Incidence, risk factors, and outcomes of second neoplasms in patients with acute promyelocytic leukemia: the PETHEMA-PALG experience.

The most important challenges in acute promyelocytic leukemia (APL) is preventing early death and reducing long-term events, such as second neoplasms (s-NPLs). We performed a retrospective analysis of 2670 unselected APL patients, treated with PETHEMA "chemotherapy based" and "chemotherapy free" protocols. Only de novo APL patients who achieved complete remission (CR) and completed the three consolidation cycles were enrolled into the analysis. Out of 2670 APL patients, there were 118 (4.4%) who developed s-NPLs with the median latency period (between first CR and diagnosis of s-NPL) of 48.0 months (range 2.8-231.1): 43.3 (range: 2.8-113.9) for s-MDS/AML and 61.7 (range: 7.1-231.1) for solid tumour. The 5-year CI of all s-NPLs was of 4.43% and 10 years of 7.92%. Among s-NPLs, there were 58 cases of s-MDS/AML, 3 cases of other hematological neoplasms, 57 solid tumours and 1 non-identified neoplasm. The most frequent solid tumour was colorectal, lung and breast cancer. Overall, the 2-year OS from diagnosis of s-NPLs was 40.6%, with a median OS of 11.1 months. Multivariate analysis identified age of 35 years (hazard ratio = 0.2584; p < 0.0001) as an independent prognostic factor for s-NPLs. There were no significant differences in CI of s-NPLs at 5 years between chemotherapy-based vs chemotherapy-free regimens (hazard ratio = 1.09; p = 0.932). Larger series with longer follow-up are required to confirm the potential impact of ATO+ATRA regimens to reduce the incidence of s-NPLs after front-line therapy for APL.

The Impact of the COVID-19 Pandemic on the Assessment of Healthcare and Anxiety Disorders in Patients with Chronic Diseases.

(1) Background: We compared the impact of the COVID-19 pandemic on the functioning and mental health of chronically ill patients, namely those with hemodialysis (HD) and diabetes (DM). (2) Methods: We used a questionnaire to collect the medical data and the Generalized Anxiety Questionnaire (GAD-7) to measure the mood status. (3) Results: In both groups, a similar percentage of patients had a past COVID-19 infection and similar opinions about pandemic-related inconveniences. The most significant limitations of the study included mask wearing and the restriction of social contact. Mental disorders were significantly more frequently reported in the DM group. Sleep problems were found in approximately 30% of patients. Approximately 20% of patients in both groups declared that the pandemic had negatively affected the quality of their sleep. The mean score of the GAD-7 scale in the HD group did not differ according to gender. In the group of DM patients, a significant difference was observed between men and women, with women scoring higher compared to men. In both groups, the percentage of patients with GAD-7 scores > 5, > 10 and > 15 did not differ significantly. (4) Conclusions: In both groups, chronically ill patients reported anxiety disorders with similar frequency. In the DM group, more severe anxiety disorders were found in women. Mental disorders were significantly more prevalent in DM patients. It seems that HD patients coped better with the psychological aspects of pandemic-related stress and limitations.

The Association between Immune Checkpoint Proteins and Therapy Outcomes in Acute Myeloid Leukaemia Patients.

The development of novel drugs with different mechanisms of action has dramatically changed the treatment landscape of AML patients in recent years. Considering a significant dysregulation of the immune system, inhibitors of immune checkpoint (ICI) proteins provide a substantial therapeutic option for those subjects. However, use of ICI in haematological malignancies remains very limited, in contrast to their wide use in solid tumours. Here, we analysed expression patterns of the most promising selected checkpoint-based therapeutic targets in AML patients. Peripheral blood of 72 untreated AML patients was used for flow cytometric analysis. Expression of PD-1, PD-L1, CTLA-4, and B7-H3 was assessed within CD4+ (Th) lymphocytes and CD33+ blast cells. Patients were stratified based on therapy outcome and cytogenetic molecular risk. AML non-responders (NR) showed a higher frequency of PD-1 in Th cells compared to those with complete remission (CR). Reduced blast cell level of CTLA-4 was another factor differentiating CR from NR subjects. Elevated levels of PD-1 were associated with a trend for poorer patients' survival. Additionally, prognosis for AML patients was worse in case of a higher frequency of B7-H3 in Th lymphocytes. In summary, we showed the significance of selected ICI as outcome predictors in AML management. Further, multicentre studies are required for validation of those data.

Molnupiravir is effective in patients with haematological malignancies.

