Rapid decline in insulin antibodies and glutamic acid decarboxylase autoantibodies with ibrutinib therapy of chronic lymphocytic leukaemia.

WHAT IS KNOWN AND OBJECTIVE: Ibrutinib is inhibiting the Bruton's tyrosine kinase (BTK), thereby influencing B-cell development. We describe an unexpected side effect of ibrutinib in two patients with chronic lymphocytic leukaemia concerning the vigorous decrease of two different diabetes-associated antibodies. CASE DESCRIPTION: Two weeks after onset of ibrutinib therapy, patient A frequently noticed symptoms of hypoglycaemia such as dizziness and blurred vision. Blood glucose declined to 35-40 mg/dL. He had to lower his insulin dose step by step. High levels of insulin antibodies which had developed during insulin therapy were detected. Seven weeks after start of ibrutinib, his insulin antibodies level had dropped by 54.6%. Patient B had a 54.1% decrease in his glutamic acid decarboxylase autoantibodies level after 7 weeks. WHAT IS NEW AND CONCLUSION: The inhibitory effect of ibrutinib on the levels of insulin antibodies and glutamic acid decarboxylase autoantibodies is a novel finding and may have implications for diabetes care.

Molecular classification of tumour cells in a patient with intravascular large B-cell lymphoma.

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal LBCL. It is characterized by the proliferation of tumour cells exclusively intraluminally in small blood vessels of different organs. The clinical manifestation depends on the type of organ affected; additionally, a haemophagocytic syndrome can be observed in some patients. OBJECTIVES: The aim was to further understand the nosology of this lymphoma as, due to its rarity and in spite of detailed immunohistochemical investigations, its exact nosology is only incompletely understood. METHODS: We used microarray-based analysis of gene expression of tumour cells isolated from a patient with primary manifestation of the lymphoma in the skin and compared it with various other diffuse LBCLs (DLBCLs) as well as a previously published DLBCL classifier. RESULTS: In unsupervised analyses, the tumour cells clustered together with non-germinal centre B-cell (non-GCB) DLBCL samples but were clearly distinct from GCB-DLBCL. Analogous to non-GCB DLBCL, molecular cell-of-origin classification revealed similarity to bone-marrow derived plasma cells. CONCLUSIONS: The IVLBCL of this patient showed molecular similarity to non-GCB DLBCL. Due to the prognostic and increasingly also therapeutic relevance of molecular subtyping in DLBCL, this method, in addition to immunohistochemistry, should also be considered for the diagnosis of IVLBCL in the future.

BTK inhibition is a potent approach to block IgE-mediated histamine release in human basophils.

BACKGROUND: Recent data suggest that Bruton's tyrosine kinase (BTK) is an emerging therapeutic target in IgE receptor (IgER)-cross-linked basophils. METHODS: We examined the effects of four BTK inhibitors (ibrutinib, dasatinib, AVL-292, and CNX-774) on IgE-dependent activation and histamine release in blood basophils obtained from allergic patients (n=11) and nonallergic donors (n=5). In addition, we examined the effects of these drugs on the growth of the human basophil cell line KU812 and the human mast cell line HMC-1. RESULTS: All four BTK blockers were found to inhibit anti-IgE-induced histamine release from basophils in nonallergic subjects and allergen-induced histamine liberation from basophils in allergic donors. Drug effects on allergen-induced histamine release were dose dependent, with IC50 values ranging between 0.001 and 0.5 µmol/L, and the following rank order of potency: ibrutinib>AVL-292>dasatinib>CNX-774. The basophil-targeting effect of ibrutinib was confirmed by demonstrating that IgE-dependent histamine release in ex vivo blood basophils is largely suppressed in a leukemia patient treated with ibrutinib. Dasatinib and ibrutinib were also found to counteract anti-IgE-induced and allergen-induced upregulation of CD13, CD63, CD164, and CD203c on basophils, whereas AVL-292 and CNX-774 showed no significant effects. Whereas dasatinib and CNX-774 were found to inhibit the growth of HMC-1 cells and KU812 cells, no substantial effects were seen with ibrutinib or AVL-292. CONCLUSIONS: BTK-targeting drugs are potent inhibitors of IgE-dependent histamine release in human basophils. The clinical value of BTK inhibition in the context of allergic diseases remains to be determined.

