Prognostic differences between carmustine, etoposide, cytarabine and melphalan (BEAM) and carmustine, etoposide, cytarabine, melphalan and fludarabine (BEAMF) regimens before autologous stem cell transplantation plus chimeric antigen receptor T therapy in patients with refractory/relapsed B-cell non-Hodgkin-lymphoma.

BACKGROUND AIMS: The combination therapy of autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell (CART) therapy has been employed to improve outcomes for relapsed or refractory (R/R) B-cell non-Hodgkin-lymphoma (B-NHL). The widely used conditioning regimen before ASCT plus CART therapy reported in the literature was carmustine, etoposide, cytarabine and melphalan (BEAM). However, whether adding fludarabine to the BEAM regimen (BEAMF) can improve the survival of patients with R/R B-NHL remains unknown. METHODS: In total, 39 and 19 patients with R/R B-NHL were enrolled to compare clinical outcomes in the BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy, respectively. RESULTS: The objective response (OR) rates at 3 months to BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy were 71.8% and 94.7%, respectively (P = 0.093). The BEAMF regimen showed a trend towards a superior duration of response compared with the BEAM regimen (P = 0.09). After a median follow-up of 28 months (range: 0.93-51.9 months), the BEAMF regimen demonstrated superior 2-year progression-free survival (PFS) (89.5% versus 63.9%; P = 0.048) and 2-year overall survival (OS) (100% vs 77.3%; P = 0.035) compared with the BEAM regimen. In the multivariable Cox regression analysis, OR at month 3 (responders) was remarkably correlated with better OS (hazard ratio: 0.112, P = 0.005) compared with OR (non-responders). CONCLUSIONS: For patients with R/R B-NHL, the BEAMF regimen before ASCT plus CD19/22 CART therapy was correlated with superior PFS and OS than the BEAM regimen, and the BEAMF regimen is a promising alternative conditioning regimen for ASCT plus CAR-T therapy.

BeEAM vs. BEAM: evaluating conditioning regimens for autologous stem cell transplantation in patients with relapsed or refractory DLBCL.

PURPOSE: To evaluate whether BeEAM is an alternative to BEAM for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). METHODS: Data of 60 patients with relapsed or refractory DLBCL who underwent ASCT from January 2018 to June 2023 in our center, including 30 patients in the BeEAM group and 30 patients in the BEAM group, were retrospectively analyzed. The time to hematopoietic reconstitution, treatment-related adverse events, number of hospitalization days, hospitalization cost, and survival benefit were compared between the two groups. RESULTS: The clinical characteristics of the patients did not significantly differ between the two groups. The median number of reinfused CD34 + cells was 5.06 × 106/kg and 5.17 × 106/kg in the BeEAM and BEAM groups, respectively, which did not significantly different (p = 0.8829). In the BeEAM and BEAM groups, the median time to neutrophil implantation was 10.2 and 10.27 days, respectively (p = 0.8253), and the median time to platelet implantation was 13.23 and 12.87 days, respectively (p = 0.7671). In the BeEAM and BEAM groups, the median hospitalization duration was 30.37 and 30.57 days, respectively (p = 0.9060), and the median hospitalization cost was RMB 83,425 and RMB 96,235, respectively (p = 0.0560). The hospitalization cost was lower in the BeEAM group. The most common hematologic adverse events were grade ≥ 3 neutropenia and thrombocytopenia, whose incidences were similar in the two groups. The most common non-hematologic adverse events were ≤ grade 2 and the incidences of these events did not significantly differ between the two groups. Median overall survival was not reached in either group, with predicted 5-year overall survival of 72.5% and 60% in the BeEAM and BEAM groups, respectively (p = 0.5872). Five-year progression-free survival was 25% and 20% in the BeEAM and BEAM groups, respectively (p = 0.6804). CONCLUSION: As a conditioning regimen for relapsed or refractory DLBCL, BeEAM has a desirable safety profile and is well tolerated, and its hematopoietic reconstitution time, number of hospitalization days, and survival benefit are not inferior to those of BEAM. BeEAM has a lower hospitalization cost and is an alternative to BEAM.

Clinical Course after Carmustine Wafer Implantation for Newly Diagnosed Adult-type Diffuse Gliomas; A controlled propensity matched analysis of a single center cohort.

