Treatment of adult patients with acute lymphoblastic leukemia in the Czech Republic in the period 2007-2020.

BACKGROUND: Pediatric-inspired protocols with prospective monitoring of minimal residual disease (MRD) are considered the standard of intensive treatment for adults with acute lymphoblastic leukemia (ALL). They have been used in the Czech Republic since 2007. PATIENTS AND METHODS: Two hundred and ninety-seven patients aged 18-65 years were treated at five hematology centers between 2007-2020 according to the GMALL 07/2003 protocol. This is a retrospective analysis of their treatment outcomes. RESULTS: In the Ph-negative cohort, 189 (93.1%) patients achieved complete remission, 5 (2.4%) patients were refractory, and early mortality was 3.0%. Seventy (34.5%) patients experienced relapse in a median of 10.6 months. Overall survival (OS) at 3 and 5 years was 63.5% and 55.9%, disease-free survival (DFS) at 3 and 5 years was 54.5% and 49.7%, respectively. Young adults under 35 years of age (P = 0.015), patients without initial CNS infiltration (P = 0.016), with MRD negativity before consolidation treatment (P < 0.001), transplanted in the 1st complete remission (P < 0.001), and subjects treated after 2012 (P = 0.05) had significantly better overall survival. In a multivariate analysis, MRD at week 11 was the only independent factor affecting OS (HR 3.06; P = 0.006). For DFS, baseline CNS infiltration (HR 2.08; P = 0.038) and MRD at week 11 (HR 2.15; P = 0.020) were significant. In the Ph-positive cohort, 84 (89.4%) patients achieved complete remission, 1 (1.0%) patient was refractory, early mortality was 4.3%. Twenty-six (27.7%) patients relapsed in a median of 8.6 months. Survival at 3 and 5 years was 57.2% and 52.4% for OS and 50.2% and 44.9% for DFS, respectively. Transplanted patients and patients diagnosed after 2012 had statistically better overall survival (P < 0.001). CONCLUSION: The introduction of pediatric-inspired protocols with treatment intensification according to MRD levels resulted in a significant improvement in the survival outcomes of adult patients with ALL.

[Treatment of adult acute lymphoblastic leukemia according to GMALL 07/2003 study protocol in the Czech Republic - the first experience]. / Lécba dospelých pacientu s akutní lymfoblastickou leukemií dle protokolu GMALL 07/2003 a její výsledky--první zkusenosti v Ceské republice.

INTRODUCTION: We present two years' experience in the treatment of adult acute lymphoblastic leukemia (ALL) according to the German GMALL 07/2003 study protocol at CELL (Czech leukemia study group--for life) hematological centers in the Czech Republic. METHODS: A total number of 37 patients were included in this analysis. We evaluated complete remission and molecular remission rate, incidence of relapse, patients' status at the end of the follow-up period, incidence of chemotherapy-related adverse events and causes of death. A statistical analysis of risk factors affecting survival was carried out. RESULTS: Complete remission was achieved in 36 (97%) patients and molecular remission in 16 (62%) of 26 evaluable patients. Disease relapse occurred in 5 (14%) patients. At the end of the follow-up period with a median of 261 days, 28 (76%) patients were alive in complete remission, one (3%) with relapsed disease and 8 (22%) dead. Treatment toxicity resulted in death in 5 cases, relapse or progression of ALL in 3 patients. Adverse events most often followed consolidation I, induction phase I, consolidation II and induction phase II. Infectious complications in the context of febrile neutropenia, GIT mucositis and side effects of PEG-asparaginase were the most common adverse events observed. The toxicity of allogeneic transplantation was not unexpected, four (25%) patients died after transplantation. Two-year progression-free and overall survival were 66% and 70%, respectively. High risk ALL, age over 35 years, CNS infiltration, disease relapse and permanent minimal residual disease were identified as the major adverse prognostic risk factors. Practical experiences and possible pitfalls of the protocol are described in the discussion. CONCLUSION: Our initial impression is promising. The treatment is feasible, the results very good and the toxicity acceptable. Patients at high risk should be headed to allogeneic transplantation, since the results ofconsolidation chemotherapy alone are very poor in this group. We believe that this study protocol could become a standard adult acute lymphoblastic leukemia treatment in the Czech Republic.

Evaluation of clinical relevance of examining K-ras, p16 and p53 mutations along with allelic losses at 9p and 18q in EUS-guided fine needle aspiration samples of patients with chronic pancreatitis and pancreatic cancer.

