ABSTRACT
Nizam's Institute of Medical Science is a premier institute of Hyderabad, established in 1980. The Medical Oncology Unit is the 1(st) comprehensive cancer center established for the state of Andhra Pradesh. The department has presented a data of total 201 patients with the median age of 32 at diagnosis. Among these 66 (33%) patients belonged to low Hasford risk group. Complete hematologic response was seen in 195 (97%) of patients. The progression free survival (PFS) was 77% for all patients while those who achieved complete cytogenetic response, PFS was 88% at 29 months.
ABSTRACT
Imatinib has shown unprecendeted success in the treatment of chronic myeloid leukemia (CML). However, over few years there have been reports regarding the primary and secondary resistance to Imatinib dampening the overall outcome in CML patients. In this study we have tried to assess the effect of dose escalation in patients resistant to standard dose of Imatinib and correlate it with presence of ABL kinase domain (KD) mutations. There were 90 patients resistant to imatinib, out which 29 patients were identified with KD mutations. The most common mutation was T315I , 9 out of 29 patients had it. 35 (38%) responded to dose escalation and had 67% event free survival (EFS) at estimated 2 years. Our results showed that dose escalation can over come resistance in some patients especially those in cytogenetic failure.
ABSTRACT
We studied kinase domain (KD) mutations, response to dose escalation, event free survival (EFS), and overall survival (OS) of 90 patients with chronic phase CML who were resistant to imatinib mesylate (IM) 400 mg. IM was escalated to 800 mg daily. There were 65 patients with hematologic failure and 25 with cytogenetic failure. Median duration on IM at resistance detection was 18 months (range, 3-48). Twenty nine (32.2%) patients had KD mutations. Of the 29, the most common were T315I in nine (31.2%) and G250E in eight (27.6%). No clinical or laboratory factor predicted for mutation detection. Of 90 patients, 50 (55.5%) achieved a complete hematologic response and 35 (39%) a major cytogenetic response. At a median of 18 months (range 3-40), 35 patients (39%) are event free and 84 (93%) are alive. The 2 year EFS and OS were 34% and 93%, respectively. The projected 2 year EFS was superior for patients with cytogenetic failure compared to those with hematologic failures (73 vs. 22%, p = 0.0001). Dose decreases were necessary in 16 (18%) and interruptions in 31 (34%). KD mutations were detected in a third of patients with T315I being the most common. IM dose escalation can induce sustained responses in patients with cytogenetic failures.
Subject(s)
Drug Resistance, Neoplasm , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Mutation , Piperazines/therapeutic use , Protein Kinases/genetics , Pyrimidines/therapeutic use , Adolescent , Adult , Aged , Antineoplastic Agents/pharmacology , Benzamides , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Humans , Imatinib Mesylate , Male , Middle Aged , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Time Factors , Treatment OutcomeABSTRACT
Chronic Myeloid leukemia is a clonal disease of multipotent haematopoietic cells associated with specific cytogenetic changes involving a translocation t(9;22) (q34:q11), more commonly known as Philadelphia Chromosome (Ph1). A total of 525 patients with CML (480 adults and 45 children) diagnosed at the Nizam's Institute of Medical Sciences, Hyderabad, formed the subjects of this study. Hematological investigations were carried out using standard methods. Unstimulated peripheral blood samples and/or bone marrow aspirates were used for cytogenetic analysis. Hematological evaluation at presentation showed that 435 were in chronic phase, 36 in accelerated phase and 54 in blast crisis. Chromosomal analysis revealed that 86.3% were Ph1 positive and 13.7% Ph1 negative. Additional chromosome changes observed during blast crisis included an extra Ph1 chromosome, Trisomy 8 and Trisomy 19. The results were correlated with survival pattern and prognosis of patients following certain treatment protocols.
