This study aimed to examine the perceived challenges and attitudes toward home-based treatment for hematology and hemato-oncology patients among physicians and nurses. A qualitative study was conducted based on 23 semistructured interviews with physicians (n = 11) and nurses (n = 12) from eight hospitals across Israel. The participants were recruited using opportunistic sampling, and the interviews were analyzed thematically using an inductive reflexive thematic analysis approach. Data saturation was achieved. Three overarching themes emerged: (1) the hospital as a safe haven: the conflict between hospital safety and the benefits of home treatment; participants emphasized the importance of hospital-based monitoring and expressed concerns about patient safety in home settings; (2) building a well-functioning home treatment system vs. fearing loss of control; while envisioning an organized, hospital-led model, participants stressed the need for trained staff, dedicated coordination, and clinical oversight; and (3) balancing costs, risks, and institutional support; participants highlighted financial disincentives, infrastructure gaps, and the role of professional trust in promoting patient acceptance. Although healthcare professionals recognize the potential benefits of home-based treatment, their support is contingent upon robust clinical protocols, institutional alignment, and clear coordination mechanisms. These findings underscore the central role of provider engagement in advancing safe and sustainable models of home care for hematology and hemato-oncology patients. The study offers practical insights that will assist in implementing health policies, developing clinical programs, and organizational planning for the safe and sustainable implementation of nonpalliative home care in hematology and hemato-oncology.

Introduction Venetoclax-based therapy has significantly altered the treatment landscape for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), demonstrating substantial efficacy in pivotal clinical trials such as CLL14 and MURANO. Nevertheless, real-world data are crucial for assessing treatment effectiveness, tolerability, and outcomes across diverse patient populations. This report presents interim findings from the prospective, observational REVEAL study, which evaluates real-world outcomes of venetoclax-based therapies in treatment-naïve (TN) and relapsed/refractory (RR) CLL/SLL patients in Israel. Methods The REVEAL study enrolled adult CLL/SLL patients initiating venetoclax-based regimens across 13 Israeli centers since February 2019. This interim analysis includes data from 304 patients (TN=154, RR=150) up to September 2024. Study endpoints encompassed clinical overall response rate (ORR), complete response (CR), progression-free survival (PFS), overall survival (OS), minimal residual disease (MRD) negativity measured in peripheral blood, and safety. Results Median ages at treatment initiation were 68 years (TN) and 70 years (RR). High-risk genetic features were more frequent in RR patients: del17p (TN 8.9%, RR 25%), TP53 mutations (TN 7.3%, RR 23%), unmutated IGHV (TN 64%, RR 80%). RR patients received a median of one prior therapy, with 44.7% previously treated with B-cell receptor inhibitors (BCRi). Most patients received venetoclax with anti-CD20 antibodies (TN: 95% obinutuzumab; RR: 73% rituximab, 10% obinutuzumab, 16% monotherapy). Median treatment durations were 12 months (TN) and 22 months (RR). In the TN cohort, the 12-month ORR was 98%, with a CR rate of 75%. After a median follow-up of 24 months, the median PFS was not reached, with a 3-year PFS of 83%. TN patients receiving a full dose of venetoclax (weighted average dose >80% of 400 mg) had a superior 2-year PFS compared to those on a reduced dose (93% vs. 71%, p=0.014). In TN patients, the 12-month MRD negativity at 10-4 was 90% and at 10-5 was 71%. The median OS was not reached for TN patients, with a 3-year OS of 86%. In the RR cohort, the 12-month ORR was 95%, with a CR rate of 64%. The median PFS for RR patients was 50.6 months, notably shorter with Del17p/TP53 mutations (24.7 months vs. median not reached, p=0.001). RR patients treated with venetoclax + rituximab or venetoclax monotherapy had a median PFS of 50.6 months and 13.2 months, respectively. For the RR patients treated with venetoclax + obinutuzumab (n=15), the median PFS was not reached. There was a significant difference between the 3 treatment regimens (p<0.001). Within the BCRi-exposed patients, those who progressed had a PFS of 20.5 months vs. 41.3 months for those intolerant to BCRi (p=0.049). In the RR cohort, full dose venetoclax showed better PFS with median PFS of 51.7 months vs. 41.3 months (p=0.045). In RR patients, 12-month MRD negativity (MRD5/MRD4 vs. MRD positive) was significantly correlated with better PFS (p=0.023). The median OS for RR patients was not reached, with a 3-year OS of 75%. Venetoclax monotherapy and prior BCRi exposure were significantly associated with an increased mortality risk compared to combination regimens (HR [95%CI] 3.7 [1.9, 7.6]) and BCRi-naïve patients (HR [95%CI] 2.22 [1.1, 4.5]). In a multivariable analysis with covariates Del(17p)/TP53, prior therapies, treatment regimen and BCRi exposure, the significant predictors of shorter PFS were: Del(17p)/TP53 (HR [95%CI]: 2.4 [1.3, 4.3]), number of prior therapies (1.6 [1.2, 2.0]) and venetoclax monotherapy vs. venetoclax + obinutuzumab (5.0, [1.1,22.1]), in RR patients. Serious adverse events (AEs) occurred in 45% of TN and 57% of RR patients, with neutropenia the most common Grade ≥3 event (TN: 23%, RR: 28%). Treatment was discontinued due to AEs in 9.7% of TN and 19% of RR cases, mainly due to neutropenia and infections. Infections were also the leading cause of death (TN:8/16, 50%, RR:10/34, 29%). Conclusions The REVEAL study confirms the real-world effectiveness and safety of venetoclax-based therapy in CLL, aligning with clinical trial data. In the relapsed/refractory (R/R) cohort, PFS was particularly favorable with venetoclax plus obinutuzumab. Our findings highlight the importance of regimen selection, treatment sequencing, and dose intensity to optimize outcomes in CLL/SLL.