AIM: To establish an optimum combination of molecular markers resulting in best overall diagnostic sensitivity and specificity for evaluation of suspicious pancreatic mass. METHODS: Endoscopic ultrasound (EUS)-guided fine needle aspiration cytology (FNA) was performed on 101 consecutive patients (63 males, 38 females, 60 +/- 12 years; 81 with subsequently diagnosed pancreatic cancer, 20 with chronic pancreatitis) with focal pancreatic mass. Samples were evaluated on-site by an experienced cytopathologist. DNA was extracted from Giemsa stained cells selected by laser microdissection and the presence of K-ras, p53 and p16 somatic mutations was tested by cycling-gradient capillary electrophoresis (CGCE) and single-strand conformation polymorphism (SSCP) techniques. In addition, allelic losses of tumor suppressor genes p16 (INK4, CDKN2A) and DPC4 (MADH4, SMAD4) were detected by monitoring the loss of heterozygosity (LOH) at 9p and 18q, respectively. RESULTS: Sensitivity and specificity of EUS-guided FNA were 75% and 85%, positive and negative predictive value reached 100%. The remaining 26% samples were assigned as inconclusive. Testing of molecular markers revealed sensitivity and specificity of 70% and 100% for K-ras mutations (P < 0.001), 24% and 90% for p53 mutations (NS), 13% and 100% for p16 mutations (NS), 85% and 64% for allelic losses at 9p (P < 0.001) and 78% and 57% for allelic losses at 18q (P < 0.05). When tests for different molecular markers were combined, the best results were obtained with K-ras + LOH at 9p (92% and 64%, P < 0.001), K-ras + LOH at 18q (92% and 57%, P < 0.001), and K-ras + LOH 9q + LOH 18q (96% and 43%, P < 0.001). When the molecular markers were used as complements to FNA cytology to evaluate inconclusive samples only, the overall sensitivity of cancer detection was 100% in all patients enrolled in the study. CONCLUSION: EUS-guided FNA cytology combined with screening of K-ras mutations and allelic losses of tumor suppressors p16 and DPC4 represents a very sensitive approach in screening for pancreatic malignancy. Molecular markers may find its use particularly in cases where FNA cytology has been inconclusive.

[Radical resection in patients with pancreatic head carcinomas. A retrospective survival analysis in a group of 307 subjects]. / Radikální resekce u nemocných s karcinomem hlavy pankreatu. Retrospektivní analýza prezívání u souboru 307 nemocných.

INTRODUCTION: The Czech Republic has the world's highest rates of pancreatic carcinomas. The pancreatic carcinoma is the fourth commonest cause of deaths due to malignancies, in our republic. Resection procedure is currently the only current treatment method, which has a curative potential and significantly prolongs a patient's life. AIM: To assess morbidity, mortality and survival of patients following radical and paliative procedures in the pancreatic head carcinoma patients. METHODS AND PATIENT GROUP: Only patients, who, based on the preoperative staging, were expected to require the following procedures, were indicated for surgery: I radical resection, i.e. stage I, II patients, 2 - palliative resection - i.e. stage III or IV patients, where no angioinvasion was detected preoperatively. Patients with peroperative detection of angioinvasion into the portomesenteric venous drainage area who required partial vein resection, were also included in the above subgroup. 3 - palliative bypass, where longer survival was expected. Radical resection included proximal pancreatoduodenectomy (PDE) with preservation of the pylorus according to Traverso-Longmire, with N1-2 lymphadenectomy and with reconstruction to an excluded jejunal loop. The same procedure was followed in cases of palliative resections. The collected data were statistically assessed using the Logrank test. From 05/1998 to 12/2006, a total of 307 patients with carcinomas of the pancreas and the Vater papila were treated. In 242 patients, the carcinoma was located within the pancreatic head, in 65 subjects, the pancreatic body and cauda were affected. Resection for the pancreatic head carcinoma was performed in 78 patients: 46 males, 32 females, the mean age was 63.5 y.o.a, with the median of 64 years. Bypass procedures were performed in 109 subjects and explorations in 55 subjects. RESULTS: Surgical procedures, with exception of 55 subjects who underwent exploration only, were performed in 187 subjects. Out of the total 78 PDEs, resections in stage I and II were performed in 22 subjects, in stage III in 41 subjects. In the group of 63 radical resection subjects, 2 subjects exited: the first one due to multiorgan failure, the second one for necrotizing postoperative pancreatitis. In the group of 15 palliative resections, 3 subjects exited. 10 patients died during the early postoperative period after palliative bypass procedures. A total of 15 subjects, i.e. 8%, exited during the early postoperative period. 5 subjects exited after resection procedures, i.e. 6.4%, 3% after radical resections. 3 subjects exited after palliative resections. Early complications were recorded in 44 subjects: pancreato-jejuno anastomosis insufficiency in 6 patients, insufficiency of hepaticojejunoanastomosis in 5 subjects, postoperative pancreatitis in 5 subjects, intraabdominal absces in 10 subjects, wounds infections with secondary healing in 19 subjects and cardiopulmonary complications in 33 subjects. In 19 subjects (43% of all complications), surgical revision was performed. Three-year survival rates were recorded in 60, resp. 29.5 and 39.5% of the patients in stage I, resp. II and III, while they were recorded in 15.6.% of the stage IVa subjects and only in 10.5% of the stage IVb subjects. There is a significant difference between survival rates of the stage I, II and III patients, compared to the stage IV patients (p < 0.005). There is no significant difference in the over- 3-years survival rates between the patients undergoing radical or palliative resections, however, the radical resection patients have significantly higher survival rates 3 months to 2 years postoperatively (p < 0.05). The radical resection subjects have significantly higher survival rates during the first 36 postoperative months, compared to the palliative resection and BDA subjects (p < 0.05). Comparison of sur vival rates in patients with radical or palliative resections is affected by a small number of the palliative resection subjects (n = 15), where no differences in survival rates were detected from the end of 9th postoperative month to the end of 3rd postoperative year. There is a significant difference in the survival rates between the resection and exploration subjects (p < 0.05). The survival rates differences between the subjects with palliative resections and BDAs cannot be evaluated in our study, due to nonhomogenity of the subjects. CONCLUSION: Radical PDEs for the pancreatic head carcinoma results in significantly longer survival of the subjects, compared to palliative bypasses. Stage I, II or III patients survive significantly longer, compared to those operated in stage IV.