Oligoclonal gammopathy: An analysis of 253 cases.

BACKGROUND: Oligoclonal gammopathy (OG) is a rare disorder of the lymphoid system that is characterized by the presence of at least 2 distinct monoclonal proteins in a patient's serum or urine. The biological and clinical characteristics of this disease are as yet poorly understood. OBJECTIVES: The study aimed to assess whether there are significant differences between patients with OG regarding the developmental history (i.e., OG diagnosed at the first presentation compared to OG that has developed in patients with an original monoclonal gammopathy) and the number of monoclonal proteins (2 compared to 3). Moreover, we attempted to determine when secondary oligoclonality develops following the original diagnosis of monoclonal gammopathy. MATERIAL AND METHODS: Patients were analyzed with regard to their age at diagnosis, sex, serum monoclonal proteins, and underlying hematological disorders. Multiple myeloma (MM) patients were additionally evaluated for their Durie-Salmon stage and cytogenetic alterations. RESULTS: Patients with triclonal gammopathy (TG: n = 29) did not differ significantly from patients with biclonal gammopathy (BG: n = 223) (p = 0.81) in terms of age at diagnosis and the dominant diagnosis (MM was the most common diagnosis (65.0% and 64.7%, respectively)). In both cohorts, myeloma patients were mainly classified to the Durie-Salmon stage III. In the TG cohort, there was a higher proportion of males (69.0%) than among patients with BG (52.5%). Oligoclonality developed at various times after diagnosis (up to 80 months in the investigated cohort). However, the occurrence of new cases was higher during the initial 30-month period following the diagnosis of monoclonal gammopathy. CONCLUSIONS: There are only small differences between patients with primary compared to secondary OG, between BG and TG, and most patients have a combination of IgGκ+IgGλ. Oligoclonality could develop at any time after the diagnosis of monoclonal gammopathy, but it happens more frequently during the first 30 months, with advanced myeloma being the most prevalent underlying disorder.

Prognostic Impact of Copy Number Alterations' Profile and AID/RAG Signatures in Acute Lymphoblastic Leukemia (ALL) with BCR::ABL and without Recurrent Genetic Aberrations (NEG ALL) Treated with Intensive Chemotherapy.

Adult acute lymphoblastic leukemia (ALL) is associated with poor outcomes. ALL is initiated by primary aberrations, but secondary genetic lesions are necessary for overt ALL. In this study, we reassessed the value of primary and secondary aberrations in intensively treated ALL patients in relation to mutator enzyme expression. RT-PCR, genomic PCR, and sequencing were applied to evaluate primary aberrations, while qPCR was used to measure the expression of RAG and AID mutator enzymes in 166 adult ALL patients. Secondary copy number alterations (CNA) were studied in 94 cases by MLPA assay. Primary aberrations alone stratified 30% of the patients (27% high-risk, 3% low-risk cases). The remaining 70% intermediate-risk patients included BCR::ABL1pos subgroup and ALL lacking identified genetic markers (NEG ALL). We identified three CNA profiles: high-risk bad-CNA (CNAhigh/IKZF1pos), low-risk good-CNA (all other CNAs), and intermediate-risk CNAneg. Furthermore, based on RAG/AID expression, we report possible mechanisms underlying the CNA profiles associated with poor outcome: AID stratified outcome in CNAneg, which accompanied most likely a particular profile of single nucleotide variations, while RAG in CNApos increased the odds for CNAhigh/IKZF1pos development. Finally, we integrated primary genetic aberrations with CNA to propose a revised risk stratification code, which allowed us to stratify 75% of BCR::ABL1pos and NEG patients.

Clinical features, etiology, and survival in patients with restrictive cardiomyopathy: A single-center experience.

