A phase 2 study of ibrutinib maintenance following first-line high-dose methotrexate-based chemotherapy for elderly patients with primary central nervous system lymphoma.

BACKGROUND: Elderly patients account for nearly 70% of all primary central nervous system lymphoma (PCNSL) cases. They cannot tolerate aggressive treatment and have poor prognosis with a median overall survival (OS) of less than 2 years and progression-free survival (PFS) of 6-16 months. Ibrutinib penetrates the blood-brain barrier and has shown activity in PCNSL. METHODS: This prospective study investigated whether ibrutinib maintenance is feasible, and whether it can benefit elderly PCNSL patients in terms of expected 2-year PFS. It is an open label, phase 2 study in newly diagnosed PCNSL patients 60-85 years old who responded to first-line high-dose methotrexate (HDMTX)-based treatment with partial or complete response. Ibrutinib maintenance (560 mg/d) was continued until disease progression or intolerable toxicity. RESULTS: Twenty patients were enrolled, with a median age of 72 years (range, 61-80). Median time on ibrutinib maintenance was 12.5 (range, 2-46) months. Twelve patients stopped treatment: five due to central nervous system relapse and seven due to adverse events that were mainly grade 2. Five patients died (25%) all due to relapse. The 1- and 2-year PFS are 90% and 72.6%, respectively, and the 2-year OS is 89%. CONCLUSIONS: The study reached its primary end points and also showed that ibrutinib maintenance is tolerated reasonably well by the elderly. Therefore, this study supports the concept that ibrutinib maintenance should be further evaluated as an optional consolidation measure in the elderly.

Clinically Complex LRBA Deficiency Due to a Founder Allele in the Georgian Jewish Population.

Pathogenic variants in LRBA, encoding the LPS Responsive Beige-Like Anchor (LRBA) protein, are responsible for recessive, early-onset hypogammaglobulinemia, severe multi-organ autoimmunity, and lymphoproliferation, with increased risk for malignancy. LRBA deficiency has a wide clinical spectrum with variable age of onset and disease severity. Three apparently unrelated patients with LRBA deficiency, of Georgian Jewish descent, were homozygous for LRBA c.6640C > T, p.R2214*, leading to a stop upstream of the LRBA BEACH domain. Despite carrying the same LRBA genotype, the three patients differed in clinical course: the first patient was asymptomatic until age 25 years; the second presented with failure to thrive at age 3 months; and the third presented at age 7 years with immune cytopenias and severe infections. Two of the patients developed malignancies: the first patient was diagnosed with recurrent Hodgkin's disease at age 36 years, and the second patient developed aggressive gastric cancer at age 15 years. Among Georgian Jews, the carrier frequency of the LRBA p.R2214* allele was 1.6% (4 of 236 Georgian Jewish controls). The allele was absent from other populations. Haplotype analysis showed a shared origin of the mutation. These three patients revealed a pathogenic LRBA founder allele in the Georgian Jewish population, support the diverse and complex clinical spectrum of LRBA deficiency, and support the possibility that LRBA deficiency predisposes to malignancy.

Toxicity and efficacy of chimeric antigen receptor T-cell therapy in patients with diffuse large B-cell lymphoma above the age of 70 years compared to younger patients - a matched control multicenter cohort study.

Data regarding efficacy and toxicity of chimeric antigen receptor T (CAR-T) cell therapy in the elderly, geriatric population are insufficient. In 2019, tisagenlecleucel and axicabtagene-ciloleucel were commercially approved for relapsed/refractory diffuse large B-cell lymphoma. From May 2019 onwards, 47 relapsed/refractory diffuse large Bcell lymphoma patients, ≥70 years underwent lymphopharesis in three Israeli centers. Elderly (n=41, mean age 76.2 years) and young (n=41, mean age 55.4 years) patients were matched based on ECOG performance status and lactose dehydrogenase levels. There were no differences in CD4/CD8 ratio (P=0.94), %CD4 naive (P=0.92), %CD8 naive (P=0.44) and exhaustion markers (both HLA-DR and PD-1) between CAR-T cell products in both cohorts. Forty-one elderly patients (87%) received CAR-T cell infusion. There were no differences in the incidence of grade ≥3 cytokine-release-syndrome (P=0.29), grade≥3 neurotoxicity (P=0.54), and duration of hospitalization (P=0.55) between elderly and younger patients. There was no difference in median D7-CAR-T cell expansion (P=0.145). Response rates were similar between the two groups (complete response 46% and partial response 17% in the elderly group, P=0.337). Non-relapse mortality at 1 and 3 months was 0 in both groups. With a median follow-up of 7 months (range, 1.3-17.2 months), 6- and 12-months progression-free and overall survival in elderly patients were 39% and 32%, and 74% and 69%, respectively. EORTC QLQ-C30 questionnaires, obtained at 1 month, showed worsening of disability and cancer-related-symptoms in elderly versus younger patients. We conclude that outcomes of CAR-T cell therapy are comparable between elderly, geriatric and younger patients, indicating that age as per se should not preclude CAR-T cell administration. Longer rehabilitation therapy is essential to improve disabilities and long-term symptoms.