Primary lymphoma of the female genital tract (PLFGT) is a rare type of extranodal lymphoma. In this retrospective study from the International Extranodal Lymphoma Study Group, we analyzed clinical data from 60 women diagnosed with PLFGT between 1982 and 2012. The median age was 52 years. Limited stage, as defined by the Ann Arbor and FIGO staging systems, was observed in 55% and 63% of cases, respectively. The uterus was the primary site of lymphoma in 25 cases, with the ovaries as the second most common site (n = 24). The most common histological subtype was diffuse large B-cell lymphoma (DLBCL, n = 44), followed by follicular lymphoma and marginal zone lymphoma (6 patients each). Two patients received surgery alone as first-line therapy, while 58 underwent systemic therapy, 16 following major surgery. Thirteen patients received consolidation radiotherapy and six were given central nervous system (CNS) prophylaxis. Twenty patients had disease progression or recurrence. Six patients with DLBCL (14%) experienced CNS relapse, which was the only site of recurrence in five of them. All but one patient with CNS relapse had primary ovarian involvement, and three had bulky disease; none of these patients had received CNS prophylaxis. With a median follow-up of 60 months, the median overall survival of the DLBCL cohort was approximately 13 years, with a 5-year survival rate of 77%. In multivariable analysis, advanced disease according to the FIGO system was the only parameter significantly associated with shorter overall, cause-specific, and progression-free survival in patients with DLBCL.

Abstract Myeloid malignancies are a heterogeneous group of clonal haematopoietic disorders, which include chronic disorders such as chronic myeloid leukaemia, polycythaemia vera, essential thrombocytosis, primary myelofibrosis, myelodysplastic syndromes, and acute disorders such as acute myeloid leukaemias. Accordingly, their neurological manifestations are manifold. Common neurological complications are thrombotic and haemorrhagic events that occur in both acute leukaemias and the more indolent entities. Direct involvement of the nervous system is typically related to acute leukaemias and includes invasion of the central nervous system (parenchymal and leptomeningeal dissemination, myeloid sarcoma, neuroleukaemiosis). Indirect neurological complications derive from cerebrovascular events related to either thrombosis in JAK-2-positive neoplasms or hyperviscosity, or haemorrhage once thrombocythemia or coagulopathy is present. Many neurological complications are iatrogenic and include diverse categories such as lumbar puncture and intrathecal or systemic chemotherapy, targeted therapies, radiotherapy, and allogeneic stem cell transplantation. Most neurological manifestations require urgent treatment and confer a poor prognosis. This chapter describes the neurological complications of myeloid malignancies in the era of contemporary treatment. Those manifestations require expert consideration of their source, as they are being identified with increasing frequency, while patients survive longer.

