Outcomes of patients with light chain (AL) amyloidosis after failure of daratumumab-based therapy.

As daratumumab use in AL amyloidosis increases, more patients will either relapse after or become refractory to daratumumab. We present the outcome of 33 patients with AL who failed on daratumumab (due to haematological relapse in 21 [64%] patients and inadequate haematological response in 12 [36%]) and received further treatment. Overall response rate in the post-daratumumab failure treatment was 55% (CR/VGPR: 14 [42%] and PR: 3 [9%] patients). Patients retreated with daratumumab and patients harbouring +1q21 had lower rates of response. Treatment of patients with AL who fail daratumumab therapy is feasible when non-cross-resistant drugs or other targeted therapies are available.

Prognostic impact of translocation t(11;14) and of other cytogenetic abnormalities in patients with AL amyloidosis in the era of contemporary therapies.

OBJECTIVES: Translocation t(11;14) is the most common cytogenetic abnormality in patients with systemic AL amyloidosis with prognostic and therapeutic relevance, which has not been clearly defined in the most recent therapeutic era. METHODS: We assessed its prognostic role in 146 newly-diagnosed patients who received novel agent-based treatment combinations. Event-free survival (EFS), a composite endpoint defined by hematological progression, start of a new treatment-line or death, and overall survival (OS) were the primary endpoints. RESULTS: Half of the patients had at least one FISH abnormality; 40% had t(11;14) which was inversely associated with other cytogenetic abnormalities. At 1, 3, and 6-month landmarks, hematologic response rates were numerically but not statistically higher in the non-t(11;14) group. Patients with t(11;14) were more frequently switched to second-line treatment within 12 months (p = .015). At median follow-up of 31.4 months, t(11;14) was associated with shorter EFS [17.1 (95% CI 3.2-10.6) vs. 27.2 months (95% CI 13.8-40.6), p = .021] and retained its prognostic significance in the multivariate model (HR:1.66, p = .029). The effect on OS was neutral, possibly due to the use of effective salvage therapies. CONCLUSIONS: Our data support the use of targeted therapies for patients with t(11;14) to avoid delays in the achievement of deep hematologic responses.

Epidemiological trends in cutaneous lymphomas in Greece.

Primary cutaneous lymphomas (PCLs) are a heterogenous group of non-Hodgkin lymphomas arising in the skin from T- or B-lymphocytes, for which there is limited epidemiological data available. To describe the disease characteristics and estimate annual incidence rates (IRs) and temporal trends of PCLs and their subtypes in Attica, Greece. A retrospective analysis of all PCL patients, diagnosed in Attica's main haemopathology referral centre from 2009 to 2021, was conducted. In total, 1,189 patients were included; 725 males and 464 females (males__females=1.56). The median age at diagnosis was 62 years. The annual IR was 2.2 new cases per 100,000 individuals. Most patients (n=979, 82.3%) were diagnosed with cutaneous T-cell lymphoma (CTCL) with a crude IR of 1.8 new cases per 100,000 person-years. Mycosis fungoides (MF) was the most common subtype (n=817, 68.7%), followed by lymphomatoid papulosis (LyP) (n=59, 5.0%). The crude IR for MF was 1.5 new cases per 100,000 person-years. Cutaneous B-cell lymphomas (CBCLs) accounted for 17.6% (n=210) of all PCLs (IR: 0.4 new cases per 100,000 person-years). PCL, CTCL and MF incidence rates increased from 2009 to 2019, followed by a decrease in 2020-2021. The incidence rate of CBCL increased steadily during the study period. The annual IRs of PCL in Greece were higher than those reported in other studies from Europe, America and Asia. The increase in IRs from 2009 to 2019 may reflect physicians' improved diagnostic efficiency. The COVID-19 pandemic may be the reason for the decline in PCL, CTCL and MF diagnoses from 2020 to 2021.

