Hossam Kamel

BACKGROUND: Minimal residual disease (MRD) studies in adult acute lymphoblastic leukemia (ALL) give highly significant prognostic information superior to other standard criteria as age, gender and total leucocytic count (TLC) in distinguishing patients at high and low risk of relapse.

OBJECTIVES: We aimed to determine the value of MRD monitoring by flowcytometry (FCM) in predicting outcome in adult Precursor ALL patients.

PATIENTS AND METHODS: Bone marrow (BM) samples were analyzed by 4-color FCM collected at diagnosis and after induction therapy (MRD1) to correlate MRD positivity with disease free survival (DFS) and overall survival (OS).

RESULTS: Study included 57 adult ALL patients (44 males and 13 females) with a median age of 22 years (18-49). DFS showed no significant difference with age, gender and initial TLC (p=0.838, 0.888 and 0.743, respectively). Cumulative DFS at 2 years was 34% for B-lineage ALL (n: 35) and 57% for T-lineage ALL (n: 18) (p = 0.057). Cumulative DFS at 2 years was 7% for MRD1 positive (high risk, HR) versus 57% for MRD1 negative patients (Low risk, LR) (p < 0.001). Cumulative DFS at 2 years was 29% for HR patients (n: 26) versus 55% for LR (n: 27) according to GMALL classification (p = 0.064). Cumulative OS did not differ according to age, gender and TLC (p = 0.526, 0.594 and 0.513, respectively). Cumulative OS at 2 years was 36% for B ALL (n: 39) versus 77% for TALL (n: 18) (p = 0.016) and was 49% for Philadelphia chromosome (Ph) negative patients versus 0% for Ph-positive patients (p < 0.001). Regarding MRD1, OS at 2 years was 18% for MRD1 HR (n: 17) versus 65% for MRD1 LR (n: 38) (p < 0.001). OS was 35% for high-risk patients (n: 30) and 62% for low-risk patients (n: 27) classified according to GMALL risk stratification (p = 0.017).

CONCLUSION: MRD by FCM is a strong independent predictor of outcome in terms of DFS and OS and is a powerful informative parameter in guiding individual treatment in ALL patients.

New series of perimidine derivatives and fused perimidines were derived from the reaction of ketene aminals 1 and 2 with diazotized anilines or hydrazonoyl chlorides. In addition, 8,10-disubstituted-[1,2,4]triazolo[4,3-a]perimidines (20a-m) were prepared through the reaction of perimidine-2-thione (15) with hydrazonoyl chlorides. The structures of the newly synthesized compounds were established on the basis of spectral data and elemental analyses. Some products were investigated for their antitumor activities against the human breast cancer cell line MCF-7 and the liver carcinoma cell line HEPG-2, and the results of some derivatives showed promising activity.

BACKGROUND: Wilms' tumor (WT1) gene overexpression has been reported in the majority of acute myeloid leukemia (AML) patients at diagnosis and has been evaluated as prognostic and minimal residual disease (MRD) marker.

PATIENTS AND METHODS: WT1 overexpression was evaluated in 68 adult AML patients at diagnosis and at the end of induction using quantitative real-time polymerase chain reaction (PCR).

RESULTS: No significant associations were encountered between WT1 overexpression at diagnosis and other prognostic factors. Complete remission (CR) was achieved in 74% of the patients with WT1 overexpression compared to 80% of patients with normal levels (P = 0.5). No significant associations were encountered between WT1 overexpression at diagnosis and disease-free survival (DFS) or overall survival (OS) (P = 0.6 and 0.3, respectively). At the end of induction, the median duration of DFS in patients achieving ≥ 2 log reduction was not reached compared to only 5 months (range: 2.1-7.9 months) in those attaining <2 log reduction (P = 0.2). The median duration of OS in patients achieving ≥ 2 log reduction was 13 months (range: 0-33.3 months) compared to 7.5 months (5.4-9.6 months) in those attaining <2 log reduction (P = 0.2). The survival at 1 year in patients achieving ≥ 2 log was double the group with <2 log reduction (67% compared to 33%).

CONCLUSION: Our results, although not reaching the level of significance, probably due to the small sample size, still suggest that the early assessment of WT1 transcript level at the end of induction in patients in CR may have a prognostic significance on clinical outcome and may thus be a useful marker for risk stratification especially in patients lacking disease-specific marker.

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PURPOSE: To assess the kinetics of molecular response to Imatinib Mesylate (IM) therapy in predicting progression free survival (PFS), sustained hematological, and cytogenetic responses in CPCML.

METHODS: Ninety five newly diagnosed CPCML Egyptian patients were treated with IM 400 mg daily dose. Cytogenetic analysis was performed at diagnosis and every 6 months. Molecular monitoring by RT-QPCR was performed at diagnosis and every 3 months during a median follow-up period (FUp) of 26 months. Mutation detection of ABL domain was performed by ASO-PCR.

RESULTS: Hematological response was 98% after three months of IM therapy. Out of 95 patients 59 showed 2 log reduction of BCR-ABL/ABL ratio after 6 months of whom 49 (83%) had complete cytogenetic response (CCyR) and 42 (71%) had major molecular response (MMR) at 12 months. BCR-ABL transcripts remained undetectable in 22 patients (39%) at 26 months. Among the remaining 34 patients not achieving 2 log reduction at 6 months only 5 (15%) had CCyR and MMR by 12 months. ABL domain mutations were detected in 11/15 (73%) resistant and suboptimal responding patients. Achieving 2 log reduction after 6 months of IM therapy significantly correlated with sustained cytogenetic and molecular responses (p<0.0001), with PFS at 2 years (p<0.03) and inversely with ABL gene mutations (p<0.001).

DISCUSSION: These data demonstrated the predictive value of early molecular response to IM in CPCML regarding disease course and PFS. A 2 log reduction at 6 months of IM treatment could be a cut off level predicting resistance, CCyR, or suggesting IM dose modification.

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