Clinico-Haematologic association and prognostic relevance of NPM1 and FLT3-ITD mutations in acute Myeloid Leukaemia

Background & Objectives: Molecular genetic abnormalities have a significant role not only in diagnosis but also in determining the clinical course and prognosis. Nucleophosmin-1 (NPM-1) is associated with good prognosis while internal tandem duplication of the fms-like tyrosine kinase-3 gene (FLT3-ITD) confers a poor prognosis. Knowledge of the status of these mutations in AML patients not only guides treatment decisions but also helps in predicting response to frontline induction and consolidation chemotherapy as well as the risk of relapse and overall survival. Our objectives were to determine the prevalence, clinico-haematological features and immunophenotypic characteristics of AML patients with FLT3-ITD and NPM1 mutation and to evaluate the response to induction therapy (CR) and disease free survival (DFS) in this cohort of patients. Methods: Patients diagnosed as AML from March 2015 to March 2017 at Armed Forces Institute of Pathology Rawalpindi were included in the study. Clinico-haematologic and immunophenotypic parameters were noted and molecular analysis for FLT3-ITD and NPM1 mutation was performed. Any correlation with cytogenetics or other molecular markers was also studied. Response to standard induction chemotherapy and disease-free survival were assessed. Results: A total of 108 cases of AML were analyzed. Median age was 35 years and 64.8% were males. The median age of the study group was 35 years. Of these, 70 (64.8%) were males while 38 (35.2%) were females. Twenty-nine (26.9%) patients were NPM1 positive, twelve (11.1%) were FLT3-ITD positive while eight (7.4%) were positive for both mutations. Patients with NPM1 mutations were associated with female gender, higher haemoglobin level and platelet counts while those with FLT3-ITD mutations were predominantly seen in male patients and had significantly higher WBC counts, bone marrow blasts, biopsy cellularity and LDH levels. CR rates of NPM1 positive, FLT3-ITD positive and both mutation positive groups were 72%, 60% and 71%, respectively. The median disease-free survival was significantly lower in the FLT3-ITD positive group (7.1 months) as compared to the NPM1 positive group (16.1 months). The median disease-free survival was 12 months and 11.9 months in the NPM1 positive/FLT3-ITD positive and the NPM1 negative/FLT3-ITD negative groups, respectively. Conclusion: AML patients harbouring NPM1 and FLT3-ITD mutations have distinct clinical and haematological characteristics. NPM1 mutations have a better CR and DFS as compared to FLT3-ITD group. How to cite this:Mahmood R, Altaf C, Malik HS, Khan SA. Clinico-Haematologic association and prognostic relevance of NPM1 and FLT3-ITD mutations in acute Myeloid Leukaemia. Pak J Med Sci. 2019;35(1):---------. doi: https://doi.org/10.12669/pjms.35.1.285 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Treatment outcome of immune thrombocytopenia

Introduction: Treatment of immune thrombocytopenia is sometimes difficult and needs personal setting. According to evidence-based guidelines, corticosteroids are suggested for first-line treatment. In case of corticosteroid ineffectiveness, second-line therapeutic options (splenectomy, immunosuppressive drugs and, recently, thrombopoietin-mimetics) may result in beneficial therapeutic effect. Aims: The aim of the authors was to examine the clinicopathological data, disease course, treatment results, and the effectiveness of novel drugs in patients with immune thrombocytopenia. Patients and methods: The authors retrospectively analysed the files of 79 immune thrombocytopenic patients (26 males and 53 females) diagnosed and treated at the hematologic in- and outpatient units of the Markusovszky Hospital, County Vas, Hungary between January 1, 2000 and December 31, 2011. Remission rates, disease-free and overall survivals in response to corticosteroids (first-line treatment), after splenectomy (in cases when corticosteroids proved to be ineffective) and following second-line treatment were analysed. Survival curves were constructed using statistical software programs. Results: Of the 79 patients during a median follow-up of 66 months (min. 3, max. 144 months), 28 patients receiving first-line corticosteroids achieved complete remission and remained in a prolonged disease-free condition (35.4%; median disease-free survival 75.5 months; min. 2, max. 140 months). Thirty-eight patients underwent splenectomy after ineffective treatment with corticosteroids or other immunosuppressive (48.0%; median disease-free survival 94.2 months; min. 6, max. 136 months). Surgical complications occurred in 2 cases, while postoperative and late infections were absent. Five patients died but death was not related to immune thrombocytemia. Second-line treatment was applied in 13 patients (16.4%) and among these patients relapse of immune thrombocytopenia after splenectomy was observed in 6 patients. Favourable effects of both conventional (immunosuppressive) and novel treatments (rituximab, thrombopoietin-mimetics) were also detected. Conclusions: More than two-thirds of patients with immune thrombocytopenia responded to corticosteroids or to splenectomy and achieved prolonged disease-free remission. Novel drugs (rituximab, thrombopoietin-mimetics) applied only in few cases produced also favourable results in patients not responding to corticosteroids and splenectomy. Orv. Hetil., 2012, 153, 1613–1621.

Feasibility and potential benefit of neoadjuvant chemotherapy for colorectal liver metastasis: A single-centered retrospective study.

465 Background: Recently, several papers have reported the advantage of neoadjuvant chemotherapy for liver limited metastatic colorectal cancer. In these papers, most study groups used criteria for non-resectability due to size and/or number of metastases. Our criteria for resectability of colorectal liver metastases (CLM) depends on the size of remnant liver volume (>30%) and expected function after the removal of all metastases. Then, we assessed the feasibility and potential benefits of chemotherapy administered before surgery to patients with CLM retrospectively. Methods: From January 2007 to April 2010, 67 chemotherapy-naive patients were diagnosed as CLM without extra-hepatic metastases. After chemotherapy, we assessed the resectability with radiological examination.Then, each case was divided in two groups, resected group and unresected group. Overall survival, median disease-free survival and postoperative complications were analyzed. Results: 63 patients received oxaliplatin-based combination regimen and 4 patients other regimen. 30 patients (resected group) received R0 resection and 37 patients (unresected group) were considered as unresectable. No serious postoperative complications were observed. Overall survival was significantly higher in resected group than in unresected group (42.3 month and 29.1 month; P<0.001). Median disease-free survival was 18.8 months in resected group (95% CI:3.02 to 31.33). According to our retrospective review, resectable cases increased from 28 of 67 patients at baseline to 33 after chemotherapy (including 3 cases considered as CR after chemotherapy only). Conclusions: Intensive treatment with neoadjuvant chemotherapy for CLM is well tolerated. Curative surgery improved significantly overall survival in patients with CLM. Neoadjuvant chemotherapy such as mFOLFOX6 may lead to increased resectability but do not increase postoperative complications. For most patients with resectable CLM, neoadjuvant chemotherapy should be considered the standard treatment. No significant financial relationships to disclose.

Ten Years Experience with Ewing's Sarcoma

The series comprises 57 consecutive patients with Ewing's sarcoma admitted to the National Cancer Institute of Milan from 1965 to 1976. In 75 % the disease was confined to one bone, while in 25 % multiple bone and/or visceral lesions were present. Patients with clinically localized tumor treated before 1971 with local therapy, showed a median disease-free survival of 5 months. After 1971, radiotherapy and/or surgery to local tumor was combined with multiple drug chemotherapy (ADM, VCR, CTX) and the projected median disease-free survival increased to 24+ months. In previously untreated patients with advanced tumor adriamycin, used as single drug, achieved an overall response rate of 73 %. This is comparable to that achieved by a new combination including ADM, VCR, CTX, CCNU (75%). This multiple drug regimen is, however, expected to prolong the duration of response.