BACKGROUND: Numerous prognostic factors have been proposed for cardiac amyloidosis (CA). The knowledge about other subtypes of restrictive cardiomyopathy (RCM) is scant. AIMS: This study aimed to elucidate the etiology and prognostic factors of RCM as well as assess cardiac biomarkers: high-sensitive troponin T (hs-TnT), growth differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and soluble suppression of tumorigenicity 2, as mortality predictors in RCM. METHODS: We enrolled 36 RCM patients in our tertiary cardiac department. All patients were screened for CA. Genetic testing was performed in 17 patients without CA. RESULTS: Pathogenic or likely pathogenic gene variants were found in 86% of patients, including 5 novel variants. Twenty patients died, and 4 had a heart transplantation during the study. Median overall survival was 29 months (8-55). The univariate Cox models analysis indicated that systolic and diastolic blood pressure, GDF-15, hs-TnT, NT-proBNP, left ventricular stroke volume, the ratio of the transmitral early peak velocity (E) estimated by pulsed wave Doppler over the early mitral annulus velocity (e'), tricuspid annulus plane systolic excursion, early tricuspid valve annular systolic velocity, the presence of pulmonary hypertension, and pericardial effusion influenced survival (P <0.05). A worse prognosis was observed in patients with GDF-15 >1316 pg/ml, hs-TnT >42 ng/l, NT-proBNP >3383 pg/ml, and pericardial effusion >3.5 mm (Kaplan-Meier analysis, log-rank test, P <0.001). CONCLUSIONS: Genetic testing should be considered in every RCM patient where light-chain amyloidosis has been excluded. Survival remains poor regardless of etiology. Increased concentrations of GDF-15, hs-TNT, NT-proBNP, and pericardial effusion are associated with worse prognosis. Further studies are warranted.

Guadecitabine vs treatment choice in newly diagnosed acute myeloid leukemia: a global phase 3 randomized study.

This phase 3 study evaluated the efficacy and safety of the new hypomethylating agent guadecitabine (n = 408) vs a preselected treatment choice (TC; n = 407) of azacitidine, decitabine, or low-dose cytarabine in patients with acute myeloid leukemia unfit to receive intensive induction chemotherapy. Half of the patients (50%) had poor Eastern Cooperative Oncology Group Performance Status (2-3). The coprimary end points were complete remission (19% and 17% of patients for guadecitabine and TC, respectively [stratified P = .48]) and overall survival (median survival 7.1 and 8.5 months for guadecitabine and TC, respectively [hazard ratio, 0.97; 95% confidence interval, 0.83-1.14; stratified log-rank P = .73]). One- and 2-year survival estimates were 37% and 18% for guadecitabine and 36% and 14% for TC, respectively. A large proportion of patients (42%) received <4 cycles of treatment in both the arms. In a post hoc analysis of patients who received ≥4 treatment cycles, guadecitabine was associated with longer median survival vs TC (15.6 vs 13.0 months [hazard ratio, 0.78; 95% confidence interval, 0.64-0.96; log-rank P = .02]). There was no significant difference in the proportion of patients with grade ≥3 adverse events (AEs) between guadecitabine (92%) and TC (88%); however, grade ≥3 AEs of febrile neutropenia, neutropenia, and pneumonia were higher with guadecitabine. In conclusion, no significant difference was observed in the efficacy of guadecitabine and TC in the overall population. This trial was registered at www.clinicaltrials.gov as #NCT02348489.

Epidemiology of multiple myeloma in Poland in the years 2008-2017.

Introduction: Multiple myeloma is the third most common blood cancer in Europe and accounts for approx. 10-15% of these cancers. The objective of this study was to determine the incidence, prevalence, mortality and survival in multiple myeloma (ICD code: C90.0) patients in Poland in the years 2008-2017. Material and methods: The analysis used the data on healthcare services provided to patients with multiple myeloma defined with the ICD-10 (International Statistical Classification of Diseases and Related Health Problems) code C90.0 and reported by healthcare entities to the National Health Fund (NFZ). Results: In 2009, the C90.0 incidence per 100,000 inhabitants was 6.4, while in 2017 it was 8.3. The prevalence in the same period increased by 76%, from 13.6/100,000 to 23.9/100,000. The mortality to prevalence ratio gradually decreased from 78% in 2008 to 22.8% in 2017. The 1-year, 3-year and 5-year survival rates in patients with this diagnosis made in the years 2009 and 2013 were 70.5%, 51.5% and 40.2% versus 78.4%, 60.3% and 48.3%, respectively. Conclusions: The incidence and prevalence of multiple myeloma and survival rates in Poland were continuously increasing in the studied period. These trends may result from the aging of Polish society, better recognisability of multiple myeloma and/or improved access to increasingly more effective therapies in Poland. The impact of these factors on the epidemiology of multiple myeloma requires further studies.