Polatuzumab-based regimen or CAR T cell for patients with refractory/relapsed DLBCL-a matched cohort analysis.

Polatuzumab (Pola)-based regimens and chimeric antigen receptor T (CAR T) cells provide superior outcome compared to conventional chemoimmunotherapy in patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). Choosing between these strategies remains controversial. The efficacy of CAR T versus Pola-rituximab(R) /Pola-bendamustine(B)-R in R/R DLBCL patients after failing ≥2 lines of treatment was compared in a retrospective, 'real-world' study. Propensity score matching, for age, lymphoma category (de-novo/transformed), number of prior lines, Eastern Cooperative Oncology Group performance status and lactate dehydrogenase level, was applied to control for differences in patients' characteristics. Response rate, progression-free survival (PFS) and overall survival (OS) were analyzed. A total of 82 patients, treated with CAR T (n=41) or Pola-based regimens (n=41), were included. No treatment-related deaths occurred with CAR T vs. 3 (7.3%) with Pola. The overall and complete response rates were 83% and 58% with CAR T vs. 66% and 44% with Pola-based-regimens (p=0.077 and p=0.18, respectively). At a median follow-up of 9 months (range 1-19.2) and 16 months (range 0.7-25.3) for the CAR T and Pola arm respectively, the median PFS has not been reached for CAR T vs. 5.6 months for Pola (95% CI 3.6-7.6, p=0.014). Median OS has not been reached for CAR T vs. 10.8 months (95% CI 2.2-19.4) for Pola (p=0.026). To conclude, in a real-world setting, treatment with CAR T achieved superior PFS and OS compared to Pola-based regimens in patients with R/R DLBCL.

Impact of contemporary regimens on the outcomes and toxicity of primary CNS lymphoma: a single-center retrospective analysis of 73 patients.

INTRODUCTION: Primary central nervous system lymphoma (PCNSL) is a rare disease with a dismal prognosis compared to its systemic large B-cell lymphoma counterpart. Real world data are limited, when considering a uniform backbone treatment. METHODS: A retrospective study of all adult patients treated sequentially with a high-dose methotrexate (HD MTX)-based regimen in a single tertiary medical center between 2003 and 2019. RESULTS: The 2015-2019 period differed from its predecessor in that most patients were treated with an HD MTX-based polychemotherapy regimen as opposed to HD MTX monotherapy (81% vs. 13%, P < .001), rituximab was given as standard of care (100% vs. 56%, P < .01), and most induction-responsive patients received consolidation treatment (70% vs. 18%, P = .01). The median progression-free and overall survival (OS) for the entire cohort (n = 73, mean age 64 years) was 9.9 and 29.8 months, respectively. Patients diagnosed between 2015 and 2019 had superior OS (P = .03) compared to those treated earlier. An interim partial response (PR) state, documented after two cycles of chemotherapy, was associated with increased incidence of progression, with only 33% of those patients achieving end-of-induction complete response. Twenty-three percent of patients developed thrombotic events and 44% developed grade 3-4 infections. HD MTX-based polychemotherapy induction was associated with both increase in thrombotic and infection incidence. CONCLUSIONS: Contemporary HD MTX-based combination therapies suggestively improved the outcomes for PCNSL, but at a cost of increased incidence of toxicity. Patients who achieve an interim PR status are at a high risk for treatment failure.