Background: Richter's syndrome (RS) is a rare histologic transformation of chronic lymphocytic leukemia (CLL), most commonly to diffuse large B-cell lymphoma (DLBCL). It is characterized by an aggressive clinical course and dismal prognosis. Treatment is usually based on regimens traditionally used for de novo DLBCL like R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-DA-EPOCH (rituximab and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin). The outcomes with chemo-immunotherapy in RS are poor, achieving a complete response rate (CRR) of about 20% to 30% of patients and median progression-free survival (PFS) and overall survival (OS) in the range of 6 and 12 months, respectively. Methods: This is a phase 2, open-label, non-randomized, single-arm, multi-center study aimed to assess the efficacy and safety of 12-month fixed duration obinutuzumab, ibrutinib, and venetoclax (GIVe) in patients with DLBCL-type RS (NCT04939363). Obinutuzumab was administered IV for 6 cycles, starting with 100 mg on day 1 and 900 mg on day 2, 1000 mg on day 8 and on day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6. ibrutinib 560 mg daily was administered orally from day 1 of cycles 1 through 12. The daily oral venetoclax regimen was initiated on day 11 of cycle 1, starting with an accelerated ramp-up, thereafter continuing at 400 mg daily until completion of cycle 12. The primary endpoint was investigator-assessed 6-month overall metabolic response rate per Lugano 2014 criteria. Other key secondary endpoints included complete metabolic response (CMR) rate, PFS, OS, and safety. Results: From August 2021 until the data cut-off on July 7, 2024, a total of 12 patients with RS were enrolled, with a median age of 78.0 years (range, 62-87), 8 (67%) were males, 8 (67%) were treatment-naïve, 4 (37%) had relapsed/refractory disease, 5 (42%) had extra-nodal disease, 8 (67%) had elevated LDH, and 9 (75%) were double or triple-expressors (Table 1). Among the 10 patients who were evaluable for response, the 3-month and 6-month OMR rates were 70.0% (7/10) and 37.5% (3/8), respectively, and the 3-month and 6-month CMR rates were 40.0% (4/10) and 25% (2/8), respectively. During a median follow-up of 23 months (range, 1-32), 6/12 (50 %) progressed and 10/12 (83.3 %) died. Median PFS was 4.4 months (95% CI, 1-11.9) and median OS was 7.8 months (95% CI: 1-32). Causes of death included RS (n=3), intractable diarrhea (n=2), infections (n=2; one case of sepsis and one case of Covid-19 during the next-line therapy with bendamustine plus rituximab), neurological deterioration (n=2), and acute myeloid leukemia (n=1). Most common related treatment-emergent adverse events (TEAEs) of all grades were neutropenia 40%, thrombocytopenia 50%, diarrhea 40%, and skin rash 50%, 2 patients developed Covid-19 and recovered during the treatment period of the study. None of the patients developed tumor lysis syndrome or atrial fibrillation. Conclusions: In elderly patients with RS, 12-month fixed duration obinutuzumab, ibrutinib, and venetoclax treatment achieved high 3-month metabolic responses. Despite the early encouraging response, the duration of response, PFS, and OS were short. This three-drug regimen appears to be less well tolerated in elderly patients with RS

