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Belantamab mafodotin, an immuno-conjugate targeting B-cell maturation antigen, showed single-agent activity in phase 1 and 2 studies, and was recently approved for heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients. Real-world data and long-term follow-up are scarce. We conducted a multisite retrospective study aimed to assess safety and efficacy of belantamab mafodotin monotherapy administered via the GSK expanded access compassionate care programme. One-hundred and six RRMM patients were treated with belantamab mafodotin between July 2019 and March 2021. The median age was 69.4 years. Patients were heavily pretreated with a median of six (range 2-11) prior therapy lines. Major adverse effects included ocular toxicity (keratopathy 68.4%, grade ≥3: 40.5%; blurred vision 36.8%, grade ≥3: 6.3%), thrombocytopenia (27.4%, grade ≥3: 17.9%) and infections (11.3%, grade ≥3: 7.5%). Median follow-up time was 11.9 [95% confidence interval (CI) 10.0-13.8] months. Overall response rate was 45.5%. Median progression-free survival was 4.7 (95% CI 3.5-5.9) months in the entire cohort and 8.8 (95% CI 6.6-10.9) months among responders. Median overall survival was 14.5 (95% CI 9.5-19.6) months, and not reached for responders. To conclude, in a real-world setting, belantamab mafodotin monotherapy showed efficacy comparable with the prospective clinical trials, with a tolerable toxicity profile.

Autoimmune manifestations are known to occur in patients with chronic lymphocytic leukemia (CLL) and of these hemolytic anemia and immune thrombocytopenia are the most well recognized. Autoimmunity may also be triggered by some of the therapeutic agents used like purine analoges and these events may sometimes be severe and even fatal. Non-hematological autoimmune stigmata occur far less frequently and are rarely encountered. Here we report a 59 year-old-woman, with CLL, who complained of recurrent headache starting 1 month after completing 6 cycles of fludarabine, cyclophosphamide, and rituximab combination therapy. Computed tomography scan of the brain showed a contrast enhancing lesion of 1 cm in diameter, with surrounding edema in the right frontal lobe. Brain MRI revealed ring enhancing lesions in the right frontal lobe and some additional small lesions in the left parietal lobe. Brain biopsy showed an inflammatory demyelinating lesion, not associated with JC virus. The patient subsequently improved after steroid therapy. Currently, after 2 years of follow-up, she remains in complete hematologic remission, has no neurological deficits, and is carefully followed by a team of neurologists and hematologists. Treating physicians should be aware of this rare autoimmune inflammatory demyelinating lesion which can occur in patients with CLL during the course of treatment and that may be linked to treatment with purine analogues like fludarabine.

OBJECTIVE To evaluate disease characteristics and long-term outcomes in patients requiring second-line treatment following fludarabine, cyclophosphamide, and rituximab (FCR), for relapsed/refractory disease (R/R), or following discontinuation due to toxicities. METHOD A retrospective analysis of 126 chronic lymphocytic leukemia patients treated with frontline FCR: 63 received second-line treatment (41 relapsed, nine refractory [SD/PD], 13 prior toxicity). Time to next treatment (TTNT) was calculated from beginning FCR to initiation of second-line therapy. Overall and event-free survival was calculated from initiation of salvage treatment (OS2/EFS2). RESULTS Median follow-up for the entire cohort was 67 and 37 months from second-line therapy. TTNT

Decreased absolute lymphocyte counts (ALCs) following frontline therapy for chronic lymphocytic leukemia may be associated with disease control, even in patients without evidence of minimal residual disease. We studied the prognostic significance of ALCs during the first year following treatment with fludarabine, cyclophosphamide, and rituximab (FCR). We evaluated 99 patients who achieved a partial response without lymphocytosis ( 1.8 vs not reached for ALC ≤ 0.7 at 9 months, P