Patients with hematologic malignancies are particularly vulnerable to severe infectious complications. SARS-CoV-2 infection is associated with a high risk of severe course and death in this patient population. In addition, immune deficits associated with both the blood cancer and the treatment used make vaccination against SARS-CoV-2 less effective than in immunocompetent individuals. Molnupiravir is one of the first oral antiviral drugs to demonstrate a significant benefit in reducing hospitalisation and death in COVID-19 in the general population. In this context, 175 haematology patients with diagnosed COVID-19, and treated with MOL between January and April 2022, came under our scrutiny with a view to defining their clinical characteristics and outcomes. The most common underlying conditions were lymphomas (45%), multiple myelomas (21%) and acute leukaemias or myelodysplastic syndrome (35%). Of all, 77% of the patients were vaccinated, and half of them received a booster. At 28 days after the breakthrough COVID-19 diagnosis, 35 (20%) subjects required hospital admission. Out of those patients, seven (4%) died during the follow-up due to the progression of COVID. Our results corroborate what has been established to date with regard to the positive clinical and safety outcomes of MOL in haematology patients with mild or moderate COVID-19.

Response to anti-SARS-CoV-2 mRNA vaccines in multiple myeloma and chronic lymphocytic leukemia patients.

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients have increased morbidity and mortality rates of COVID-19 due to immunosuppression associated with the disease and ongoing therapy. The same immune impairment accompanying CLL and MM also affects suboptimal vaccine response. The study assessed the effectiveness of the humoral and T cell-mediated immunity following mRNA COVID-19 vaccination (using either BNT162b2 or mRNA-1273) in short-term (2-5 weeks after second dose) and long-term follow-up (12 weeks after vaccination). Between March and August 2021, blood samples were obtained from 62 CLL and 60 MM patients from eight different hematology departments in Poland. Total anti-RBD antibodies were detected in 37% MM patients before vaccination, increased to 91% and 94% in short- and long-term follow-up, respectively. In CLL, serological responses were detectable in 21% of patients before vaccination and increased to 45% in the short-term and 71% in long-term observation. We detected a tendency to higher frequencies of specific CD8+ T cells against SARS-CoV-2 after vaccination compared to samples before vaccination in MM patients and no changes in frequencies of specific T cells in CLL patients. Our study provides novel insights into mRNA vaccination efficacy in immunocompromised MM and CLL patients, and our findings highlight that specific CD8+ T cells against SARS-CoV-2 might be induced by vaccination but do not correlate positively with serological responses.

The role of NPM1 alternative splicing in patients with chronic lymphocytic leukemia.

OBJECTIVES: Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease with heterogeneous clinical course. Recent studies revealed a link between NOTCH1 mutation and the overexpression of MYC and MYC-related genes involved in ribosome biogenesis and protein biosynthesis, such as nucleophosmin-1 (NPM1), in CLL cells. In the present study, we aim to evaluate the impact of the NOTCH1 mutation on the MYC and MYC induced NPM1 expression in CLL cells via quantification of their transcripts. METHODS: Using qRT-PCR, we analyzed the levels of MYC and three main NPM1 splice variants in 214 samples collected from CLL patients. We assessed the impact of each splice variant on CLL prognostic markers, including the IGHV, TP53, NOTCH1, SF3B1, and MYD88 mutational status, cytogenetic aberrations, and laboratory features. RESULTS: Significantly higher levels of NPM1.R1 transcripts in patients with unmutated compared to mutated IGHV status were found. The median time to first treatment (TTFT) in patients with a high level of NPM1.R1 was significantly shorter compared to the group with low NPM1.R1 levels (1.5 vs 33 months, p = 0.0002). Moreover, in Multivariate Cox Proportional Hazard Regression Model NPM1.R1 splice variant provided an independent prognostic value for TTFT. CONCLUSION: In conclusion, our study indicates the prognostic significance of the level of NPM1.R1 expression and suggests the importance of splicing alterations in the pathogenesis of CLL.

Does the Change in the Diagnostic Criteria for Gestational Diabetes in Poland Affect Maternal and Fetal Complications? A Prospective Study.

Background and objectives: Gestational diabetes mellitus (GDM) is a significant risk factor of maternal and fetal complications. The aim of the study was to compare two groups of patients with GDM treated in 2015/2016 (Group-15/16), and in 2017/2018 (Group-17/18) and to answer the question whether the change in the diagnostic criteria for GDM affected maternal and fetal complications. Materials and Methods: A retrospective analysis was conducted. The study included 123 patients with GDM (58 patients/Group-15/16 and 65 patients/Group-17/18). Results: No significant differences were found between the groups. In Group-17/18, GDM was significantly more often diagnosed based on fasting glycemia (33.8%) compared with Group-15/16 (22.4%; p = 0.000001). GDM was significantly more often diagnosed based on 2-h oral glucose tolerance test (OGTT; 44.8%) compared with Group-17/18 (29.2%; p = 0.000005). In Group-15/16, insulin was started in 51.7% of patients compared with 33.8% in Group-17/18 (p = 0.04287). Despite more frequent insulin therapy in Group-15/16, insulin was started later (30th week of gestation) and significantly more frequently in older patients and those with higher BMI values compared with Group-17/18 (27th week of pregnancy). The number of caesarean sections and spontaneous deliveries was also similar in both periods. No difference was found in the prevalence of neonatal complications, including neonatal hypo-glycemia, prolonged jaundice or heart defect. In addition, no differences were found between the parameters in newborns. Conclusions: The change in the criteria for the diagnosis and treatment of GDM translated into the mode of diagnosis and currently it is more often diagnosed based on abnormal fasting glycemia. Currently, a lower percentage of patients require insulin therapy. However, less frequent inclusion of insulin may result in higher postprandial glycemia in the third trimester of pregnancy in mothers, thus increasing the risk of neonatal hypoglycemia immediately after delivery.