Akt Signaling Pathway Is Activated in the Minor Salivary Glands of Patients with Primary Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is an autoimmune exocrinopathy of mainly the salivary and lacrimal glands associated with high prevalence of lymphoma. Akt is a phosphoinositide-dependent serine/threonine kinase, controlling numerous pathological processes, including oncogenesis and autoimmunity. Herein, we sought to examine its implication in pSS pathogenesis and related lymphomagenesis. The expression of the entire and activated forms of Akt (partially and fully activated: phosphorylated at threonine-308 (T308) and serine-473 (S473), respectively), and two of its substrates, the proline-rich Akt-substrate of 40 kDa (PRAS40) and FoxO1 transcription factor has been immunohistochemically examined in minor salivary glands (MSG) of pSS patients (n = 29; including 9 with pSS-associated lymphoma) and sicca-complaining controls (sicca-controls; n = 10). The entire and phosphorylated Akt, PRAS40, and FoxO1 molecules were strongly, uniformly expressed in the MSG epithelia and infiltrating mononuclear cells of pSS patients, but not sicca-controls. Morphometric analysis revealed that the staining intensity of the fully activated phospho-Akt-S473 in pSS patients (with or without lymphoma) was significantly higher than sicca-controls. Akt pathway activation was independent from the extent or proximity of infiltrates, as well as other disease features, including lymphoma. Our findings support that the Akt pathway is specifically activated in MSGs of pSS patients, revealing novel therapeutic targets.

Consolidation with a short course of daratumumab in patients with AL amyloidosis or light chain deposition disease.

Daratumumab has major and rapid activity in AL amyloidosis with favourable toxicity. We used as a consolidation a short course of daratumumab in 25 patients with AL amyloidosis or light chain deposition disease (LCDD), who had not achieved a haematologic complete response (hemCR) after standard therapy with bortezomib, cyclophosphamide and dexamethasone (VCD). We evaluated minimal residual disease (MRD) and changes in the bone marrow (BM) microenvironment before and after consolidation using next generation flow cytometry (NGF). At the time of consolidation, 21 patients were in very good partial response (VGPR) and four in partial response (PR); all had detectable MRD. One month after consolidation completion, 8 patients (32%) achieved a hemCR, of whom 5 (20%) became also MRD negative. In the BM, we observed significant changes in B-cell precursors, naïve B-cells, T-cells, CD27+ NK & NKT cells, mast cells and erythroblasts. After a median follow-up of 25 months, none of the patients in hemCR has relapsed and all have achieved an organ response; a haematologic relapse occurred in 6/17 patients that did not achieve hemCR. In conclusion, consolidation with a short course of daratumumab can improve depth of response in patients with AL amyloidosis or LCDD and significantly affects BM environment.

+3179G/A Insulin-Like Growth Factor-1 Receptor Polymorphism: A Novel Susceptibility Contributor in Anti-Ro/SSA Positive Patients with Sjögren's Syndrome: Potential Clinical and Pathogenetic Implications.

BACKGROUND: Alterations of the insulin-like growth factor (IGF) pathway along with genetic variations of the IGF1 receptor (IGF1R) gene have been linked to the development of systemic autoimmunity, possibly through apoptosis induction. This study aims to investigate whether genetic variations of the IGF1R contribute to Sjögren's syndrome (SS) pathogenesis and explores potential functional implications. METHODS: DNA extracted from whole peripheral blood derived from 277 primary SS patients, complicated or not by lymphoma, and 337 Healthy controls (HC) was genotyped for the rs2229765 IGF1R polymorphism using the RFLP-PCR assay. Gene expression of IGF1R and IGF1 isoforms, caspases 1, 4, and 5, and inflammasome components NLRP3, ASC, IL1ß, IL18, IL33, IGFBP3, and IGFBP6 were quantitated by RT-PCR in total RNA extracted from minor salivary gland biopsies (MSGs) of 50 SS patients and 13 sicca controls (SCs). In addition, IGF1R immunohistochemical (IHC) expression was assessed in formalin-fixed, paraffin-embedded MSG tissue sections derived from 10 SS patients and 5 SCs. RESULTS: The prevalence of the A/A genotype of the rs2229765 IGF1R polymorphism was significantly higher in the anti-Ro/SSA positive SS population compared to healthy controls (24.8% vs. 10.7%, p = 0.001). Moreover, IGF1Rs at both mRNA and protein levels were reduced in SS-derived MSGs compared to SCs and were negatively associated with caspase 1 transcripts. The latter were positively correlated with NLRP3, ASC, and IL1ß at the salivary gland tissue level. IGF1R expression in peripheral blood was negatively correlated with ESR and IgG serum levels and positively correlated with urine-specific gravity values. CONCLUSIONS: The rs2229765 IGF1R variant confers increased susceptibility for seropositive primary SS. Dampened IGF1R mRNA and protein expression in salivary gland tissues could be related to increased apoptosis and subsequently to the activation of inflammasome pathways.

A rare case of duodenal-type follicular lymphoma in rectum appearing as hyperplastic polyp with metachronous appearance in duodenum and stomach.

