain, which cleaves the target, and a flanking sequence, which confers specificity of the ribozyme binding to target RNA.  Ribozymes can be targeted against BCR/ABL mRNA. Maxizyme, cleaves bcr-abl mRNA only in cells with bcr-abl junction sequence42.

c) catalytic RNA subunit of RNase P.M1-RNA with guide sequences recognize theoncogenic messengers at the fusion point RNA and  cleave specificallythe chimeric molecules created by chromosomal abnormalities43.

d) Phosphatidyl inositol - 3 kinase (PI - 3 kinase): is involved in cell proliferation.  PI - 3 kinase inhibitor, wortmannin inhibited CML colony growth in vitro.

e). Gene therapy: One promising strategy involves the cotransduction of a patient's hematopoietic stem cells with a drug resistance gene and anti-BCR-ABL antisense sequences. This might allow for the elimination of any residual disease in the host or graft by chemotherapy while rendering any drug-resistant, malignant CML haematopoietic stem cells functionally normal44.


Figure 1. Suggested Algorithm for the management of CML : 45

 

Early Chronic Phase

HLA identical sibling

<50 yrs?

Yes

<50 yrs?

No

Allo BMT

IFN alpha 

Cytogenetic response at 12 months?

Yes

No

Continue IFN alpha  Allo BMT  (Late Chronic Phase)
Accelerated phase - not possible
Investigational Treatment

 

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Address for correspondence

Dr.K.Pavithran, MD,DM

Department  of  Haematology

Medical College Hospital,

Trivandrum-695011

Email: pavith90@hotmail.com

 

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