Ristocetin-induced platelet aggregation for monitoring of bleeding tendency in CLL treated with ibrutinib.

Bleeding because of impaired platelet function is a major side effect of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. We quantitatively assessed ristocetin-induced platelet aggregation (RIPA) in 64 patients with chronic lymphocytic leukemia (CLL) under ibrutinib at 287 time points. Eighty-seven bleeding episodes in 39 patients were registered (85 Common Toxicity Criteria (CTC) grade 1 or 2, 2 CTC grade 3) during a median observation period of 10.9 months. At times of bleeding, RIPA values were significantly lower (14 vs 28 U; P<0.0001). RIPA was impaired in patients receiving concomitant antiplatelet therapy or anticoagulation (14 vs 25 U, P=0.005). A gradual decline of median RIPA values was observed with increasing bleeding severity. Importantly, no CTC grade 2 or 3 bleeding were observed with RIPA values of >36 U. Sequential monitoring indicated a decrease of RIPA values from a median of 17 to 9 U within 2 weeks after initiation of treatment as well as an increase above the critical threshold of 36 U within 7 days when ibrutinib was paused. Low RIPA values were similar during treatment with another BTK inhibitor, CC292. Quantitative assessment of platelet function is a practical tool to monitor bleeding tendency under BTK-inhibitor therapy.

Lupus anticoagulant and thrombosis in splenic marginal zone lymphoma.

INTRODUCTION: Splenic marginal zone lymphoma (SMZL) is a rare low-malignant Non-Hodgkin lymphoma (NHL), in which immune mediated paraneoplastic phenomena such as autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia (ITP) and C1 esterase inhibitor deficiency are relatively common. MATERIALS AND METHODS: We performed a multicenter retrospective study in 70 patients on the prevalence and clinical features of antiphospholipid antibodies (aPLA) in SMZL. RESULTS AND CONCLUSIONS: Nine patients (13%) had the diagnosis of a lupus anticoagulant (LA). The occurrence of venous thromboembolic events was significantly higher in LA positive patients compared to LA negative patients (4/9 [44%] vs 5/61 [8%], p = 0.002), especially within 12 months after splenectomy (3/6 [50%] vs 2/28 [7%], p = 0.007). None of the patients with LA had a persistent complete remission of LA after splenectomy, but complete remission of LA was achieved in 2/2 patients after rituximab-bendamustine immuno-chemotherapy. In conclusion, our data show a relatively high prevalence of aPLA in SMZL and an increased risk of postsplenectomy thrombosis in these patients. The fact that rituximab-bendamustine was effective for eradicating LA may be considered as an argument for using immuno-chemotherapy as first line therapy in SMZL patients with LA.

Alemtuzumab in chronic lymphocytic leukemia: final results of a large observational multicenter study in mostly pretreated patients.

This retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced B-cell chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (B-PLL) to definitely describe the impact of this antibody in clinical routine use. Data were collected from 208 consecutive, mainly pretreated, patients with CLL (n = 202), and B-PLL (n = 6) who had received alemtuzumab. Response, progression-free survival (PFS), and overall survival (OS) in various settings were assessed, and toxicities were documented. In these routine patients, a comparably low cumulative dose of alemtuzumab (median, 403 mg) was applied. In CLL, overall response rate was 32 %, and various pre-therapeutic parameters were predictive for inferior response, among them, the prior administration of ≥3 therapy lines (P < 0.001), refractoriness to fludarabine (P = 0.002), and bulky lymphadenopathy (P = 0.003). PFS and OS after start of alemtuzumab were 6.2 and 21.0 months, respectively. Bulky lymphadenopathy was the prominent risk factor for both inferior PFS (P < 0.001) and OS (P = 0.002). In B-PLL, four patients experienced a fatal outcome, whereas two patients had some benefit with alemtuzumab. The main adverse effects were CMV reactivation (20 %) and a broad spectrum of infections, which together were the main reasons for treatment interruption and/or premature termination. In conclusion, alemtuzumab administered even at low dose levels was effective but overall considerably toxic in routine CLL patients. We emphasize that alemtuzumab remains an important therapeutic option in subsets of CLL patients.

