Revealing a Phenotypical Appearance of Ibrutinib Resistance in Patients With Chronic Lymphocytic Leukaemia by Flow Cytometry.

Background: Ibrutinib is widely known as an effective and well-tolerated therapeutical choice of the chronic lymphocytic leukaemia (CLL). However, acquired resistance may occur during the treatment, causing relapse. Early detection of ibrutinib resistance is an important issue, therefore we aimed to find phenotypic markers on CLL cells the expression of which may correlate with the appearance of ibrutinib resistance. Methods: We examined 28 patients' peripheral blood (PB) samples (treatment naïve, ibrutinib sensitive, clinically ibrutinib resistant). The surface markers' expression (CD27, CD69, CD86, CD184, CD185) were measured by flow cytometry. Furthermore, the BTKC481S resistance mutation was assessed by digital droplet PCR. Moreover, the CLL cells' phenotype of a patient with acquired ibrutinib resistance was observed during the ibrutinib treatment. Results: The expression of CD27 (p = 0.030) and CD86 (p = 0.031) became higher in the clinically resistant cohort than in the ibrutinib sensitive cohort. Besides, we found that high CD86 and CD27 expressions were accompanied by BTKC481S mutation. Our prospective study showed that the increase of the expression of CD27, CD69 and CD86 was noticed ahead of the clinical resistance with 3 months. Conclusion: Our study suggests that the changes of the expression of these markers could indicate ibrutinib resistance and the examination of these phenotypic changes may become a part of the patients' follow-up in the future.

Beneficial Effect of Lenalidomide-Dexamethason Treatment in Relapsed/Refractory Multiple Myeloma Patients: Results of Real-Life Data From 11 Hungarian Centers.

In Hungary, the cost of lenalidomide-based therapy is covered only for relapsed multiple myeloma (MM) patients, therefore lenalidomide is typically used in the second-line either as part of a triplet with proteasome inhibitors or as a doublet. Lenalidomide-dexamethasone is a standard treatment approach for relapsed/refractory MM, and according to recent large randomized clinical trials (RCT, the standard arm of POLLUX, ASPIRE, TOURMALINE), the progression-free survival (PFS) is expected to be approximately 18 months. We surveyed ten Hungarian centers treating MM and collected data of 278 patients treated predominantly after 2016. The median age was 65 years, and patients were distributed roughly equally over the 3 international staging system groups, but patients with high risk cytogenetics were underrepresented. 15.8% of the patients reached complete response, 21.6% very good partial response, 40.6% partial response, 10.8% stable disease, and 2.5% progressed on treatment. The median PFS was unexpectedly long, 24 months, however only 9 months in those with high risk cytogenetics. We found interesting differences between centers regarding corticosteroid type (prednisolone, methylprednisolone or dexamethasone) and dosing, and also regarding the choice of anticoagulation, but the outcome of the various centers were not different. Although the higher equivalent steroid dose resulted in more complete responses, the median PFS of those having lower corticosteroid dose and methylprednisolone were not inferior compared to the ones with higher dose dexamethasone. On multivariate analysis high risk cytogenetics and the number of prior lines remained significant independent prognostic factors regarding PFS (p < 0.001 and p = 0.005). Our results show that in well-selected patients Lenalidomide-dexamethasone can be a very effective treatment with real-world results that may even outperform those reported in the recent RCTs. This real world information may be more valuable than outdated RCT data when treatment options are discussed with patients.

Hodgkin's lymphoma-related vanishing bile duct syndrome / Hodgkin-lymphomához társult eltunoepeút-szindróma.

Összefoglaló. Az eltunoepeút-szindróma ritka, rossz prognózisú kórkép. Az epeutak progresszív destrukciójával, az intrahepaticus epeutak eltunésével jár, epepangáshoz, biliaris cirrhosishoz, végül májelégtelenséghez vezet. A háttérben álló kiváltó okok között infekciók, ischaemia, gyógyszermellékhatások, illetve daganatos megbetegedések szerepelhetnek. A malignitások közül a leggyakrabban a Hodgkin-lymphomához társult formájával találkozhatunk. Cikkünkben egy fiatal, Hodgkin-lymphomás betegünk esetét szeretnénk bemutatni, akinél az icterus hátterében eltunoepeút-szindróma igazolódott, melyet egyéb okok kizárását követoen szövettani mintavétellel igazoltunk. A két ciklus ABVD-protokoll szerinti kezelést követo PET/CT az alapbetegség tekintetében komplett metabolikus remissziót igazolt. A klinikai javuláshoz azonban hosszú hónapokra volt szükség. Végül az epeúteltunés esetünkben reverzibilis folyamatnak bizonyult, az alapbetegség tekintetében a komplett metabolikus remisszió elérésével az epeút-károsodás megállítható volt. Orv Hetil. 2021; 162(22): 884-888. Summary. destruction and loss of the intrahepatic bile ducts leading to cholestatis, biliar chirrosis and finally liver failure. It has been described in different pathologic conditions including infections, ischemia, adverse drug reactions and malignancies. The Hodgkin's lymphoma-associated type occurs most frequently among the forms of the disease of malignant origin. In this report, we introduce the case of a 32-year-old male patient with Hodgkin's lymphoma, diagnosed with vanishing bile duct syndrome upon liver biopsy as a root cause behind his icterus. The PET/CT has proven complete metabolic remission after 2 cycles of ABVD chemoterapy. Clinical improvement, however, occurred only after several months. Finally the loss of bile ducts proved to be a reversible process, the complete metabolic remission of Hodgkin's lymphoma resulted in the regeneration of the bile ducts. Orv Hetil. 2021; 162(22): 884-888.