Hyperplastic polyps consist a very frequent finding in colonoscopy having a very low potential to malignancy. According to the international guidelines, it is recommended that all polyps should be resected except for diminutive (≤ 5 mm) rectal and rectosigmoid polyps which are predicted with confidence to be hyperplastic. Therefore, in departments where optical diagnosis can be ensured, a "resect and discard" strategy may be implemented for diminutive polyps. In our case, a duodenal-type follicular lymphoma was detected in a 5 mm rectum polyp with hyperplastic appearance. After 4 months, the lymphoma was detected also in stomach and duodenum. Under therapy with Rituximab, she is in remission. To our knowledge, there has never been reported such a case in the literature. Furthermore, it alerts us that we should be very cautious with the optical diagnosis and the "resect and discard strategy".

Lipoprotein-Associated Phospholipase A2: A Novel Contributor in Sjögren's Syndrome-Related Lymphoma?

Background: B-cell non-Hodgkin's lymphoma (B-NHL) is one of the major complications of primary Sjögren's syndrome (SS). Chronic inflammation and macrophages in SS minor salivary glands have been previously suggested as significant predictors for lymphoma development among SS patients. Lipoprotein-associated phospholipase A2 (Lp-PLA2)-a product mainly of tissue macrophages-is found in the circulation associated with lipoproteins and has been previously involved in cardiovascular, autoimmune, and malignant diseases, including lymphoma. Objective: The purpose of the current study was to investigate the contributory role of Lp-PLA2 in B-NHL development in the setting of primary SS. Methods: Lp-PLA2 activity in serum samples collected from 50 primary SS patients with no lymphoma (SS-nL), 9 primary SS patients with lymphoma (SS-L), and 42 healthy controls (HC) was determined by detection of [3H]PAF degradation products by liquid scintillation counter. Moreover, additional sera from 50 SS-nL, 28 SS-L, and 32 HC were tested for Lp-PLA2 activity using a commercially available ELISA kit. Lp-PLA2 mRNA, and protein expression in minor salivary gland (MSG) tissue samples derived from SS-nL, SS-L patients, and sicca controls (SC) were analyzed by real-time PCR, Western blot, and immunohistochemistry. Results: Serum Lp-PLA2 activity was significantly increased in SS-L compared to both SS-nL and HC by two independent methods implemented [mean ± SD (nmol/min/ml): 62.0 ± 13.4 vs 47.6 ± 14.4 vs 50.7 ± 16.6, p-values: 0.003 and 0.04, respectively, and 19.4 ± 4.5 vs 15.2 ± 3.3 vs 14.5 ± 3.0, p-values: <0.0001, in both comparisons]. ROC analysis revealed that the serum Lp-PLA2 activity measured either by radioimmunoassay or ELISA has the potential to distinguish between SS-L and SS-nL patients (area under the curve [AUC]: 0.8022, CI [95%]: 0.64-0.96, p-value: 0.004 for radioimmunoassay, and AUC: 0.7696, CI [95%]: 0.66-0.88, p-value: <0.0001, for ELISA). Lp-PLA2 expression in MSG tissues was also increased in SS-L compared to SS-nL and SC at both mRNA and protein level. ROC analysis revealed that both MSG mRNA and protein Lp-PLA2 have the potential to distinguish between SS-nL and SS-L patients (area under the curve [AUC] values of 0.8490, CI [95%]: 0.71-0.99, p-value: 0.0019 and 0.9444, CI [95%]: 0.79-1.00, p- value: 0.0389 respectively). No significant difference in either serum Lp-PLA2 activity or MSG tissue expression was observed between SS-nL and HC. Conclusions: Lp-PLA2 serum activity and MSG tissue mRNA/protein expression could be a new biomarker and possibly a novel therapeutic target for B-cell lymphoproliferation in the setting of SS.

Clinical significance of PD-1 and PD-L1 molecules in patients with diffuse large B-cell lymphoma, not otherwise specified: Correlation with clinical and pathological findings.