Bing-Neel Syndrome, a Rare Presentation of Waldenström Macroglobulinemia-A Multicenter Report by the Polish Lymphoma Research Group.

Bing-Neel syndrome (BNS) is a rare presentation of Waldenström macroglobulinemia (WM). BNS is a consequence of the central nervous system (CNS) involvement by lymphoplasmacytic lymphoma (LPL) and, rarely, the peripheral nervous system. The data on BNS are extremely scarce. Therefore, we performed a multicenter retrospective analysis of BNS patients diagnosed and treated in centers aligned with the Polish Lymphoma Research Group. The analysis covers the years 2014-2021. Eleven patients were included, 55% females and the median age at BNS diagnosis was 61 years. The median time from WM to BNS was 3.5 years; 27% of patients did have a diagnosis of WM and BNS made simultaneously or within 30 days from each other. Isolated parenchymal involvement was the least frequent (20%). Patients were treated with different regimens, mostly able to cross the blood-brain barrier, including 18% treated with ibrutinib first line. The cumulative objective response to treatment was 73%. With the median follow-up of 20 months (95% CI, 2-32), the 36-month estimates were: overall survival (OS) 47%, progression-free survival (PFS) 33%, and cumulative incidence of BNS-associated death 41%. The performance status according to ECOG was significant for PFS (HR = 7.79) and the hemoglobin concentration below 11 g/dL was correlated with PFS. To conclude, BNS is a very rare manifestation of WM. It is associated with a poor outcome with most patients succumbing to BNS.

Allogeneic hematopoietic stem cell transplantation for adult HLH: a retrospective study by the chronic malignancies and inborn errors working parties of EBMT.

Hemophagocytic lymphohistiocytosis (HLH; hemophagocytic syndrome) is a rare syndrome of potentially fatal, uncontrolled hyperinflammation. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated in primary, recurrent or progressive HLH, but information about its outcomes in the adult population is limited. We obtained data about 87 adult (≥18 years of age) patients retrospectively reported to the EBMT. The median survival time was 13.9 months. The three and five-year overall survival (OS) was 44% (95% CI 33-54%). Among 39 patients with a follow-up longer than 15 months, only three died. Relapse rate was 21% (95% CI 13-30%), while NRM reached 36% (95% CI 25-46%). Younger patients (<30 years of age) had better prognosis, with an OS of 59% (95% CI 45-73%) at three and five years vs 23% (95% CI 8-37%) for older ones. No difference in survival between reduced and myeloablative conditioning was found. To our knowledge, this is the largest report of adult HLH patients who underwent allo-HSCT. Patients who survive the first period after this procedure can expect a long disease-free survival. Both reduced intensity and myeloablative conditioning have therapeutic potential in adult HLH.

Effectiveness of tinnitus therapy using a mobile application.

BACKGROUND: The World Health Organization reports that the number of tinnitus sufferers is increasing year on year. Given the common use of mobile devices and the availability of applications designed to support patients in tinnitus therapy and reduce tinnitus severity, patients seeking help are likely to try this form of support. The aim of this study was to evaluate the effectiveness of a mobile application in tinnitus sound therapy, in this case ReSound Tinnitus Relief™. METHODS: The study involved 52 patients hospitalized for tinnitus. All participants used the free ReSound Tinnitus Relief application for 6 months. The application is based on sound therapy. Patients were advised to use the application for at least 30 min per day, the sounds should not completely mask the tinnitus, and they should be listened to via a loudspeaker. The effects of the therapy were evaluated by means of standardized questionnaires for tinnitus severity: the Tinnitus Handicap Inventory and the Tinnitus Functional Index. RESULTS: The study showed a reduction in tinnitus severity as measured by both questionnaires. The general severity decreased after the first 3 months and again in the following 3 months of using the application. In both questionnaires the biggest changes were observed in the subscales of emotions. CONCLUSIONS: Results obtained here from standardized questionnaires indicate that the tested application may contribute to tinnitus reduction. However, it is advisable to conduct further research on the applicability of such technology in medical practice.

