Leukemia is a haematological malignancy associated with the Philadelphia chromosome. It accounts for about 3.6 % of all haematological malignancies worldwide.1 In Nigeria CML prevalence remains unknown but studies done in Lagos give an incidence of 90.3 cases annually.

For many years the treatment for CML has included hydroxyurea, interferon alpha with or without cytarabine and busulfan, with hemopoietic cell transplant (HCT) therapy giving a potential of cure.

The introduction of targeted therapy using tyrosine kinase inhibitors has revolutionized the management of CML. During the IRIS trial, Imatinib was compared to treatment with combination treatment with interferon and cytarabine. Due to the superiority of Imatinib demonstrated by this study, it has now become the standard of care. Cases of failure on treatment with imatinib have been documented, with therapeutic failure to imatinib seen in approximately 10% to 15% of patients and can be classified as primary or secondary depending on whether an initial decline in disease levels is observed or not Risk factors for failure on imatinib are yet to be fully established with the Sokal and Hasford scores being used to predict cytogenetic response in some centres 6.

In Nigeria, most of the patients on Imatinib receive the medication via the GIPAP, an international assistance programme which provides Philadelphia chromosome positive (Ph+ve) CML patients with imatinib mesylate (Glivec®) at no cost. There had been no studies done to determine; treatment response, the proportion of patients who fail on imatinib and to describe their clinical-pathologic characteristics.

1.2      RESEARCH QUESTION

What is the treatment response of leukemia patients to imatinib therapy, and what are the clinical and haematological characteristics of patients with imatinib failure?

1.3      OBJECTIVES

1.4          Broad objective

Broadly we were to determine the hematologic treatment response, proportion of CML patients with hematologic imatinib failure, and to describe the clinical and haematological characteristics of patients with imatinib failure.

1.4.1     Primary objectives

The primary objectives were to determine the hematologic treatment response of CML patients receiving imatinib therapy, the proportion of CML patients with hematologic failure and to describe clinical and haematological characteristics of patients with hematologic failure and compare this with those of patients with optimal response.

1.4.2     Secondary objectives

Our secondary objectives were to determine the possible predictors of imatinib failure in patients with Ph +ve CML and to determine the proportion of patients with imatinib failure in relation to the Sokal and Hasford scores.

CHAPTER TWO

LITERATURE REVIEW

2.1      Leukemia

Leukemia is a clonal myeloproliferative disorder associated with the Philadelphia chromosome (Ph), a balanced translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11) producing BCR-ABL oncoprotein as illustrated in figure 1. It is characterized by proliferation of mature granulocytes (neutrophils, eosinophils, and basophils) and their precursors.

Peter C. Nowell and David Hungerford in 1960 at Philadelphia, Pennsylvania, noticed an abnormally small chromosome 22 in the cells of patients with CML, which got named Ph chromosome. This made CML the first cancer shown to be caused by an underlying genetic abnormality.8 Later, in 1973, Janet Rowley reported that Ph chromosome represents a balanced reciprocal translocation between long arms of chromosomes 9 and 22

The chromosome is detected in about 95% of patients, 11 this genetic abnormality results in the formation of a unique gene product (BCR-ABL), which results in a constitutively active tyrosine kinase. It is this deregulated tyrosine kinase that is implicated in the development of CML and is the target of current therapies

BCR-ABL oncogene mediates the development and maintenance of CML through interaction with multiple downstream signalling partners resulting in altered cellular adhesion, activation of mitogenic signalling, defective DNA repair, and inhibition of apoptosis: all these lead to transformation of hematopoietic stem cells.11 The Signaling Pathways of BCR-ABL are illustrated in figure 2.

Fig 1: The Translocation of t(9;22)(q34;q11) in CML10

The Philadelphia (Ph) chromosome is a shortened chromosome 22 that results from the translocation of 3' ABL segments on chromosome 9 to 5' BCR segments on chromosome 22. Breakpoints (arrowheads) on the ABL gene are located 5' of exon a2 in most cases. Various breakpoint locations have been identified along the BCR gene on chromosome 22. Depending on which breakpoints are involved, different-sized segments from BCR are fused with the 3' sequences of the ABL gene. This results in fusion messenger RNA molecules (e1a2, b2a2, b3a2, and e19a2) of different lengths that are transcribed into chimeric protein products (p190, p210, and p230) with variable molecular weights and presumably variable function.

The abbreviation m-bcr denotes minor breakpoint cluster region, M-bcr major breakpoint cluster region, and μ-bcr a third breakpoint location in the BCR gene that is downstream from the M-bcr region between exons e19 and e20.

Figure 2: Signaling Pathways of p210 BCR–ABL.10

Several regions of BCR–ABL serve as important control elements for RAS, which is at the center of the most prominent signaling pathways in CML. Activation of RAS is mediated through a series of adapter proteins, such as GRB2, CBL, SHC, and CRKL. Adapter proteins also connect p210BCR–ABL to focal adhesion complexes, PI-3 kinase, and other messenger systems such as JAK–STAT kinases. Signaling events downstream of RAS are less well characterized. They appear to involve mainly mitogen-activated protein kinases (MAPKs), preferably the JUN kinase (JNK) pathway. BAP-1 denotes BCR-associated protein 1, GRB2 growth factor receptor–bound protein 2, CBL casitas B-lineage lymphoma protein, SHC SRC homology 2–containing protein, CRKL CRK-oncogene–like protein, JAK–STAT Janus kinase–signal transducers and activators of transcription, FAK focal adhesion kinase, SOS son-of-sevenless, GDP guanosine diphosphate, GTP guanosine triphosphate, SRE stimulated response element, Ser–thr serine–threonine, Y177 a conserved tyrosine residue, GEF GDP– GTP exchange factor, and SH SRC homology domain.

Epidemiology

Aetiology: The only known risk factors for CML are high doses of ionizing radiation and occupational exposure to benzene as evidenced by 20-25 fold increase in the incidence of all leukaemia‟s among atomic bomb survivors.13 CML accounts for 0.34% of all cancers, 3.6% of all haematological malignancies and 0.08% of all cancer mortalities. It also accounts for 15% of all adult leukaemias.1, 14. The median age of onset is 45 to 55 years.

In Nigeria CML Prevalence remains unknown, Ministry of health records between 1998 and 2002 estimate a mean of 90.3 cases of CML per 100,000 people in Lagos annually. A retrospective study done on 104 patients treated for CML between April 1990 and August 2000, at Ibom National Hospital, Lagos, Nigeria showed age range of 10-72years with a median of 35 years which is a decade younger than the age of 45 years described among Whites.15

Apart from on average younger patient age group, the other differences in patient characteristics which have been noticed when African patients are compared with patients from other populations include high incidence of cytogenetic abnormalities and long duration of time between diagnosis and onset of treatment.

2.1.1     Clinical features of CML

About 40% of CML patients are asymptomatic and therefore diagnosis is based on abnormal blood count.10 The commonest physical finding is splenomegaly which occurs in about 50% of CML patients, followed by hepatomegaly. Fatigue, anorexia, and weight loss are the commonest symptoms.

The disease is characterized by an overabundance of hematopoietic stem cells and progresses through Chronic, accelerated and blast phases with more than 80% of patients being diagnosed in the chronic phase.11, 14 Median duration of chronic phase is 5-6 years.