Summary This multicentre study evaluated 5-year progression-free (PFS) and overall survival (OS) in early and advanced Hodgkin lymphoma (HL), where therapy was individualized based on initial prognostic factors and positron emission tomography-computed tomography performed after two cycles (PET-2). Between September 2006 and August 2013, 359 patients aged 18–60 years, were recruited in nine Israeli centres. Early-HL patients initially received ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) ×2. Depending on initial unfavourable prognostic features, PET-2-positive patients received additional ABVD followed by involved-site radiotherapy (ISRT). Patients with negative PET-2 and favourable disease received ISRT or ABVD ×2; those with unfavourable disease received ABVD ×2 with ISRT or, alternatively, ABVD ×4. Advanced-HL patients initially received ABVD ×2 or escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone; EB) ×2 based on their international prognostic score (≤2 or ≥3). PET-2-negative patients further received ABVD ×4; PET-2-positive patients received EB ×4 and ISRT to residual masses. With a median follow-up of 55 (13–119) months, 5-year PFS was 91% and 69% for PET-2-negative and positive early-HL, respectively; 5-year OS was 100% and 95%, respectively. For advanced-HL, the PFS was 81% and 68%, respectively (P = 0·08); 5-year OS was 98% and 91%, respectively. PET-2 positivity is associated with inferior prognosis in early-HL, even with additional ABVD and ISRT. Advanced-HL patients benefit from therapy escalation following positive PET-2. EB can be safely de-escalated to ABVD in PET-2-negative patients.

In recent years, there have been major advances in the treatment of chronic lymphocytic leukemia (CLL) particularly since the development of novel therapeutic agents, mostly “biological drugs.” One of the obvious advantages of these agents is the decreased rate of infectious complications occurring during the course of therapy, compared to the use of standard immuno-chemotherapy regimens. Here, we describe 3 patients with CLL and 1 with mantle cell lymphoma who developed severe life-threatening pneumonias, during monotherapy with ibrutinib. The first case was a 70-year-old woman with relapsed CLL who developed bilateral pneumonia with hypoxia 1 week after starting ibrutinib. She did not respond to broad-spectrum antibiotics and was treated empirically with trimethoprim-sulphamethoxazole and improved. In the second case, we describe a 76-year-old woman with relapsed CLL who developed recurrent pneumonia after 3 years of treatment with ibrutinib. Presuming that ibrutinib was the cause of pneumonitis with secondary infection, it was stopped with subsequent improvement. The third patient a 67 year-old man died because of severe bilateral necrotizing pneumonia due to invasive aspergillosis and mucormycosis with pulmonary hemorrhage. The fourth patient with relapsed mantle cell lymphoma died because of severe bilateral pneumonia, caused by pseudomonas and candida, despite receiving appropriate antibiotics. From this experience, we hypothesize that the etiology of severe pneumonia associated with ibrutinib treatment is probably multifactorial, involving factors like preexisting immune-suppression, drug induced pneumonitis and infections. We suggest that patients with CLL or other lymphoproliferative disorders with suspected pneumonia during monotherapy with ibrutinib should be very carefully evaluated and need to undergo complete diagnostic workup to establish an exact diagnosis. Understanding which patients with CLL or lymphoma treated with kinase inhibitors are at a higher risk for developing pulmonary complications could be one of the important future challenges, when selecting the best available therapy for these patients.

Several studies have demonstrated the prognostic value of neutrophil-lymphocyte ratio (NLR) in patients with solid tumors and non–Hodgkin lymphoma. In contrast, there is only sparse data on its prognostic role in patients with classical Hodgkin lymphoma (cHL). The aim of our study was to establish whether NLR could serve as an independent prognostic factor in a cohort of 990 patients with nodular sclerosis (NS)-cHL. After analysis of the log hazard ratio (HR) as a function of NLR, we chose the value 6 as cutoff. Patients with NLR >6 had a worse progression-free survival and overall survival compared to those with NLR ≤6; 84% vs 75% and 92% vs 88%, at 5 years, with an HR of 1.65 and 1.82, respectively. Multivariate analysis showed that the risk remained high with HR 1.44 and HR 1.54 in progression-free survival and overall survival, respectively. In summary, our study shows that NLR is a robust and independent prognostic parameter in NS-cHL, both in early and advanced disease. It is inexpensive and simple to apply. Thus, we conclude that NLR, possibly in combination with the international prognostic score and absolute monocyte count, is a useful guide for physicians treating NS-cHL patients.