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Secondary central nervous system lymphoma (SCNSL) confers a dismal prognosis and treatment advances are constrained by the lack of prospective studies and real-world treatment evidence. Aims: To determine real-world patient characteristics, treatments and outcomes of SCNSL. Methods: Patients with SCNSL of all entities were included at first diagnosis from June 2011 to June 2022 and patient characteristics, treatment data, and outcomes were prospectively collected in the Secondary CNS Lymphoma Registry (SCNSL-R) (NCT05114330). Kaplan Meier estimator was applied to estimate OS for baseline covariables at the time of SCNSL diagnosis, and log-rank test was used for comparison of survival curves. To assess, if HDT-ASCT had a positive effect on OS in patients achieving a CR or PR upon induction therapy, we applied a multivariable Cox proportional hazards model controlling for known prognostic factors in SCNSL by modelling HDT-ASCT treatment as a time-dependent covariable. Results: 279 patients from 47 institutions in Germany, Switzerland, Israel and Austria were enrolled and 243 patients (median age: 66 years; range: 23-86) were available for analysis. Of those, 49 (20%) patients presented with synchronous (cohort I) and 194 (80%) with metachronous SCNSL (cohort II). The predominant histology was diffuse large B-cell lymphoma (DLBCL, 68%), followed by follicular lymphoma grade I-IIIA (n=16, 7%) and mantle cell lymphoma (n=13, 5%). At initial diagnosis before CNS involvement, cohort II patients most frequently presented with Ann Arbor stage IV (n=110; 57%) and extranodal involvement (n=156, 80%). Bone marrow was the most commonly affected extranodal site at initial lymphoma diagnosis in cohort II (n=56, 29%), followed by involvement of kidney/adrenal, gastrointestinal (each n=25, 13%), lung/pleura, and testes (each n=23, 12%) Median overall survival (OS) from diagnosis of CNS involvement was 17·2 months (95% CI 12-27·5), with longer OS in cohort I (60·6 months, 95% CI 45·5-not estimable (NE)) than cohort II (11·4 months, 95% CI 7·8-17·7). Predominant induction regimens included R-CHOP/high-dose MTX (cohort I) and high-dose MTX/cytarabine (cohort II). Rituximab was used in 166 (68%) of patients with B-cell lymphoma. The overall response rate to induction therapy was 54%, with 84 (35%) and 46 (19%) patients achieving a complete response (CR) and partial response (PR), respectively. When CNS relapse of DLBCL was accompanied by a systemic relapse, patients had inferior outcomes compared to those with isolated CNS involvement (17·2 months (95% CI 9·7-30·6) vs 6·6 months (95% CI 3·8-9), p=0·0026). A total of 103 patients (42%) underwent HDT-ASCT, with BCNU/Etoposide/Thiotepa being the most prevalent regimen in 25 (24%) patients. Patients who achieved partial response (PR) or better benefitted from consolidating high-dose therapy and autologous hematopoietic stem cell transplantation (HDT-ASCT) (HR adjusted 0·49, 95% CI 0·24-0·97, p = 0·0418). Summary/Conclusion: This study is the largest prospective cohort of SCNSL patients providing a comprehensive overview of an international real-world treatment landscape and outcomes. Prognosis was better in patients with SCNSL involvement at initial diagnosis (cohort I) and consolidating HDT-ASCT prolonged survival in patients with PR or better. For rational clinical trial design, a precise understanding of the real-world treatment landscape of SCNSL is crucial and provided by our prospective registry study. Keywords: Real world data, CNS lymphoma, Clinical trial, DLBCL

Abstract BACKGROUND Primary central nervous system lymphoma (PCNSL) is a rare disease with an incidence of 0.4/per 100,000 person-years. As there is a limited number of prospective randomized trials in PCNSL, large retrospective studies on this rare disease may yield information that might prove useful for the future design of randomized clinical trials. MATERIAL AND METHODS We retrospectively analyzed the data of 222 newly diagnosed PCNSL patients treated in 5 referral centers in Israel between 2001-2020. During this period, combination therapy became the treatment of choice, rituximab has been added to the induction therapy, and consolidation with irradiation was largely laid off and was mostly replaced by high-dose chemotherapy with or without autologous stem cell transplantation. RESULTS Patients older than 60 comprised 67.5% of the study population. First-line treatment included high-dose methotrexate (HD-MTX) in 94% of patients with a median MTX dose of 3.5gr/m2 (range 1.14-6 gr/m2) and a median cycle number of 5 (range 1-16). Rituximab was given to 136 patients (61%) and consolidation treatment to 124 patients (58%). Patients treated after 2012 received significantly more treatment with HD-MTX and rituximab, more consolidation treatments, and autologous stem cell transplantation. The overall response rate was 85% and the complete response (CR)/unconfirmed CR rate was 62.1%. After a median follow-up of 24 months, the median PFS and OS were 21.9 and 43.5 months respectively with a significant improvement since 2012 (PFS:12.5 vs. 34.2 p=0.006 and OS:19.9 vs 77.3 p=0.0003). A multivariate analysis found that the most important factors related to OS were obtaining a CR followed by rituximab treatment and ECOG performance status. CONCLUSION The observed improvement in outcomes may be due to multiple components such as an intention to treat all patients regardless of age with HD-MTX- based combination chemotherapy, treatment in dedicated centers, and more aggressive consolidation with the INTRODUCTION of HDC-ASCT.

