Abstract

INTRODUCTION

Chronic myelogenous leukemia was recognized as a distinct entity in the mid-1800s. The modern history of chronic myeloid leukemia (CML) was initiated by Nowell and Hungerford in 1960. They used newly developed techniques to detect a small chromosome in metaphase preparations of marrow cells from CML patients.[1]

CML accounts for 15% of cases of leukemia in the United States. There is a slight male preponderance (male-to-female ratio 1.6:1). Its annual incidence is about 1.5 cases per 100,000 individuals. This incidence has not changed over in the past few decades and it increases with age. The median age at diagnosis is 55-60 years; it is uncommon in children and adolescents; only 2.7% of CML cases are younger than 20 years.

Incidence remains almost constant all over the world. CML is the most common adult leukemia in India.[2,3]

In the 1990s, the recommended approach to manage a newly diagnosed patient with CML-chronic phase (CP) was allogeneic stem cell transplantation (allo-SCT), especially if the patient was relatively young and had suitable donor; for other patients’ interferon-alpha with or without cytarabine was recommended.

From 2000 onward imatinib at 400 mg daily became the preferred initial treatment[4] and this practice received substantial support from the interim results of the immediate risk-stratification improves survival (IRIS) study published in 2003;[5] the 7-year update for patients who received imatinib as first-line treatment showed an actuarial overall survival of 86% and also showed that responding patients whose disease had not progressed in any way in their first 3 years of the study were extremely unlikely to relapse at a later stage and also unlikely to suffer from any late onset side effects. However, the 7-year update also showed that only 57% of the original patient cohort was still in continuing complete cytogenetic response (CCyR) taking imatinib on study according to the original protocol.[6]

A case can be made for offering initial treatment by transplantation for the rare patient with a genetically identical twin since the risk of transplant-related mortality is extremely low with syngeneic donors. Until recently some investigators recommended an initial allograft for younger patients with a high probability of surviving the transplant based on the European scoring system,[7] but even this approach has now fallen from favor.

PATIENTS AND METHODS

Retrospective analysis of cases of CML enrolled in Glivec International Patient Assistance Program at our center from February 2002 to July 2009 was done.

Assessment of new patient of CML at our center includes the following:

1. History and physical examination, complete blood count with differential and platelet count and chemistries.
2. Bone marrow aspiration and biopsy if aspiration dry.
3. Testing for the presence of the Philadelphia (Ph) chromosome by cytogenetic analysis and for the presence of the BCR-ABL fusion gene by fluorescence in situ hybridization (FISH). Reverse-transcription polymerase chain reaction (PCR) not available at Gujarat Cancer and Research Institute (GCRI).
4. We are following World Health Organization criteria for accelerated phase (AP) and blast phase (BP) of CML.

WHEN WE CHANGE DOSE OF IMATINIB

We follow recommendations of European Leukemia Net (2006) for defining imatinib failure [Table 2].

Table 2

We do conventional cytogenetics at every 6 months interval; if report is inconclusive due to the absence of metaphase cell then we repeat it.

If patient comes under definition of imatinib failure then we increase dose of imatinib from 400 mg to 600 mg and further to 800 mg. Most of patients at our center are not affording for second generation tyrosine kinase inhibitors.

Dasatanib: We have treated only 8 patients with Dasatanib mainly those patients who progressed on imatinib. 2 patients have achieved long-term hematological remission and are presently taking Dasatanib. One patient is in Molecular complete response (CR).

If patient not responding to maximum dose of imatinib or does not tolerate then change to hydroxyurea.

IMATINIB AND PREGNANCY

Imatinib could be teratogenic in certain circumstances, so women taking the drug have been routinely advised to take steps to avoid conception. Nonetheless, some women have conceived while taking imatinib and in most cases where the pregnancy went to term the baby appears to have been normal. Certain specific developmental abnormalities including hypospadias, exomphalos and defective skeletal formation have been seen more often than would have been expected in women not taking imatinib[9] and the advice to avoid pregnancy while being treated with the drug must be upheld.

Little is known about the possible harmful effect of imatinib on male spermatogenesis, so again no firm recommendations can be offered to the potential father treated with i matinib.

RESULTS

RESPONSE

• Patients achieving CHR – 96%
• Mean time to achieve CHR – 2.03 months
• CHR in less than 3 months – 87%
• Patients achieving CCyR – 36%
• Mean time to achieve CCyR – 17.25 months
• Patients achieving partial CyR (PCyR) – 23%
• Mean time to achieve PCyR – 13.08 months.

CONCLUSION

CML mainly present in CP in our patient population and 96% achieved CHR. The CCyR was seen in approximately 36% of patients which was slightly less than compared to patients in IRIS study where 57% had shown CCyR. Around 30-50% population has some toxicity but Grade IV toxicity requiring intervention was present in less than 1% cases.

Footnotes