Previous studies have shown an increase risk of second malignancies after non-Hodgkin's lymphoma (NHL), which is probably related to a combination of factors including genetic predisposition, molecular background, host immunological status and therapy administered. Here, we determined the incidence of NHL and risk of second solid tumours and haematological malignancies among survivors of NHL diagnosed in Israel during 1980-2011. Data were collected from the records of the Israeli National Cancer Registry. The total cohort of 24 666 NHL-patients included 22 601 Jews and 2065 Arabs. Median age of diagnosis for Jews was 61.3 years and 48.2 for Arab patients. Of the Jews with NHL, 11 265 (50%) were of European-American origin, 5005 (22%) Asian or African and 6114 (27%) were born in Israel. Second cancers were recorded in 2010 NHL survivors, 1918 Jews and 92 Arabs, representing a rate of 8.5%, and 4.5% o, respectively. Second malignancies in all recorded sites were more frequent than in the general population, with a standardized incidence ratio (SIR) of 1.28 for Jewish men, 1.25 for Jewish women, 1.73 for Arab men and 1.98 for Arab women. This higher risk was even more pronounced for the 309 cases with secondary haematological malignancies (secondary haematological malignancies of 1.97, 1.81, 4.48 and 4.15, respectively). Our findings show that there is an increased risk of second malignancies occurring after diagnosis of NHL in Israel, particularly for haematological malignancies such as leukaemia and NHL. The differences we report in the incidence of NHL and the types of second malignancies occurring among Jews and Arabs suggest that ethnicity and genetic susceptibility may be important relevant risk factors. Copyright © 2016 John Wiley & Sons, Ltd.

BACKGROUND Primary splenic diffuse large B-cell lymphoma (PS-DLBCL), an uncommon type of non-Hodgkin lymphoma, has been investigated only in small patient series before the rituximab era. The therapeutic role of splenectomy in addition to immunochemotherapy is unknown. METHODS The databases of 7 medical centers in Israel were searched for patients diagnosed with PS-DLBCL in 1982-2013, and clinical, treatment, and outcome data were collected for 87 patients. The mean patient age was 59.6 years; 57.5% were male. RESULTS Patients presented with abdominal pain (81%), B symptoms (59%), splenomegaly (84%), splenic masses (97%), and high lactate dehydrogenase (LDH) levels (84%); 61% had stage I or II disease. The diagnosis was made with core-needle biopsy in 46 patients and with diagnostic splenectomy in 39 patients. Eighty patients (92%) were treated with cyclophosphamide, doxorubicin, vincristine, and prednisone; 68 (78%) received rituximab. A complete response was achieved in 67 patients (77%), and a partial response was achieved in 8 (9%). At 5 years, the overall survival (OS) rate was 77%, and the progression-free survival (PFS) rate was 67%. When patients were stratified by splenectomy at diagnosis, the OS rates were 91% for splenectomized patients and 68% for nonsplenectomized patients (P = .08), and the PFS rates were 85% and 55%, respectively (P = .02). The respective values for the subgroup with early-stage disease were 96% and 63% for OS (P = .009) and 90% and 51% for PFS (P = .01). In a multivariate analysis, a low Eastern Cooperative Oncology Group performance status and splenectomy independently predicted better PFS (P

Richter's syndrome (RS) is the rare development of an aggressive lymphoid malignancy in a patient with pre-existing chronic lymphocytic leukemia (CLL). Data on RS is sparse and mostly derived from case reports or small series of patients and only a few larger cohorts have been published. The purpose of this large retrospective study was to summarize our national experience with RS in CLL, examine possible risk factors, and analyze relevant demographic, laboratory and clinical parameters, including results of therapy and outcome. We first evaluated data obtained from 119 patients with RS diagnosed during 1971–2010 from 12 medical centers in Israel. The final cohort summarized consisted of 81 patients with RS who developed only diffuse large B-cell lymphoma (DLBCL) after exclusion all cases with insufficient data and those who were not DLBCL. Median overall survival from time of diagnosis of RS was 8 months; after applying the Richter score, patients could be stratified into three prognostic groups, while all other clinical and laboratory parameters evaluated had no prognostic significance. Prior therapy for CLL had no impact on RS survival (P = 0.8) and patients with therapy “naive” RS and those who had already received chemotherapy prior to developing RS, had the same survival. The addition of rituximab to chemotherapy for RS improved 2 years overall survival from 19% in the chemotherapy alone arm to 42% (P value of 0.001). Although prognosis of patients with RS remains dismal, this retrospective observation provides support for the use of chemo-immunotherapy in DLBCL-RS. Am. J. Hematol. 89:E218–E222, 2014. © 2014 Wiley Periodicals, Inc.