Methotrexate-induced primary cutaneous diffuse large B-cell lymphoma with an 'angiocentric' histological morphology.

A patient with a 25-year history of rheumatoid arthritis and a 3-year history of methotrexate treatment developed a generalized papular rash. The papules rapidly became necrotic and then resolved, leaving a depressed scar. The rapid course of lesion development and regression was reminiscent of pityriasis lichenoides. Histology revealed a nodular infiltrate composed of a mixture of pleomorphic large B cells positive for CD20, CD30 and CD79a, and of small T cells positive for CD3 and CD4. The T cells had a striking angiocentric distribution, with some of the vessels exhibiting fibrinoid necrosis of the vessel wall reminiscent of lymphomatoid granulomatosis. However, B cells were consistently negative for Epstein-Barr virus (EBV) antigen expression. A thorough examination excluded involvement of organs other than the skin. Thus, this patient was classified as having a rare form of an EBV-negative primary cutaneous T-cell-rich B-cell lymphoma in association with methotrexate treatment.

MALT lymphoma in patients with autoimmune diseases: a comparative analysis of characteristics and clinical course.

MALT lymphoma, especially of extragastric origin, is thought to be associated with an underlying autoimmune disease (AD) in a significant proportion of patients. No systematic assessment of the clinical characteristics of MALT lymphoma arising in AD as opposed to patients without AD has been performed so far. Therefore, all patients diagnosed and treated for MALT lymphoma at our institution have prospectively undergone routine clinical and serological assessment for AD since 1997. In total, 158 patients were available for analysis, and 61 out of 158 patients (39%) were diagnosed with an underlying AD. Patients with AD were predominantly women and significantly younger at lymphoma diagnosis (56 versus 67 years, P=0.004), with a significantly higher rate of extragastric lymphomas (P=0.012). Furthermore, lymphomas in these patients showed a lower frequency of trisomy 3 (P=0.04) and a significantly lower response rate to Helicobacter pylori eradication therapy in the case of gastric lymphomas (P=0.03). All other parameters including estimated median time to relapse were comparable between both groups. Our data suggest that patients with AD develop MALT lymphoma significantly earlier in life. The clinical course, however, does not appear to be adversely influenced by the presence of AD, as neither rate of relapse nor times to relapse or survival are significantly different.

Influence of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone on serologic parameters and clinical course in lymphoma patients with autoimmune diseases.

BACKGROUND: As patients with B-cell lymphomas suffering from an underlying autoimmune condition undergoing therapy with the CD20 antibody rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) offer the unique possibility of monitoring effects of therapy on various rheumatologic parameters, we have evaluated serologic autoimmune markers and the clinical outcome of patients with autoimmune diseases (ADs) who received lymphoma treatment with R-CHOP during the course of their disease. PATIENTS AND METHODS: We have retrospectively analysed 13 patients with non-Hodgkin's lymphoma who concurrently suffered from ADs and were treated with the R-CHOP regimen. Subjective parameters along with rheumatoid factor (RF) and antinuclear antibodies (ANA) were serially measured. RESULTS: The median levels of RF were 901 IU/ml [inter-quartile-range (IQR) 189-2520] before and 75 IU/ml (IQR 45-644) after therapy (P = 0.028). The median levels of ANA were 800 (IQR 140-2560) before and 100 (40-1280) after therapy (P = 0.027). Ten (77%) patients showed clinical improvement of their autoimmune symptoms, two (15%) reported no difference and one (7%) patient with rheumatoid arthritis-related worsening symptoms during therapy with R-CHOP. The autoimmune-related symptoms recurred after a median time of 7 weeks (IQR 6-8) in seven patients. In terms of lymphoma response, 11 patients achieved a complete remission and two a partial remission. CONCLUSIONS: This analysis indicates that R-CHOP given for lymphoma treatment is also effective for therapy of concurrent rheumatoid diseases. Both rheumatoid parameters as well as clinical symptoms showed a significant decrease during treatment with this immunochemotherapy. The effects on the rheumatic diseases, however, seem to be of limited duration.