PURPOSE: To investigate a possible chemorefractoriness mechanism of a Diffuse Large B-Cell Lymphoma (DLBCL) histological subtype, specifically of DLBCL, not otherwise specified (DLBCL, NOS), namely the effect of programmed cell death-1 (PD-1) immunoreceptor signalling, considering that the identification of additional negative prognostic factors can lead to better prognostication and therapeutic approaches. METHODS: We conducted a retrospective study of DLBCL, NOS patients, gathering their clinical features and combining them with PD-1 and its ligand (PD-L1) expression at the time of diagnosis as well as their response to treatment. RESULTS: No statistically significant difference was found when comparing PD-L1 positive to PD-L1 negative patients, while overall survival (OS) and duration of complete response (CR) were better for PD-L1 negative patients but the difference was not statistically significant. CONCLUSIONS: PD-L1 expression was not found to have any prognostic value for our cohort of DLBCL, NOS patients. What is more, the number of PD-1 positive tumour infiltrating lymphocytes was not associated with PD-L1 expression neither on malignant nor on non-malignant cells.

Timing and impact of a deep response in the outcome of patients with systemic light chain (AL) amyloidosis.

A rapid and deep haematologic response is fundamental in order to improve outcomes of patients with AL amyloidosis. We evaluated the impact of timing and depth of haematologic response at early time points (at 1 and 3 months from the start of therapy) in 227 consecutive previously untreated AL patients, who received bortezomib-based primary therapy. After 1 month of therapy, 30.5% had ≥VGPR, 28% PR and 36% no response (NR), with 11% having iFLC <20 mg/L and 15% dFLC <10 mg/L. Deep haematologic response at 1 month (either ≥VGPR or iFLC <20 mg/L or dFLC <10 mg/L), was associated with a high organ response rate. The survival of patients with ≥VGPR was significantly better than those with PR and NR at 1-month landmark (p < .001) but this benefit was mainly driven by those with iFLC <20 mg/L. The depth of haematologic response at 1 month was significant across all Mayo stages. At 3 months, 46% of the patients had not significantly improved the depth of their response but even patients that improved their response from an iFLC ≥20 mg/L at 1 month to iFLC <20 mg/L at 3 months still had inferior outcome to those with an early deep response. Thus, in patients with AL amyloidosis, a very rapid and deep response is crucial, especially for those at high risk, targeting very low FLC levels within the first month of therapy.

Multiple osteolytic lesions due to Double-Expressor Primary non-Hodgkin Lymphoma of the Bone.

Primary non-Hodgkin lymphoma of the bone (PLB) is a rare type of non-Hodgkin's lymphoma (NHL) that affects the skeletal system with or without regional lymph node involvement. We present the case of a 74-year-old female patient with pain due to multifocal osteolytic lesions. The diagnosis of diffuse large B-cells (non-GCB) phenotype was made by clinical, laboratory, histopathological examination accompanied by an extensive immunohistochemical profile of one of the skeletal lesions.

Multiple osteolytic lesions due to Double-Expressor Primary non-Hodgkin Lymphoma of the Bone

Primary non-Hodgkin lymphoma of the bone (PLB) is a rare type of non-Hodgkin's lymphoma (NHL) that affects the skeletal system with or without regional lymph node involvement. We present the case of a 74-year-old female patient with pain due to multifocal osteolytic lesions. The diagnosis of diffuse large B-cells (non-GCB) phenotype was made by clinical, laboratory, histopathological examination accompanied by an extensive immunohistochemical profile of one of the skeletal lesions.

Primary treatment of light-chain amyloidosis with bortezomib, lenalidomide, and dexamethasone.

Bortezomib and dexamethasone with cyclophosphamide (CyBorD) or melphalan (BMDex) are commonly used primary treatments for light-chain (AL) amyloidosis, but limited data exist on bortezomib with immunomodulatory drug combinations. We report our experience with primary therapy with a bortezomib, lenalidomide, and dexamethasone (VRD) "light" regimen in 34 consecutive patients with AL amyloidosis. The majority (79%) had cardiac involvement, 15% and 23% were Mayo stage 3A and 3B, respectively, and 54% had renal involvement. After the first VRD cycle, 71% of patients achieved a hematologic response (44% at least very good partial response [VGPR]). On intent to treat, 11 (32%) achieved a complete response (of whom 5 of 11 were minimal residual disease [MRD] negative at 10-5), 17 (50%) a VGPR, and 2 (7%) a partial response. The 12-month survival was 73%. Starting lenalidomide dose was 5 mg in 86% of patients. Hematologic toxicity was mild; nonhematologic toxicities included rash (grade 3/4 [16%]), infections (grade ≥3 [12%]), constipation (grade ≥3 [9%]), and peripheral neuropathy (grade 2 [20%]); 37.5% of patients required lenalidomide dose reduction, 27% discontinued lenalidomide, 38% required bortezomib dose reduction, and 12% discontinued bortezomib. We compared VRD to CyBorD in 68 patients matched for Mayo stage and baseline difference between involved minus uninvolved serum free light chain levels, and observed a trend for deeper response at 3 and 6 months with VRD. In conclusion, VRD can be an active regimen for newly diagnosed patients with AL amyloidosis able to induce very deep hematologic responses at the expense of increased toxicity.