Cladribine Combined with Low-Dose Cytarabine as Frontline Treatment for Unfit Elderly Acute Myeloid Leukemia Patients: Results from a Prospective Multicenter Study of Polish Adult Leukemia Group (PALG).

Acute myeloid leukemia (AML) in older unfit patients is a therapeutic challenge for clinical hematologists. We evaluated the efficacy and safety of a novel low-intensity regimen consisting of low-dose cytarabine and cladribine (LD-AC+cladribine) in first-line treatment of elderly (≥60 years) AML patients not eligible for intensive chemotherapy (IC) who had either the Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 or the hematopoietic cell transplantation comorbidity index (HCT-CI) score ≥3. The induction phase included two cycles of LD-AC+cladribine. Patients who achieved at least partial remission (PR) received maintenance treatment with LD-AC alone. Overall, 117 patients with a median age of 70 years were enrolled. Adverse cytogenetics, ECOG PS ≥2 and HCT-CI score ≥3 was observed in 43.5%, 60%, and 58% of patients, respectively. The response rate (≥PR) was 54% (complete remission [CR], 32%; CR with incomplete hematologic recovery [CRi], 5%). A median overall survival (OS) was 21 and 8.8 months in CR/CRi and PR group, respectively. Advanced age (≥75 years) and adverse cytogenetics had a negative impact on OS. The 56-day mortality rate was 20.5%. In conclusion, LD-AC+cladribine is a beneficial therapeutic option with a predictable safety profile in elderly AML patients not eligible for IC.

Adjuvant therapy in type 1 diabetes mellitus.

Not required for Clinical Vignette.

Sexual Dysfunction in Young Women with Type 1 Diabetes.

INTRODUCTION: Sexual dysfunctions (SD) are chronic complications that can develop due to vascular complications or autonomic neuropathy. Additionally, such complications can be of hormonal, infectious or psychogenic etiology. OBJECTIVES: The aim of study was to assess the sexual function and acceptance of the chronic disease in young sexually active women with type 1 diabetes (T1DM). MATERIALS AND METHODS: A total of 169 female patients with T1DM completed two standardized questionnaires, the Female Sexual Function Index (FSFI) and the Acceptance of Illness Scale (AIS). Other medical data were collected from medical history. RESULTS: The mean FSFI score was 27.96 ± 5.00, and the mean AIS score was 29.67 ± 8.28. The score < 26 points in FSFI was obtained by 28.7% of patients. Analysis of correlation between the FSFI and the AIS showed that the higher the score on the FSFI, the higher the score on the AIS. Patients who underwent regular physical activity (55%) had a significantly higher acceptance of the disease (p = 0.0026) and reported painful intercourse significantly less frequently (p = 0.01). The value of HbA1c in the study group was 7.31 ± 1.25%. Patients with poorer glycemic control (HbA1c > 8%) obtained significantly lower scores on the FSFI (p = 0.03), whereas no differences were found on the AIS. Diabetes-related complications were observed in 25.5% of patients. The presence of chronic complications did not affect the results of the FSFI or the AIS. Patients with diabetes and hypertension had poorer functioning in the sexual sphere and had significantly lower scores on the FSFI. Past or present history of depression was reported by 36% of patients and also negatively affected acceptance of diabetes (p = 0.0015). Patients who reported recurrent urinary tract infections (17%) achieved significantly lower scores on the FSFI (p = 0.03) and showed that sex-related pain was significantly more prevalent (p = 0.02). In the case of the statement related to the embarrassment of people around the patient due to diabetes, patients with lower scores complained of SD significantly more often (p = 0.0033). Past deliveries, the type of labor, the use of contraceptives or the number of sexual partners had no influence on the overall assessment in both scales. However, in terms of desire, women who had delivered obtained higher scores (p = 0.0021). CONCLUSION: SD in women with T1DM may result from diabetes-related complications, hormonal disorders or recurrent genital or urinary tract infections. However, they usually have a psychological basis due to the lack of acceptance of the problems related to the treatment of diabetes.