Background: Richter's syndrome (RS) is an aggressive histologic transformation of chronic lymphocytic leukemia (CLL), most commonly to diffuse large B-cell lymphoma (DLBCL). RS is characterized by a rapid clinical course, low responses to therapy, and poor long-term survival. Chemoimmunothreapy for RS achieves overall response rates of 40% to 60%, and median progression-free survival (PFS) and overall survival (OS) of 3 to 10 months and 6 to 21 months, respectively. More recently, single targeted agents of either ibrutinib or venetocolax have been shown some clinical activity in RS. Furthermore, ibrutinib combined with venetoclax with or without anti-CD20 antibodies has a synergistic activity in CLL, resulting in deep and prolong responses along with a good safety profile. Methods: This is a prospective phase 2, open-label, non-randomized, single-arm, multi-center study aimed to assess the efficacy and safety of ibrutinib, venetoclax, and obinutuzumab in treatment-naïve or relapsed/refractory patients with biopsy-confirmed RS to DLBCL (NCT04939363). The experimental regimen consisted of 12 months of fixed-duration treatment with obinutuzumab, ibrutinib, and venetoclax. Obinutuzumab was administered at a dose of 100 mg intravenously on day 1, 900 mg on day 2, and then 1000 mg on day 8 and 15 of cycle 1. On day 1 of the subsequent five cycles, obinutuzumab at a dose of 1000 mg was administered. Ibrutinib was administered at a dose of 560mg orally daily initiated together with the first obinutuzumab infusion on day 1 of cycle 1 and was continued throughout the 12 treatment 28-day cycles. Venetoclax was given at a dose of 400 mg orally daily for 12 treatment cycles after an accelerated ramp-up phase from day 15 in cycle 1. The primary endpoint was investigator-assessed overall response rate (ORR) defined as the proportion of patients who achieve complete metabolic response (CR) and partial metabolic response (PR) determined by PET-CT imaging at 6 months per Lugano 2014 criteria. Other key endpoints included; investigator-assessed ORR at 3 and 12 months, PFS, Duration of response (DOR), OS, and safety. Results: From August 2021 until the data cut-off on July 20, 2023, a total of 10 patients with RS were enrolled. Median age was 76.0 (range, 62‒88) years and 70% were male. Six patients were treatment-naïve, 4 had relapsed/refractory RS, 50% had extra-nodal disease, 70% had elevated LDH, 70% were double or triple expressors, and the median number of prior therapies among the R/R patients was 1 (Table 1). Median follow-up was 255 days (95% CI, 158.7-351.3), median treatment duration was 160 days (range: 29-362) and treatment is still ongoing in 3 patients. At 3 and 6 months, the ORRs were 70.0% (7/10) and 22.2% (2/9), respectively, and CR rates (CRRs) were 40.0% (4/10) and 11.1% (1/9), respectively. At the data cutoff, 6/10 (60.0%) patients progressed and 5/10 (50.0%) died. The median PFS was 162 days (95% CI, 66.9-257.1), median DOR 272 days, and median OS was 228 days (95% CI: 184.2-271.8). The causes of death included RS in 2 patients and one case each of Covid-19, secondary malignancy, and general deterioration. Most common related treatment-emergent AEs (TEAEs) of all grades were neutropenia 40%, thrombocytopenia 50%, diarrhea 40%, and skin rash 50%, 2 patients developed Covid-19 who recovered during the protocol. None of the patients developed tumor lysis syndromes. Conclusions: In patients with RS triplet treatment with ibrutinib, venetoclax, and obinutuzmab was well tolerated, achieved high rates of early metabolic response (ORR-70% and CRR-40%) at 3 months. Given the high early response rate but subsequent progression, this triplet therapy may serve as a bridge to consolidation with cellular therapy.