Evaluation of regulatory T cells (Tregs) alterations in patients with multiple myeloma treated with bortezomib or lenalidomide plus dexamethasone: correlations with treatment outcome.

The exact role of regulatory T cells (Tregs) in multiple myeloma (MM) has not been yet determined. Data regarding alterations of Tregs during therapy with novel agents (NA), i.e., bortezomib and lenalidomide are conflicted and limited. We evaluated prospectively alterations of Tregs and searched for correlations with disease characteristics, response, and outcome in 29 patients with active MM treated with either bortezomib-dexamethasone (BD; 11 patients) or lenalidomide-dexamethasone (LenDex, 18 patients). Additionally, we recorded changes of lymphocytes subsets and cytokines related to Tregs function and MM biology, i.e., interleukin (IL) 6, 2, 17, and TGF-ß. Compared with controls, patients had significantly higher median levels of Tregs%, IL-6, and IL-17 (p < 0.001). Median CD4 T and B cells frequencies were significantly lower, whereas CD8 T and natural killers were increased compared to controls. In BD group, no significant alterations of Tregs% were observed. Patients treated with LenDex, displayed a significant reduction of Tregs% (p < 0.001) especially those who achieved at least very good partial response (≥vgPR) (p = 0.04). Lymphocyte subsets or cytokines did not significantly change during therapy. In summary, Tregs% are higher in patients with active MM compared with controls, and they significantly decrease after treatment with LenDex but not with BD; After therapy with LenDex, Tregs reduction between baseline and major response correlated with achievement of ≥vgPR suggesting a possible predictive role, that may contribute to therapeutic strategy.

Lymphoepithelioma-like breast carcinoma.

Nasopharyngeal lymphoepithelioma is an undifferentiated carcinoma in a dominated lymphoplasma-histiocyte stroma. Lymphoepithelioma-like carcinoma of the breast is the mammary counterpart of the lymphoepithelioma of the nasopharynx and is characterised by proliferation of poorly differentiated malignant cells within a prominent lymphoid infiltrate. It is a very rare primary carcinoma of the breast first reported in 1994 by Kumar and Kumar. Fewer than 40 cases have been reported in the English literature. In this manuscript a case of lymphoepithelioma-like carcinoma of the breast in a 57-year-old patient is reported along with a literature review on this rare entity.

Increased expression of platelet derived growth factor receptor ß on trephine biopsies correlates with advanced myeloma.

PURPOSE: Multiple myeloma (MM), a major cause of cancer mortality, is considered the second most frequent haematological malignancy in Europe. Angiogenesis is a multifactorial process that drives the tumorigenesis in solid tumors and in MM. The platelet derived growth factor (PDGF) receptors are cell surface tyrosine kinase receptors and play an important role in angiogenesis, cancer cell proliferation and dissemination. Few studies have been conducted regarding the expression of PDGF receptors and the correlation with clinical-pathological parameters and prognosis in MM. The purpose of our study was to evaluate, for the first time, in a large cohort of newly-diagnosed MM (NDMM) patients, the expression of PDGF receptor α and ß (PDGFR α, ß) in bone marrow trephine biopsies and investigate the association of PDGFR α, PDGFR ß with angiogenesis in the bone marrow, assessed by bone marrow microvessel density (MVD), clinical characteristics and prognosis. METHODS: In this retrospective study, we assessed the relation of PDGFR α and PDGFR ß immunohistochemical expression with MVD in formalin-fixed paraffin-embedded bone marrow sections from 120 NDMM patients. The immunoreactivity of PDGFR α and ß was examined on the basis of positive plasma cells (PCs) with specific cut off values. RESULTS: PDGFRα and PDGFRß were frequently expressed on malignant PCs. We found that increased PDGFRß expression was strongly associated with advanced disease and adverse prognosis. The expression of PDGFRα and MDV were not correlated with specific features. CONCLUSION: This analysis showed highly expressed PDGFRα and ß PCs of NDMM patients and indicated that high PDGFRß expression at diagnosis was associated with advanced-stage disease.