Objectives Hypogammaglobulinemia, commonly encountered in chronic lymphocytic leukemia (CLL), is one of the main causes of morbidity and mortality; however, its prognostic significance in patients diagnosed in early stages of disease remains uncertain. The aim of this study was to evaluate the predictive power of hypogammaglobulinemia at Bonet stage A. Methods Using the database of the Israeli CLL Study Group, we analyzed the relationship between low serum levels of IgG, IgA, and IgM; the presence of paraproteinemia, as well as other well-recognized prognostic markers in CLL; and time to first treatment (TTT) and overall survival. A total of 1113 patients consecutively diagnosed during the last 25 yrs with Binet stage A CLL were evaluated, and baseline information on serum immunoglobulin levels was found in 857 of the cases. Results Overall survival times correlated with age >65 yr, male gender, the presence of lymphadenopathy, high serum beta 2-microglobulin (b2m), CD38 and ZAP-70 expression, but not with low levels of immunoglobulin or the presence of paraproteinemia. By univariate analysis, patients with low IgA levels had a shorter TTT; however, on multivariate analysis, the presence of lymphadenopathy (P 0.02), b2m (P 0.04), CD38 (P

Myeloproliferative neoplasms (MPNs) are malignant disorders originating from clonal expansion of a single neoplastic stem cell and characteristically show an increase in bone marrow reticulin fibers. Lysyl oxidases (LOXs) are copper-dependent amine oxidases that play a critical role in the biogenesis of connective tissue by crosslinking extracellular matrix proteins, collagen and elastin. Expression of LOX gene family members is increased in disorders associated with increased fibrosis. To evaluate involvement of LOX gene family in various MPNs. In-situ hybridization was used to detect Lysyl-Oxidase family members in bone marrow biopsies from patients with different MPNs. We compared normal bone marrows and those from patients with polycythemia vera, essential thrombocythemia, chronic myeloid leukemia, and primary myelofibrosis (PMF). Serum levels of lysyl-oxidase from patients with PMF and healthy controls were also examined. LOX gene family was not detected in normal bone marrows. All members of the LOX gene family were over expressed in PMF. In other MPNs a differential pattern of expression was observed. Differences in gene expression were statistically significant (P < 0.010). The medianserum LOX levels in normal controls was 28.4 ± 2.5 ng\ml and 44.6 ± 9.44 ng\ml in PMF (P = 0.02). The varying pattern of expression of LOX genes may reflect differences in the pathophysiology of bone marrow fibrosis in these MPNs. These observations could be used as the basis for future targeted therapy directed against bone marrow fibrosis.

BACKGROUND: Bone marrow (BM) biopsies from patients with chronic lymphocytic leukemia (CLL) may show reticulin fibrosis at diagnosis, but its significance remains unclear. This study sought to assess the prognostic impact of BM reticulin fibrosis in patients with previously untreated CLL. METHODS: Data was reviewed from untreated CLL patients in the national Israel CLL database, followed during 1987 to 2012. All bone marrow biopsies were graded for reticulin fibrosis using a modified scoring system containing 4 grades (0-3), based on the European consensus report. Grade of reticulin fibrosis was correlated with overall survival (OS), outcome, and a number of well-recognized prognostic factors for CLL. RESULTS: The final cohort included 176 patients (122 males and 51 females). Median age was 63 years (range, 32-86 years) and the 5-year OS was 77.1%. Grade of BM reticulin fibrosis correlated with OS (P < .0001) and mortality (P = .001), and separated patients into 2 groups with different survival curves. Advanced reticulin fibrosis (grades 2-3) was associated with thrombocytopenia (platelet counts of < 100,000/mm3) (P = .025), anemia (P = .018), elevated β2-microglobulin < 4000 μg/mL (P = .048), and the presence of 11q deletion (P = .0015). CONCLUSIONS: There was a significant correlation between poor survival and grade of BM reticulin fibrosis. This staining procedure is easy to perform and can readily be added routinely when examining BM biopsies in CLL, because the findings do have prognostic implications. Cancer 2013. © 2013 American Cancer Society.