Characteristics and outcomes of adults with cytomegalovirus-associated thrombocytopenia: a case series and literature review.

Cytomegalovirus (CMV) is a ubiquitous virus that infects people worldwide. CMV is known to trigger thrombocytopenia, but this association is probably underdiagnosed since CMV infection in healthy adults is usually either asymptomatic or causes only mild symptoms. A systematic literature review was carried out and yielded 23 publications that reported 25 patients. All haematology centres in Israel were searched for adult immunocompetent patients with CMV-associated thrombocytopenia, and five new cases were identified. The median age of the combined 30 patients was 33 years (range 18-80), 73% were men, 77% presented with CMV-related symptoms, 48% had enlarged spleens, 95% had atypical lymphocytes in peripheral blood and 68% had elevated transaminase levels. The response rate to first-line steroid-containing regimens was only 31%, whereas 11 patients who were treated with an anti-CMV agent had a response rate of 82%. Moreover, four patients received thrombopoietin receptor agonists (TPO-RA) to which three (75%) responded. Taken together, these distinctive features of a case with thrombocytopenia should alert to CMV infection as the source. While steroids were effective in less than one-third of the cases, both anti-CMV therapy and TPO-RA exhibited excellent efficacy, suggesting that those agents should be introduced earlier in the therapeutic course.

Radiotherapy in mantle cell lymphoma: A literature review.

Mantle cell lymphoma (MCL) is a B-cell malignancy, comprising between 3% and 10% of all adult-onset non-Hodgkin lymphomas. MCL is considered incurable with current treatment modalities and most patients require multiple lines of treatment during their lifetime. MCL is very sensitive to radiotherapy (RT), even when delivered in low doses. In limited-stage MCL, RT can enable the de-escalation of systemic therapy. RT monotherapy is a valid option for frail patients. In advanced-stage disease, RT is very potent mode of palliation, even in heavily pretreated and chemo-resistant patients. Furthermore, it can provide a respite during which systemic treatment is unnecessary. In general, RT has a favorable toxicity profile and can be repeated as necessary for local relapse or distant disease. This effective, safe, and relatively inexpensive modality of therapy has been underutilized for patients with MCL. In this review, we will outline the use of RT for limited and advanced-stage disease and its potential application in combination with novel drugs.

Characteristics, management and outcome of DLBCL patients, presenting with simultaneous systemic and CNS disease at diagnosis: A retrospective multicenter study.

The incidence of systemic diffuse large B cell lymphoma (DLBCL) concurrently involving the central nervous system (CNS) at diagnosis, is very low and data regarding the clinical course of these patients are scarce. We investigated characteristics, efficacy of treatment regimens including consolidative autologous stem cell transplantation and outcome of patients presenting with concomitant systemic and CNS DLBCL. The records of 44 patients, diagnosed between 2004 and 2017, who fulfilled the inclusion criteria, were retrospectively reviewed. CNS involvement was diagnosed as solely parenchymal in 41%, solely leptomeningeal in 43%, and paranchymal with leptomeningeal in 11% of the patients. Induction regimens were anthracycline-based combined with high-dose methotrexate (HD-MTX) in 80% (n = 35) of patients, anthracycline-based combined with intrathecal MTX in 3, cytarabine-based (without antracyclines) in 2, HD-MTX in 1 and palliative in three. Five of 41 patients treated with chemotherapy died of treatment-related toxicity, all due to infections. Nineteen patients had consolidative autologous transplantation. Overall response rate following induction was 80% (complete responses 66% and partial responses 15%). All relapses (n = 11) occurred within less than 2 years. Within a median follow-up of 26.8 months, 3-years projected overall survival (OS) and progression free survival rates for the entire cohort were 56% ± 8.3 and 42% ± 8.9, respectively. In multivariate analysis, RCHOP-HD MTX-based induction [HR = 0.228, (0.054-0.964)], administration of 3.5 g/m2 MTX [HR = 0.735 (0.620-0.871)], and attaining CR following induction [HR = 0.185, (0.051-0.667)] predicted longer OS. RCHOP-HD MTX can provide prolonged remissions in DLBCL patients presenting with concomitant systemic and CNS involvement whereas role of autograft remains uncertain.