Real-world data on the efficacy and safety of daratumumab treatment in Hungarian relapsed/refractory multiple myeloma patients.

Daratumumab is a human anti-CD38 monoclonal antibody used in the treatment of refractory and relapsed multiple myeloma. We investigated the efficacy and safety of daratumumab therapy in a real-world setting. Ninety-nine Hungarian patients were included; 48 received monotherapy, while lenalidomide and bortezomib combinations were administered in 29 and 19 cases, respectively. Overall response rate was assessable in 88 patients, with 12 complete, 10 very good partial, 34 partial, and seven minor responses. At a median duration of follow-up of 18.6 months, median progression-free survival (PFS) among all patients was 17.0 months. These values were inferior in the bortezomib combination and monotherapy groups. Patients with early-stage disease (ISS1) had better survival results than those with stage 2 or 3 myeloma (p = 0.009). Heavily pretreated patients had inferior PFS compared to those with 1-3 therapies (p = 0.035). Patients with impaired renal function had PFS results comparable with those having no kidney involvement. There were 10 fatal infections, and the most frequent adverse events were mild infusion-associated reactions and hematologic toxicities. Our results confirm that daratumumab is an effective treatment option for relapsed/refractory MM with an acceptable safety profile in patients with normal and impaired renal function.

Mutant p53 expression and apoptotic activity of Helicobacter pylori positive and negative gastritis in correlation with the presence of intestinal metaplasia.

BACKGROUND: Mutation of the p53 gene is detectable in most cases of gastric cancer, as it is the most common genetic alteration in human malignancies. It is also well documented that Helicobacter pylori infection plays an important role in gastric carcinogenesis. There is still no clarification, however, concerning how genetic instability influences the homeostasis of gastric epithelium. We have studied the effect of H. pylori infection on apoptosis of the antral epithelium in the presence/absence of intestinal metaplasia and the expression of the p53 oncoprotein. The relationship between these two processes is analysed. METHODS: Antral biopsies were taken from 36 patients who underwent routine upper endoscopy (17 men, 19 women, mean age 61.0 years). The biopsies were fixed in formalin and embedded in paraffin. Patients were classified into two histological groups: (1) as chronic gastritis without intestinal metaplasia (n = 19), and (2) chronic gastritis with intestinal metaplasia (n = 17). An immunohistochemical method was used to detect the expression of p53 oncoprotein, and the terminal transferase mediated dUTP nick end-labelling (TUNEL) method was used to detect apoptotic cells. RESULTS: In the absence of intestinal metaplasia, both the apoptotic index (0.0272 +/- 0.011 vs 0.0128 +/- 0.006) and expresssion of p53 (35.55 +/- 31.16 vs 18.33 +/- 19.65) were significantly higher in H. pylori positive cases compared to H. pylori negative cases. In the presence of intestinal metaplasia, p53 expression was further increased (P < 0.05), but apoptosis was similar to that observed in H. pylori negative gastritis without intestinal metaplasia. In the presence of intestinal metaplasia, H. pylori infection did not influence apoptosis (0.013 +/- 0.004 vs 0.011 +/- 0.004), or p53 ratio (70.16 +/- 22.54 vs 68.50 +/- 28.96). In the sequence of gastritis-intestinal metaplasia the two indices show a close negative correlation (P < 0.05). CONCLUSION: In the absence of intestinal metaplasia H. pylori infection increases both apoptotic activity and expression of p53 oncoprotein in the gastric mucosa. The lack of increased apoptosis with a higher p53 expression in the presence of intestinal metaplasia suggests an increased genetic instability and also may suggest that mutation of the p53 gene is an early step in the multistep process of gastric carcinogenesis.