Ice-cream used as cryotherapy during high-dose melphalan conditioning reduces oral mucositis after autologous hematopoietic stem cell transplantation.

Oral mucositis (OM) is one of the most frequent adverse events of high-dose conditioning chemotherapy with melphalan prior to autologous hematopoietic stem cell transplantation (AHSCT). It significantly reduces the patients' quality of life. One of the preventive strategies for OM is cryotherapy. We retrospectively analyzed whether commercially available ice-cream could prevent OM during the melphalan infusion. We retrospectively analyzed 74 patients after AHSCT to see whether there is any correlation between OM and cryotherapy (ice-cream), melphalan dose (140 mg/m2 or 200 mg/m2). The incidence of OM in our study inversely correlated with cryotherapy in the form of ice-cream. Out of 74 patients receiving conditioning chemotherapy with high-dose melphalan, 52 received cryotherapy. Fifteen patients in the cryotherapy group (28.84%) developed OM, whereas 13 patients (59.09%) developed it in the group without cryotherapy. In a multiple linear regression test cryotherapy remained a significant protective factor against OM (p = 0.02) We have also seen the relationship between melphalan dose with OM (p < 0.005). Cryotherapy in the form of ice-cream is associated with a lower rate of OM and, therefore, could potentially be used as a cost-effective, less burdensome, and easy to implement method in prevention of oral mucositis.

Prevalence of hypogammaglobulinemia and its management with subcutaneous immunoglobulin supplementation in patients after allogeneic hematopoietic stem cell transplantation-a single-center analysis.

Secondary immunodeficiencies are frequently observed after allo-HSCT. The efficacy of subcutaneous IgG preparations in this population is unknown. A retrospective single-institution study involved 126 adult patients transplanted in 2012-2019 for hematological malignancies. Patients were tested every 2-3 weeks for plasma IgG concentration during the 1st year after transplantation and supplemented with facilitated subcutaneous immunoglobulin when they either had IgG concentration < 500 mg/dl or between 500 and 700 mg/dl and recurrent infection. The IgG concentration < 500 mg/dL was diagnosed in 41 patients, while 500-700 mg/dL in 25 and altogether 53 patients received IgG supplementation. The median number of IgG administrations was 2. The median time to the first IgG administration after allo-HSCT was 4.1 months, while to the next administration (if more than one was required) 53 days (prophylactic group) and 32 days (group with infections). We did not observe any significant toxicity. Two situations were associated with increased probability of meeting criteria for IgG supplementation: diagnosis of either acute lymphoblastic leukemia (ALL) or chronic lymphocytic leukemia (CLL) (83.8% versus 39.3% for other diagnosis, p = 0.000) and the systemic use of corticosteroids (64.2% versus 31.5% for patients without systemic corticosteroids, p = 0.005). Over 40% of the adult recipients may require at least incidental immunoglobulin supplementation during the first year after allo-HSCT. Low IgG concentrations are associated with inferior outcomes. The subcutaneous route of IgG administration appeared to be safe and may allow for long persistence.

Leukaemia cutis for clinicians, a literature review.

Leukaemia cutis (LC) describes infiltration of the skin by leukaemia cells, resulting in clinically identifiable cutaneous lesions. LC has a wide range of clinical manifestations, which can make it difficult to distinguish LC from other skin changes. In a group of patients, LC can be the first manifestation of leukaemia, therefore skin biopsy is crucial for the diagnosis. In this mini review, we discuss various types of leukaemia most frequently represented in leukaemia cutis, in both children and adults and skin changes in multiple myeloma, focusing on the clinical presentation of LC and prognosis in patients.

Impact of pre-transplantation sinus abnormalities assessed by Lund-Mackay scoring system on sinusitis occurrence after allogeneic hematopoietic cell transplantation in acute leukemia patients.