Some patients with lymphoma have monocytosis at diagnosis, but its significance is unclear. The recently recognized subpopulation, monocytic myeloid-derived suppressor cells (M-MDSCs), has immunoregulatory function, suppresses host anti-tumour immunity and plays a role in cancer tolerance. Data from 91 untreated patients with diffuse large B-cell lymphoma (DLBCL) were evaluated for monocytosis >1000/mm(3) at diagnosis and its significance compared with a number of well-established prognostic factors for DLBCL including age, stage, gender, B symptoms, extranodal sites, LDH and CRP levels, bone marrow involvement and International Prognostic Index (IPI) score. In 23 of these patients with DLBCL and 15 healthy controls, the proportion of M-MDSCs in the peripheral blood was determined by flow cytometry. Monocytosis was found in 17.6% of the patient cohort examined. In the multivariate analysis, bone marrow involvement, IPI score and monocytosis were the only independent prognostic factors seen to be associated with decreased progression free and overall survival. Patients with DLBCL had on average increased M-MDSCs counts at diagnosis compared with controls, which returned to normal after achieving remission. In conclusion, monocytosis was identified as an independent prognostic factor in DLBCL and correlated with worse overall survival. The significant increases in the M-MDSCs pool observed in some of the cases examined may possibly help to explain why monocytosis is associated with poor outcome in these patients.

Summary Merkel cell carcinoma (MCC) is a rare aggressive skin tumour that appears to be associated with a large number of other tumours. We collected all reported cases in Israel and estimated its association with other tumours, including haematological malignancies. The population based Israel Cancer Registry identified 335 patients with MCC diagnosed between1989 and 2010. Ninety-seven percent were in the Jewish population; median age at diagnosis for Jewish patients was 73·4 and 55·6 years for the Arab population. Other associated malignancies were encountered in 92 patients (27·4%) with MCC (90 Jews, two Arabs). Of the Jewish cases, 66 presented with an associated malignancy before, and 24 after, the diagnosis of MCC. Solid tumours were not significantly increased among patients with MCC. Thirty-one of these associated cancers (34·4%) were haemato-oncological malignancies, 24 were detected before and seven after the diagnosis of MCC. The standardized incidence ratio (SIR) for haematological malignancy was 3·67 for males and 3·62 for females, and the most frequent haemato-oncological neoplasias recorded were chronic lymphocytic leukaemia (45%) and lymphomas (29%). Although MCC is rare, clinicians should be aware of the possible association with B-cell lymphoproliferative disorders when evaluating patients with neuroendocrine skin tumours.

Budd-Chiari syndrome (BCS) is characterized by hepatic venous outflow obstruction, which sometimes may be life threatening, with the development of fulminant hepatic failure. In cases of this kind, the most frequent underlying cause of BCS, myeloproliferative neoplasms (MPN), should always be excluded first, and molecular analysis of the Janus Kinase 2 (JAK2) mutation must always be performed [1]. While the association of BCS with polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis is well documented, hypereosinophilia has only been described in sporadic cases [2–7]. Furthermore, Jak2 mutation in association with hypereosinophilia has been reported very rarely and its prevalence in this disorder still requires further investigation [8,9]. To the best of our knowledge, cases with the above association occurring together with BCS have not been reported until now. Here, we describe a young woman presenting with idiopathic eosinophilia, JAK2 mutation, and BCS. We also elaborate briefly on the biological mechanism and clinical features of this rare entity. In our opinion, this case supports the formal inclusion of hypereosinophilic syndrome (HES) in the WHO MPN category and also raises the possible pathogenetic contribution of eosinophils, or their products, in MPN-associated splanchnic vein thrombosis.