Prognostic significance of molecular staging by PCR-amplification of immunoglobulin gene rearrangements in diffuse large B-cell lymphoma (DLBCL).

The prognostic value of the detection of peripheral blood (PB) and/or bone marrow (BM) involvement by polymerase chain reaction (PCR) amplification of rearranged immunoglobulin heavy chain (IgH) and immunoglobulin kappa light chain (Igkappa) genes was evaluated in 155 patients with diffuse large B-cell lymphomas (DLBCL). Immunoglobulin gene rearrangements (IgR) were detected in 35/155 (23%) patients. The presence of IgR in PB/BM was related to clinical stage (CS I-III vs CS IV; P<0.001), histopathological detection of BM involvement (P<0.001), and the International Prognostic Index (P<0.001). IgR-positive cases had a significantly lower complete remission (CR) rate (18/35, 51%) than IgR-negative patients (85/120, 71%; P=0.042), and a significantly poorer overall survival (OAS) at 5 years (25 vs 66%; P<0.001). There was a significant difference in the estimated OAS at 5 years between patients with negative BM histology and negative PCR results (66%), patients with negative BM histology but positive IgR (37%), and patients with positive BM histology (12%). Our results indicate that molecular methods improve the accuracy of staging in patients with DLBCL and define a group of patients with normal bone marrow histology who have a significantly poorer OAS due to molecular detection of PB/BM involvement.

Diffuse large B-cell lymphomas with plasmablastic/plasmacytoid features are associated with TP53 deletions and poor clinical outcome.

To define reproducible criteria for subgroups of diffuse large B-cell lymphomas (DLBCL), including lymphomas with plasmablastic/plasmacytoid features (PB/PC-Fs), we investigated 66 DLBCL; the samples were categorized as either centroblastic (CB), immunoblastic (IB) or PB/PC-F applying standardized morphologic criteria. Blinded specimens were reviewed by three independent pathologists. The final consensus classification included 44 CB (67%), seven IB (10%) and 15 PB/PC-F (23%). The interobserver agreement between two centers (Vienna, Würzburg) was 93.5%. Most PB/PC-F were CD20+, cIgM+, MUM-1+, CD138+/-, bcl-6-, corresponding to an activated B-cell phenotype. Immunoglobulin-V(H) gene mutation analysis was consistent with a germinal or postgerminal center-cell origin. By fluorescence in situ hybridization analysis, 11/13 (85%) PB/PC-F had a monoallelic TP53 deletion. The pretreatment characteristics of patients with PB/PC-F included a tendency for more B symptoms, extranodal disease and a higher IPI. Importantly, PB/PC-F were resistant to standard chemotherapy (complete remission rate 47%, relapse rate 71%) and even autologous stem-cell transplantation. The median overall survival (OS) (14 months, P<0.002) and disease-free survival (6 months, P=0.02) were significantly shorter compared to patients with CB and IB. The OS difference was pronounced within the low and low-intermediate IPI risk group (P<0.001). Our data indicate a strong association of plasmablastic/plasmacytoid morphology with TP53 deletions, poor response to chemotherapy and short survival.