BACKGROUND:Secondary central nervous system lymphoma (SCNSL) confers a dismal prognosis and treatment advances are constrained by the lack of prospective studies and real-world treatment evidence. METHODS:Patients with SCNSL of all entities were included at first diagnosis and patient characteristics, treatment data, and outcomes were prospectively collected in the Secondary CNS Lymphoma Registry (SCNSL-R) (NCT05114330). FINDINGS:279 patients from 47 institutions were enrolled from 2011 to 2022 and 243 patients (median age: 66 years; range: 23-86) were available for analysis. Of those, 49 (20 %) patients presented with synchronous (cohort I) and 194 (80 %) with metachronous SCNSL (cohort II). The predominant histology was diffuse large B-cell lymphoma (DLBCL, 68 %). Median overall survival (OS) from diagnosis of CNS involvement was 17·2 months (95 % CI 12-27·5), with longer OS in cohort I (60·6 months, 95 % CI 45·5-not estimable (NE)) than cohort II (11·4 months, 95 % CI 7·8-17·7, log-rank test p < 0.0001). Predominant induction regimens included R-CHOP/high-dose MTX (cohort I) and high-dose MTX/cytarabine (cohort II). Rituximab was used in 166 (68 %) of B-cell lymphoma. Undergoing consolidating high-dose therapy and autologous hematopoietic stem cell transplantation (HDT-ASCT) in partial response (PR) or better was associated with longer OS (HR adjusted 0·47 (95 % CI 0·25-0·89), p = 0·0197). INTERPRETATION:This study is the largest prospective cohort of SCNSL patients providing a comprehensive overview of an international real-world treatment landscape and outcomes. Prognosis was better in patients with SCNSL involvement at initial diagnosis (cohort I) and consolidating HDT-ASCT was associated with favorable outcome in patients with PR or better.

WHAT IS THIS SUMMARY ABOUT?:This is a plain language summary of a publication describing long-term results from the RESONATE-2 study with up to 8 years of follow-up. The original paper was published in Blood Advances in June 2022. WHAT WERE THE RESULTS?:Researchers looked at 269 adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had not received any treatment for their CLL/SLL. Study participants were randomly divided into two groups: 136 participants received treatment with a drug called ibrutinib, and 133 participants received treatment with a drug called chlorambucil. Participants in the study were treated and followed for up to 8 years, with results showing that more participants who took ibrutinib (59%) were alive without worsening of their disease at 7 years after starting treatment than participants who took chlorambucil (9%). Almost half of the participants (42%) were able to stay on ibrutinib treatment for up to 8 years. WHAT DO THE RESULTS OF THE STUDY MEAN?:In people with CLL or SLL, more participants who were taking ibrutinib were alive without worsening of their disease after 7 years compared with participants who took chlorambucil. Clinical Trial Registration: NCT01722487 (ClinicalTrials.gov) Clinical Trial Registration: NCT01724346 (ClinicalTrials.gov).

