Impact of MLL::AF9 Gene Rearrangement on Survival of Acute Myeloid Leukaemia Patients: An Insight into Pakistani Population.

OBJECTIVE: To ascertain the frequency of the MLL::AF9 gene rearrangement and its association with survival in Pakistani patients suffering from acute myeloid leukaemia (AML). STUDY DESIGN: Analytical study. Place and Duration of the Study: Department of Haematology, National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan, from 2015 to 2020. METHODOLOGY: Patients without a history of past AML chemotherapy, aged from 10 to 75 years, were included. Individuals with metastatic cancer, chronic myeloid leukaemia, or other haematological conditions were excluded. Identifying the MLL::AF9 gene involved RNA extraction, cDNA synthesis, and Real-time PCR amplification. The Chi-square test was used to examine the relationship between survival and the MLL::AF9 mutation. A Welch two-sample t-test was used to evaluate survival days depending on the MLL::AF9 gene rearrangement, while ANOVA was used to analyse survival days across various death statuses. RESULTS: The mean age of 130 patients was 36.65 ± 13.01 years, with 64.62% being males. The most common leukaemia type was AML-M2 (n = 32, 24.62%). During the study follow-up, 22.31% were still alive, 40.77% died, and the status of 36.92% were unknown. MLL::AF9 gene rearrangement was present in 11.54%. The group with MLL::AF9 gene rearrangement had significantly longer mean 'survival days' (1,542.33 ± 926.07) compared to the group without the gene rearrangement (206.42 ± 359.57, p <0.001). CONCLUSION: MLL-AF9 mutation was present in 11.54%. Age and MLL::AF9 gene rearrangement were significant predictors of survival in leukaemia patients. KEY WORDS: Acute myeloid leukaemia, MLL::AF9, Gene rearrangement, Survival.

P-Loop mutations-Negative prognosticators in tyrosine kinase inhibitors resistant chronic myeloid leukemia patients.

INTRODUCTION: P-Loop mutations in CML patients prevent the conformational change in BCR-ABL1 necessary for drug binding. The present study aimed to evaluate the impact of mutations in this domain on the prognosis of the disease and also to associate the baseline Sokal relative risk score with the overall survival in non-responding CML patients. METHODS: Blood samples were analyzed using ARMS-PCR and then an association was assessed between presence/absence of mutations, hematological and molecular response, disease progression, overall survival, and Sokal score. RESULTS: Of the total 250 CML patients, 102 were found to be treatment-resistant. Fifty-three patients harbored P-Loop mutations with G250E (12.7%) being most frequent. Complete hematological response and major molecular response were achieved by only 27.7% and 5.7 patients, respectively. Worst survival (57.1%) was observed in Y253H positive patients while according to Sokal score in high-risk patients harboring Y253F (50%) and E255V (50%). CONCLUSION: The presence of P-Loop domain mutations negatively impacted the prognosis of the disease in terms of disease advancement and overall survival. So, the timely performance of the BCR-ABL1 mutational analysis and the modifications in the treatment plan based on the mutation identified would help in a better outcome of the disease.

Outcome of Inversion 16 in TKD Positive and Negative Acute Myeloid Leukemia Patients.

abstract.

Chronic Myeloid Leukemia--Prognostic Value of Mutations.

Chronic myeloid leukemia (CML) is a stem cell disorder characterized by unrestricted proliferation of the myeloid series that occurs due to the BCR-ABL fusion oncogene as a result of reciprocal translocation t(9;22) (q34;q11). This discovery has made this particular domain a target for future efforts to cure CML. Imatinib revolutionized the treatment options for CML and gave encouraging results both in case of safety as well as tolerability profile as compared to agents such as hydroxyurea or busulfan given before Imatinib. However, about 2-4% of patients show resistance and mutations have been found to be one of the reasons for its development. European Leukemianet gives recommendations for BCR-ABL mutational analysis along with other tyrosine kinase inhibitors (TKIs) that should be administered according to the mutations harbored in a patient. The following overview gives recommendations for monitoring patients on the basis of their mutational status.

Prognostic involvement of nucleophosmin mutations in acute myeloid leaukemia.

Nucleophosmin (NPM1) is a protein of highly conserved nature which works as a molecular chaperone and is mostly found in nucleoli. NPM also involved in the maturation of preribosomes and duplication of centrosomes. Furthermore, it is also active in control and regulation of the ARF-p53 tumor suppressor pathway. A high rate of incidence and prognostic involvement is reported by various authors in AML patients. In AML it behaves as a favorable prognostic marker. NPM mutations are more frequently associated with normal-karyotype AML and are usually absent in patients having abnormal or poor cytogenetic. NPM mutations are not frequent in other hematopoietic tumors .Two main types of mutations have been described to date. Both of these cause abnormal cytoplasmic localization of NPM1. Their high incidence rate in normal karyoptype and their favorable nature make those mutations hot spot or front face mutations which should be checked before treatment starts.

Molecular involvement and prognostic importance of fms-like tyrosine kinase 3 in acute myeloid leukemia.

AML (Acute myeloid leukemia) is a form of blood cancer where growth of myeloid cells occurs in the bone marrow. The prognosis is poor in general for many reasons. One is the presence of leukaemia-specific recognition markers such as FLT3 (fms-like tyrosine kinase 3). Another name of FLT3 is stem cell tyrosine kinase-1 (STK1), which is known to take part in proliferation, differentiation and apoptosis of hematopoietic cells, usually being present on haemopoietic progenitor cells in the bone marrow. FLT3 act as an independent prognostic factor for AML. Although a vast literature is available about the association of FLT3 with AML there still is a need of a brief up to date overview which draw a clear picture about this association and their effect on overall survival.