INTRODUCTION: Screening sinonasal evaluation is routinely performed before allogeneic hematopoietic cell transplantation (allo-HCT), however, data supporting such evaluation is inconsistent. O b j e c t i v e s: Assessment of the utility of screening sinonasal evaluation with computed tomography (CT). METHODS: A retrospective analysis of acute leukemia patients who underwent allo-HCT, for whom screening sinonasal CT scans were reevaluated, and for whom Lund-Mackay score (LMS) was calculated. R e s u l t s: Forty-eight patients, the median age at allo-HCT 38 years (18-58), 52% males, were included. 79% had acute myeloid leukemia (AML), 21% acute lymphoblastic leukemia (ALL). Conditioning intensity was myeloablative in 96% of patients, 21% of patients received total body irradiation. 19% of patients had a history of sinusitis before allo-HCT. Screening sinus CT was performed a median of 22 days before allo-HCT. The median LMS was 1 point (0- 10). The severity of sinus abnormalities was: no abnormalities (31%), mild (67%), moderate (2%), severe (0%). Mucosal thickening was the most frequent abnormality (69%). Eleven patients experienced sinusitis after a median of 93 days (11-607) after allo-HCT. 1-year cumulative incidence of sinusitis was 22%. No threshold of LMS and no type of sinus abnormalities were correlated with sinusitis development after allo-HCT. Mild sinus disease at screening did not negatively impact survival in comparison to no sinus disease. C o n c l u s i o n s: Despite the fact, that majority of analyzed patients had either no or mild sinus disease at screening a significant proportion of patients developed sinusitis after allo-HCT. Evaluation of LMS before allo-HCT did not help predict the development of sinusitis after the procedure.

IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen.

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2+) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients' outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37-0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.

Perspectives for the Use of CAR-T Cells for the Treatment of Multiple Myeloma.

During recent years considerable progress has been made in the treatment of multiple myeloma. However, despite the current improvements in the prognosis of this malignancy, it always ends with relapse, and therefore new therapy approaches for destroying resistant cancer cells are needed. Presently, there is great hope being placed in the use of immunotherapy against refractory/relapsed multiple myeloma which is unresponsive to any other currently known drugs. The most promising one is CAR-T cell therapy which has already shown tremendous success in treating other malignancies such as acute lymphoblastic leukaemia (ALL) and could potentially be administered to multiple myeloma patients. CAR-T cells equipped with receptors against BCMA (B-cell maturation antigen), which is a surface antigen that is highly expressed on malignant cells, are now of great interest in this field with significant results in clinical trials. Furthermore, CAR-T cells with other receptors and combinations of different strategies are being intensively studied. However, even with CAR-T cell therapy, the majority of patients eventually relapse, which is the greatest limitation of this therapy. Serious adverse events such as cytokine release syndrome or neurotoxicity should also be considered as possible side effects of CAR-T cell therapy. Here, we discuss the results of CAR-T cell therapy in the treatment of multiple myeloma, where we describe its main advantages and disadvantages. Additionally, we also describe the current results that have been obtained on using combinations of CAR-T cell therapies with other drugs for the treatment of multiple myeloma.

Pseudoneutropenia as a factor-limiting access to chemotherapy for cancer patients: the effect of a simple meal.

BACKGROUND: Absolute neutrophil count (ANC) below 1.5 G/l or 1 G/l is commonly used as a factor to determine the decision to administer antineoplastic treatment including chemotherapy and novel agents to cancer patients. This practice is based on observations that below this ANC, there is an increased risk of bacterial and fungal infection. This is further based on the assumption that this parameter always correctly reflects the true shortage of these germ-fighting cells in patients. In reality, the circulating pool of neutrophils is only one of four reservoirs (bone marrow, circulating, marginal and tissue pools) and its size is influenced not only by shortage but also by transient shift of cells between these reservoirs. The aim of this study was to evaluate whether repeated blood collection affects ANC in the patient. METHODS: We retrospectively analysed the medical records of cancer patients with 0.8 G/l ≤ ANC < 1.5 G/l in whom CBC was repeated based on the physician's decision, which was done on the same day roughly 2 h after the first one. RESULTS: The patients at the time of repeating CBC had consumed breakfast. In 31 out of 32 patients, ANC exceeded 1 G/l or 1.5 G/l and antineoplastic treatment was administered as originally planned. There were no infectious complications observed. CONCLUSION: Cancer patients should not be fasting prior to blood collection, with the exception of special and rare situations. To achieve the maximum clinical benefit, delays and/or reductions of antineoplastic treatment should be avoided wherever possible. Pseudoneutropenia is an unnecessary reason for postponing chemotherapy.