Introduction: Primary lymphoma of the female genital tract (PLFGT) is an uncommon extranodal lymphoma. There are few reported series of PLFGT in the literature, and most of them are case reports. Methods: We retrospectively collected and analyzed data on presentation, treatment, and outcome of 60 female patients (pts) diagnosed with PLFGT between 1982 and 2013. Our aim was to investigate baseline features associated with patient outcome (including age, stage, LDH, IPI, PS, bulky disease, primary site, aggressive histology, and use of rituximab). Univariable and multivariable analyses were performed using the log-rank test and a stepwise Cox regression, respectively. Results: The median age at diagnosis was 52 years. Ann Arbor stage I-II was observed in 32 pts while 38 pts had localized disease according to the FIGO staging systems. Uterus was the primary site in 26 pts, 23 had ovarian involvement and 11 had vaginal or vulvar involvement. Fourteen pts had multiple gynecologic sites affected at diagnosis. Diffuse large B-cell lymphoma (DLBCL) was the most common subtype, occurring in 39 patients, followed by extranodal marginal zone lymphoma and follicular lymphoma (6 patients each). Surgery alone was given to 2 patients as first-line therapy, while systemic therapy was administered to 58, 16 of whom had undergone previous major surgery. Consolidation radiotherapy was given to 13 patients, all but one of whom had pelvic lesions. Six patients received central nervous system (CNS) prophylaxis (4 high-dose methotrexate, 1 intrathecal methotrexate, and 1 unspecified prophylaxis). Fifty-four patients responded to treatment (49 complete and 5 partial responses), while 20 experienced disease progression or relapse. Of those, 6 relapsed in the CNS (which was the only recurrence site in 5). All but one patient with CNS relapse had ovarian involvement, 3 had bulky disease, and none had received previous prophylaxis. With a median follow-up of 60 months, progression-free survival (PFS) at 5 and 10 years was 66% and 57%, respectively. At the last follow-up, 44 patients were alive (42 of whom were in complete remission), 13 had died from lymphoma, and 2 had died from other causes, while 1 patient was lost to follow-up. The median overall survival was 12.7 years with 5- and 10-year overall survival (OS) of 77% and 68%, respectively. Only FIGO advanced disease remained significantly associated with poorer PFS and OS at multivariable analysis. Conclusions: This PLFGT survey showed the prognostic impact of gynecological staging procedures and a sizeable risk of CNS relapse. These findings may have treatment implications and highlight the utility of multidisciplinary management, as well as the need for further research to identify predictive factors for CNS relapse Keyword: Extranodal non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Primary central nervous system lymphoma (PCNSL) is a rare disease with an incidence of 0.4/per 100,000 person-years. As there is a limited number of prospective randomized trials in PCNSL, large retrospective studies on this rare disease may yield information that might prove useful for the future design of randomized clinical trials. We retrospectively analyzed the data of 222 newly diagnosed PCNSL patients treated in five referral centers in Israel between 2001 and 2020. During this period, combination therapy became the treatment of choice, rituximab has been added to the induction therapy, and consolidation with irradiation was largely laid off and was mostly replaced by high-dose chemotherapy with or without autologous stem cell transplantation (HDC-ASCT). Patients older than 60 comprised 67.5% of the study population. First-line treatment included high-dose methotrexate (HD-MTX) in 94% of patients with a median MTX dose of 3.5 g/m(2) (range 1.14-6 g/m(2)) and a median cycle number of 5 (range 1-16). Rituximab was given to 136 patients (61%) and consolidation treatment to 124 patients (58%). Patients treated after 2012 received significantly more treatment with HD-MTX and rituximab, more consolidation treatments, and autologous stem cell transplantation. The overall response rate was 85% and the complete response (CR)/unconfirmed CR rate was 62.1%. After a median follow-up of 24 months, the median progression-free survival (PFS) and overall survival (OS) were 21.9 and 43.5 months respectively with a significant improvement since 2012 (PFS: 12.5 vs. 34.2 p = 0.006 and OS: 19.9 vs. 77.3 p = 0.0003). A multivariate analysis found that the most important factors related to OS were obtaining a CR followed by rituximab treatment and Eastern Cooperative Oncology Group performance status. The observed improvement in outcomes may be due to multiple components such as an intention to treat all patients regardless of age with HD-MTX-based combination chemotherapy, treatment in dedicated centers, and more aggressive consolidation with the introduction of HDC-ASCT.

BackgroundElderly 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. MethodsThis 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. ResultsTwenty 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%. ConclusionsThe 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.

Patients with chronic lymphocytic leukemia (CLL) have an impaired antibody response to coronavirus disease 2019 (COVID-19) vaccination. Here, we evaluated the antibody response to a third BNT162b2 mRNA vaccine in patients with CLL/small lymphocytic lymphoma (SLL) who failed to achieve a humoral response after standard 2-dose vaccination regimen. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies were measured 3 weeks after administration of the third dose. In 172 patients with CLL, the antibody response rate was 23.8%. Response rate among actively treated patients (12.0%; n = 12/100) was lower compared with treatment-naive patients (40.0%; n = 16/40; OR = 4.9, 95% CI 1.9-12.9; P < .001) and patients off-therapy (40.6%; n = 13/32; OR = 5.0, 95% CI 1.8-14.1; P < .001), (P < .001). In patients actively treated with Bruton's tyrosine kinase (BTK) inhibitors or venetoclax +/- anti-CD20 antibody, response rates were extremely low (15.3%, n = 9/59, and 7.7%, n = 3/39, respectively). Only 1 of the 28 patients (3.6%) treated with anti-CD20 antibodies <12 months prior to vaccination responded. In a independent variables that were associated with response included lack of active therapy (OR = 5.6, 95% CI 2.3-13.8; P < .001) and serum immunoglobulin A levels >= 80 mg/dL (OR = 5.8, 95% CI 2.1-15.9; P < .001). In patients with CLL/SLL who failed to achieve a humoral response after standard 2 dose BNT162b2 mRNA vaccination regimen, close to a quarter responded to the third dose of vaccine. The antibody response rates were lower during active treatment and in patients with a recent exposure (<12 months prior to vaccination) to anti-CD20 therapy.