Toxicity and efficacy of autologous hematopoietic cell transplantation in elderly patients with aggressive lymphoma: a historical prospective study.

High-dose therapy followed by autologous hematopoietic cell transplantation (HCT) prolongs overall survival in patients under 65 years old with relapsed aggressive lymphoma. We aimed to explore the toxicity and efficacy of HCT in patients over 65 years with aggressive lymphoma compared with younger patients. We compared the transplantation outcomes between patients ≥ 65 years (n = 58) and 55-64 years (n = 44) with chemosensitive aggressive lymphoma (DLBCL, MCL and TCL) that underwent HCT between 1999 and 2016 in the Tel-Aviv Medical Center. The median age was 68 (range, 65-74) and 61 (range, 55-64) years, respectively. There were no differences in the incidences of grade 3-4 mucositis, documented infections and pulmonary complications between the two groups. There was no difference in the incidences of secondary malignancies, relapse (p = .26), non-relapse mortality, (p = .77) and overall survival (p = .53). Multivariate analysis revealed that smoking was a risk factor for non-relapse mortality, while partial remission and > 2 lines of treatment prior HCT were associated with higher risk for relapse. Psycho-socioeconomic score was associated with prolonged hospitalization after HCT and recurrent hospitalizations. We conclude that patients ≥ 65 years old with aggressive lymphoma, compared to younger counterparts, have similar transplantation outcome. Improving habits and psychosocial factors may further improve outcomes in these patients.

Medical Cannabis Use by Hodgkin Lymphoma Patients: Experience of a Single Center.

Hodgkin lymphoma (HL) is one of the most curable malignancies. Despite its effectiveness, chemotherapy is often associated with adverse events (AEs) such as nausea, anorexia, and impairment of general well-being. Our objective was to assess the extent of medical cannabis use among HL patients and evaluate its efficacy in controlling chemotherapy-related AEs. Patterns of medical cannabis use and efficacy were evaluated using physician-completed application forms, medical files, and patient-completed questionnaires, for all consecutive adult HL patients treated at the Tel-Aviv Medical Center between June 2010 and November 2016. One-hundred and thirty-three patients met the inclusion criteria. The median age of the cohort was 37 years, 53% were male, 46% were diagnosed at an early stage, and 88% achieved a complete response to treatment. Fifty-one patients (38%) used medical cannabis. There were no significant differences in baseline characteristics between cannabis users and nonusers. Cannabis users reported improvement in pain, general well-being, appetite, and nausea in 94, 87, 82, and 79% of cases, respectively. Importantly, 81.5% reported a high overall efficacy of cannabis in relieving symptoms. AEs related to cannabis use itself were mild. Thus, medical cannabis use is prevalent in this HL cohort, and appears to be effective in ameliorating chemotherapy-related AEs.

An unusual indication for splenectomy in hairy cell leukaemia: a report of three cases with persistent splenomegaly after chemoimmunotherapy.

We describe three cases of relapsed hairy cell leukaemia (HCL) treated with pentostatin plus rituximab. All three achieved bone marrow complete remission but had persistent splenomegaly and hypersplenism. Because of the clinical uncertainty of its significance, they were all splenectomized. The spleen histology showed no evidence of HCL, but a five-fold thickening of the splenic capsule and areas of fibrosis in the red pulp. This process may have contributed to the lack of elasticity and caused the persistent splenomegaly. We discuss the clinical implications for future patient management. The three patients remain in remission at 1 + , 5 + and 9 + years.

Knowledge and Practices Regarding Prevention of Central Venous Catheter Removal-Associated Air Embolism: A Survey of Nonintensive Care Unit Medical and Nursing Staff.