Metformin therapy in pregnancy [Zastosowanie metforminy w ciazy].

Gestational diabetes mellitus (GDM), i.e. a carbohydrate metabolism disorder at pregnancy, is one of the most common metabolic complications that occur during this period. Pancreatic b-cell dysfunction and insulin resistance during pregnancy are considered the main causes of the condition. It is currently estimated that GDM is confirmed in 1-25% of patients. Diagnosis and appropriate management allow to reduce the risk of complications in newborns and the perinatal mortality rate and also improve the prognosis for mother and offspring. Metformin is taken by many patients before pregnancy due to both previously diagnosed type 2 diabetes and in the treatment of prediabetes, obesity and polycystic ovary syndrome (PCOS) as part of therapy for insulin resistance. The use of metformin in pregnancy has been controversial for many years, particularly in terms of the safety of continuation of drug therapy. Available scientific data indicate both benefits and possible drug-related adverse effects in offspring of metformin-treated patients. This problem is related not only to patients with type 2 diabetes, but also to those with PCOS who are at increased risk of miscarriage, preterm delivery and the diagnosis of GDM in subsequent stages of pregnancy. Conclusive and uniform recommendations for the use of metformin at each stage of pregnancy have not been established yet due to the doubts about the mechanisms of action of the drug, particularly at the cellular level. This review paper presents the current state of knowledge on the use of metformin during pregnancy.

Insulin therapy - new directions of research.

Insulin therapy is the most effective method of lowering blood glucose. Over 100 years have passed the studies for the optimisation of insulin action. To date, subcutaneous insulin administration has been the basic route of insulin delivery. The search for insulin therapy is simultaneously conducted in the following directions: the optimisation of insulin action, automatisation, and the decrease in the invasiveness of insulin delivery methods. The optimisation of insulin action has led to the discovery of ultra-rapid-acting human insulin analogues, ultra-long-acting human insulin analogues, and biosimilar insulin. Automatisation referred to the "artificial pancreas" and closing the loop system in insulin pump therapy. The decrease in the invasiveness of insulin delivery methods is focused on alternative routes of insulin administration. (Endokrynol Pol 2016; 67 (3): 314-324).

Prognostic relevance of HSP70 antigen and antibody measurement in patients with acute myeloid leukemia of intermediate and unfavorable cytogenetic risk.

INTRODUCTION: Heat shock proteins (HSPs) are overexpressed in many types of cancers and are implicated in tumor cell proliferation, differentiation, invasion, metastasis, death, and recognition by the immune system. It has been postulated that the HSP70 protein can be used as a prognostic indicator of overall patient survival in many types of cancer including leukemia. OBJECTIVES: The aim of the study was to evaluate the concentrations of anti­HSP70 antibody and its antigen in the peripheral blood of patients with acute myeloid leukemia (AML), as well as to assess the usefulness of this measurement. PATIENTS AND METHODS: The study included 80 patients with AML of intermediate and high cytogenetic risk, scheduled for allogenic stem cell transplantation after initial intensive chemotherapy. Plasma concentrations of anti­HSP70 antibodies and HSP70 antigen were measured by enzyme­linked immunosorbent assay. The antigen was additionally measured by Western blot analysis. The control group consisted of healthy subjects. RESULTS: Patients with AML had significantly higher anti­HSP70 antibody concentrations compared with the control group. The concentration of HSP70 antigen as well as anti­HSP70 antibody showed no associations with the type of response after induction chemotherapy. However, patients with higher antigen levels and lower anti­HSP70 antibody levels had significantly shorter overall survival. CONCLUSIONS: The study suggests that anti­HSP70 antibodies and HSP70 antigen may be valuable indicators of a poor prognosis in patients with AML.

Secondary acute lymphoblastic leukaemia in a multiple myeloma patient.

Secondary acute leukaemia (s-ALL) is a destructive complication in patients who have been previously treated for other cancer. Secondary acute lymphoblastic leukaemia is rarely reported whereas secondary acute myeloid leukaemia is much more common. Chromosomal 11q23 abnormality, frequently detected in therapy-related acute myeloid leukaemia, is the most common cytogenetic alteration in secondary ALL too. However, s-ALL cases without 11q23 abnormality have rarely been described. Furthermore, there are only a few published medical reports describing occurrence of acute lymphoblastic leukaemia in multiple myeloma (MM) patients. We would like to present our experience with a patient with MM, who developed ALL without 11q23 abnormality, nine years after alkylating-agent containing treatment. The course of the disease was complicated by thrombosis that obstructed the possibility of effective treatment. In conclusion, it should be kept in mind that the development of a more aggressive neoplasm related to chemotherapy treatment as well as the inherent genetic instability of normal and abnormal lymphoid progenitors may affect overall survival of an indolent lymphoma patient.