Genomic abnormalities, including del(17p)/TP53 mutation, del(11q), unmutated IGHV, and mutations in BIRC3, NOTCH1, SF3B1, and XPO1 predict poor outcomes with chemoimmunotherapy in chronic lymphocytic leukemia. To better understand the impact of these high-risk genomic features on outcomes with first-line ibrutinib-based therapy, we performed pooled analysis of two phase 3 studies with 498 patients randomized to receive ibrutinib- or chlorambucil-based therapy with median follow-up of 49.1 months. Ibrutinib-based therapy improved overall response rates (ORRs), complete response rates, and progression-free survival (PFS) versus chlorambucil-based therapy across all subgroups. In ibrutinib-randomized patients with versus without specified genomic features, ORR and PFS were comparable across subgroups. PFS hazard ratio (95% CI) for del(17p)/TP53 mutated/BIRC3 mutated: 1.05 (0.54-2.04); del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV: 1.11 (0.69-1.77); unmutated IGHV: 1.79 (0.99-3.24); and NOTCH1 mutated 1.05 (0.65-1.69). This integrated analysis demonstrated efficacy of first-line ibrutinib-based treatment irrespective of cytogenetic and mutational risk features. Registered at ClinicalTrials.gov (NCT01722487 and NCT02264574).

We report long-term follow-up from the RESONATE-2 phase 3 study of the once-daily Bruton's tyrosine kinase inhibitor ibrutinib, which is the only targeted therapy with significant progression-free survival (PFS) and overall survival (OS) benefit in multiple randomized chronic lymphocytic leukemia (CLL) studies. Patients (≥65 years) with previously untreated CLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n = 136) or chlorambucil 0.5-0.8 mg/kg ≤12 cycles (n = 133). With up to 8 years of follow-up (range, 0.1-96.6 months; median, 82.7 months), significant PFS benefit was sustained for ibrutinib vs chlorambucil (hazard ratio [HR], 0.154; 95% confidence interval [CI], 0.108-0.220). At 7 years, PFS was 59% for ibrutinib vs 9% for chlorambucil. PFS benefit was also observed for ibrutinib- vs chlorambucil-randomized patients with high-risk genomic features: del(11q) (HR, 0.033; 95% CI, 0.010-0.107) or unmutated immunoglobulin heavy chain variable region (HR, 0.112; 95% CI, 0.065-0.192). OS at 7 years was 78% with ibrutinib. Prevalence of adverse events (AEs) was consistent with previous 5-year follow-up. Ibrutinib dosing was held (≥7 days) for 79 patients and reduced for 31 patients because of AEs; these AEs resolved or improved in 85% (67 of 79) and 90% (28 of 31) of patients, respectively. With up to 8 years of follow-up, 42% of patients remain on ibrutinib. Long-term RESONATE-2 data demonstrate sustained benefit with first-line ibrutinib treatment for CLL, including for patients with high-risk genomic features. These trials were registered at www.clinicaltrials.gov as #NCT01722487 and #NCT01724346.

Acute myeloid leukemia (AML) comprises a heterogeneous group of aggressive blood malignancies that arise from clonal expansion of malignant hematopoietic precursor cells in the bone marrow. Neurologic manifestations of these malignancies are manifolds. AML is the most common form of acute leukemia in adults and this review describes the neurologic complications in this age group. Neurologic symptoms and signs may develop in AML either from a direct neoplastic involvement of the central or the peripheral nervous system or as an indirect effect of the disease process. Direct involvement of the nervous system includes invasion of the central or the peripheral nervous system (parenchymal and leptomeningeal dissemination, myeloid sarcoma, neuroleukemiosis). Thrombotic and hemorrhagic events are common manifestations of indirect involvement of the nervous system and they are the outcome of hyperleukocytosis, thrombocytopenia and coagulopathy. Many neurologic complications are iatrogenic and include diverse categories such as lumbar puncture and intrathecal or systemic chemotherapy and targeted therapies, radiotherapy and allogeneic stem cell transplantation. Most neurologic manifestations require urgent treatment and confer a poor prognosis. This review describes the neurologic complications of acute myeloid malignancies in the era of contemporary treatment. Those manifestations require expert consideration of their origin as they are being identified with increasing frequency as patients survive longer.