INTRODUCTION: Air embolism is a potentially serious complication of central venous catheter (CVC) use. While CVC insertion is usually performed by a trained specialist, extraction is frequently the responsibility of junior staff members. This complication can be easily prevented by following several simple measures described in common guidelines. AIM: We conducted a single-center survey to assess knowledge and practices concerning the prevention of air embolism associated with CVC removal among healthcare workers from nonintensive care units. METHODS: The correct answers to the questionnaire were determined according to best-practice recommendations for CVC removal. Based on a comparison of the total sum of correct answers between the categories of groups, factors that predicted the level of knowledge were identified using an independent sample t test. RESULTS: Of the 156 respondents, one-third were unfamiliar with air embolism as a complication of CVC extraction. Almost 80% were unaware of the existence of a CVC removal protocol. Almost half of respondents did not follow guidelines regarding patient position when removing a CVC, 72% did not ask the patient to perform the Valsalva maneuver during the procedure, and 54% did not ask the patient to remain supine after the procedure. Adherence to the protocol was correlated with professional experience, with a lower level among those with experience of less than 1 year and, particularly, among interns. CONCLUSIONS: Our survey revealed inappropriately low awareness of CVC removal-associated air embolism risk and low familiarity with CVC removal best-practice recommendations among nonintensive care unit healthcare workers. Staff members with experience of less than 1 year, including interns, were found to have a lower level of knowledge. These findings emphasize the importance of development and distribution an internal hospital protocol and the integration of educational intervention into a preliminary internship program.

Myxedema Coma-associated Pancytopenia: A Case Report.

Pancytopenia is defined as a reduction in red blood cells, white blood cells, and platelets, and can pose as a diagnostic challenge due to the multitude of causes. Myxedema coma is the manifestation of severe untreated hypothyroidism. This case report presents a rare instance of myxedema coma-associated pancytopenia in a 53-year-old man with a history of untreated hypothyroidism. The patient presented with altered mental status and vital instability, and on further workup was found to have pancytopenia. During his hospital stay his symptomatic hypothyroidism was identified, and he was treated with intravenous levothyroxine, hydrocortisone, and supportive care. The patient's clinical status improved gradually, with normalized blood counts upon discharge. This case underscores the significance of considering myxedema coma in the differential diagnosis of pancytopenia, especially in older patients with limited healthcare access. Increased awareness of this association can aid clinicians in timely diagnosis and management, preventing potential complications associated with untreated hypothyroidism.

Addition of Nivolumab Tailored by Expansion of CAR-T Cells in Patients with Stable/Progressive Large B Cell Lymphoma at Lymphodepletion-A Phase 2, Prospective Interventional Study.

Patients with large B-cell lymphoma (LBCL) in stable or progressive disease (SD/PD) at lymphodepletion prior to chimeric antigen receptor T cell (CAR-T) therapy have an inferior outcome. we hypothesized that enhancing in-vivo expansion of CAR-T cells could overcome this grim prognosis leading to improved outcomes. We conducted a phase 2 prospective trial (NCT05385263) investigating the addition of nivolumab to enhance CAR-T cell expansion and response in patients with SD/PD-LBCL. Eligible patients received 1 dose of nivolumab between day +5 and +9 post CAR-T infusion. An additional dose of nivolumab was administered on day +19 only to patients whose CAR-T cell levels in peripheral blood were below 100 cells/µL at day +7. Twenty patients were enrolled and received anti-CD19 CAR-T (Axicabtagene ciloleucel, n = 12; tisagenlecleucel, n = 8). Eight were ineligible to receive nivolumab due to active CAR-T-associated toxicities. Overall, the protocol was safe. One-month PET-CT showed an 84% overall response rate (complete response, 53%). The cumulative incidence of progression-free survival at 6 and 12 months were 50% (95% CI 36%-64%) and 42% (95% CI 26%-58%), respectively. The cumulative incidence of overall survival at 6 and 12 months were 85% (95% CI 72%-98%) and 51% (95% CI 31%-71%), respectively. Nivolumab administration significantly reduced PD-1 expression on all immune cells. CAR-T cell expansion was similar between nivolumab-eligible and noneligible patients. Notably, there was a significant enrichment of CD45RO-CD27+ CD8+ cells and CD45RO-CD27+ CD8+ CAR-T cells in the nivolumab-eligible group compared to those ineligible, suggesting that specific cell enrichment could potentially contribute to an enhanced response rate. We conclude that the addition of nivolumab based on CAR-T cell expansion in patients with SD/PD-LBCL is safe and yields promising early response rates.

JAK2 mutation: an aid in the diagnosis of occult myeloproliferative neoplasms in patients with major intraabdominal vein thrombosis and normal blood counts.

BACKGROUND: Janus kinase-2 (JAK2) is mutated in a high proportion of patients with polycythemia vera and in a smaller number with essential thrombocythemia and primary myelofibrosis. Mutated JAK2 is an important diagnostic marker for myeloproliferative neoplasm (MPN) and may also play a major role in the pathogenesis of MPN. OBJECTIVES: To evaluate the prevalence of mutated JAK2 (JAK2-V617F) among patients with major intraabdominal vein thrombosis who had normal blood counts at diagnosis of the initial event. METHODS: The medical records of patients who presented with a major intraabdominal venous thrombosis and normal peripheral blood counts were obtained. JAK2-V617F mutation status was determined by real-time polymerase chain reaction. RESULTS: Twenty-two patients were available for this analysis and 9 (41%) were found to have JAK2-V617F. Patients with positive JAK2-V617F were younger and had more frequent clinical splenomegaly than those with wild-type JAK2. CONCLUSIONS: A high proportion of patients presenting with "idiopathic" major intraabdominal vein thrombosis and normal blood counts carry JAK2-V617F. We recommend searching for the mutation in this clinical setting to detect patients with occult MPN.

Lymphoproliferative disease detected by breast cancer screening.

OBJECTIVE: To determine the rate of lymphoproliferative disease (LPD) in women undergoing routine breast cancer screening (BCS). BCS can reveal pathologies other than carcinoma that involve the breast and lymph tissue. The few studies that have described cases in which BCS led to the diagnosis of LPD were based on small series and focused on imaging rather than clinical characteristics. SETTING AND METHODS: A multi-center retrospective study in Israel, investigating LPD rate and characteristics among women diagnosed with LPD via BCS. RESULTS: Thirty-four patients out of 14,400 consecutive women undergoing BCS at Tel Aviv Sourasky Medical Center during the study period were diagnosed with LPD, suggesting a diagnosis rate of 0.24%. The enlarged cohort (n = 45), including 11 patients that were retrieved from the databases of three other centers, demonstrates a predominant histological diagnosis of non-aggressive LPD (n = 33). Thirty-four (76%) had a suspicious axillary lymph node, and 11 had a breast lesion. The median maximal lesion size was 1.95 cm (range 0.8-6.5). Disease was localized in 60% of patients (stage 1 and 1E). Univariate analysis revealed that lymphocyte count was inversely associated with aggressive histology. At median follow-up of 39 months, all but three patients were alive. These three had been diagnosed with non-aggressive LPD which had never been treated and died from unrelated causes. CONCLUSIONS: The LPD detection rate via BCS was 2.36 per 1000 screens. The majority of LPDs were non-aggressive. Nearly a third were aggressive, most detected at an early stage, and the clinical outcome was generally favorable.

Lower Patient Anxiety and Unchanged Levels of Adherence to Hemato-Oncologic Treatment in Response to New Measures to Reduce Hospital Exposure Risk to COVID-19.

OBJECTIVE: Hemato-oncology patients are at high risk for morbidity and mortality from coronavirus disease (COVID-19). The resultant heightened anxiety among these patients may negatively affect adherence to therapy and treatment-related outcome. We aimed to assess whether the adoption of precautionary measures provided by the medical team led to a reduction in COVID-19-related anxiety and, consequently, to successful execution of treatment plans. METHODS: All adult hemato-oncology patients actively treated or being followed-up at the outpatient service at Tel Aviv Sourasky Medical Center between March 25 and May 3, 2020, were invited to answer a questionnaire that focused on their anxiety and adherence to treatment following new measures to reduce risk of infection during the first COVID-19 outbreak. RESULTS: One hundred and fifty patients (representing 24% of those being approached), average age 67 years, 52% male, and 57% undergoing antineoplastic therapy, responded to the survey. The introduction of precautionary measures resulted in a significant reduction in anxiety level in all patients, irrespective of age, sex, or treatment status. Attendance to scheduled visits in day care and outpatient clinics remained unchanged. Adherence to planned blood and imaging tests were 81% and 73%, respectively, and 93% of the patients were satisfied with their medical care. Thirty-two percent of patients used telemedicine. Satisfaction with telemedicine was highest among non-actively treated patients and those experiencing high anxiety levels. CONCLUSION: Reorganization of the hemato-oncology unit and provision of information to patients reduced COVID-19-related anxiety and enabled the same delivery of therapy as that prior to the pandemic.