PURPOSE: It remains unclear whether combining carmustine wafer (CW) implantation with the standard treatment for adult-type diffuse gliomas is safe and has a prognostic impact. This study aimed to investigate the prognostic value and safety of CW implantation. METHODS: Adult patients with IDH-wild-type and -mutant gliomas, grades 3-4 treated with surgical resection, radiotherapy, and temozolomide chemotherapy between 2013 and 2023 were surveyed. CWs were implanted except in cases of intraoperative wide ventricle opening or marked preoperative brain swelling. For survival analyses, a case-matched dataset based on propensity score matching (PSM), including multiple factors (patient background, diagnosis, and extent of resection) was generated. Progression-free survival (PFS), overall survival (OS), and frequency of complications of CW implantation (brain edema, infection, and cerebrospinal fluid leakage) were compared between the CW and non-use groups. RESULTS: In total, 127 patients (75 in the CW use group and 52 in the non-use group) were enrolled. Regardless of stratification, no significant differences in PFS and OS were observed between the CW use and non-use groups. The frequency of postoperative brain edema was significantly higher in the CW use group than in the non-use group. An adjusted dataset containing 41 patients in the CW use and nonuse groups was generated. Even after PSM, CW implantation had no prognostic effect. CONCLUSIONS: CW implantation with standard treatment demonstrated little beneficial effect for the present strategy of CW use.

Improved survival outcomes despite older age at diagnosis: an era-by-era analysis of patients with primary central nervous system lymphoma treated at a single referral centre in the United Kingdom.

Observational studies with long-term follow-up of patients with primary central nervous system lymphoma (PCNSL) are scarce. Patient data over a period of four decades were retrospectively analysed from databases at Nottingham University Hospitals Trust, UK. The cohort was delineated by two distinct therapeutic eras; the first from 01/01/1982 to 31/12/2010 (n = 147) and the second 01/01/2011 to 31/07/2020 (n = 125). The median age at diagnosis was significantly older in the second era compared to the first (69 and 65 years respectively, P = 0·003). The 3-, 6- and 12-month overall survival (OS) rates in the second era were significantly higher compared to the first, at 85%, 77%, 62% versus 56%, 49%, 38% respectively (log-rank test P < 0·0001). On multivariate analysis, high-dose methotrexate (HD-MTX)-based induction protocols employed in the second era were associated with improved OS compared to those used in the first [hazard ratio (HR) 0·40, 95% confidence interval (CI) 0·28-0·57]. Within the second era, superior OS rates were seen with the use of intensive HD-MTX protocols (including consolidation with high-dose chemotherapy and autologous stem cell transplantation) compared to non-intensive HD-MTX schedules (HR 0·47, 95% CI 0·22-0·99). Initiating chemotherapy within 14 days of biopsy and use of rituximab were independently associated with improved OS and progression-free survival during the second era. These data suggest that prompt treatment initiation and use of intensive HD-MTX- and rituximab-based protocols have resulted in improved survival outcomes for patients.

A dose-dense short-term therapy for human immunodeficiency virus/acquired immunodeficiency syndrome patients with high-risk Burkitt lymphoma or high-grade B-cell lymphoma: safety and efficacy results of the "CARMEN" phase II trial.

A few prospective trials in HIV-positive patients with Burkitt lymphoma (BL) or high-grade B-cell lymphoma (HGBL) have been reported. Investigated therapies have shown good efficacy but relevant safety problems, with high rates of interruptions, severe mucositis, septic complications, and fungal infections. Here, we report the results of a multicentre phase II trial addressing a new dose-dense, short-term therapy aimed at maintaining efficacy and improving tolerability. The experimental programme included a 36-day polychemotherapy induction followed by high-dose cytarabine-based consolidation and response-tailored BEAM (carmustine, etoposide, cyatarabine, and melphalan)- conditioned autologous stem cell transplantation (ASCT). This therapy would be considered active if ≥11 complete remissions (CR) after induction (primary endpoint) were recorded among 20 assessable patients. HIV-positive adults (median age 42, range 26-58; 16 males) with untreated BL (n = 16), HGBL (n = 3) or double-hit lymphoma (n = 1) were enrolled. All patients had high-risk features, with meningeal and bone marrow infiltration in five and nine patients respectively. The experimental programme was safe and active in a multicentre setting, with only two episodes of grade 4 non-haematological toxicity (hepatotoxicity and mucositis), and no cases of systemic fungal infections; two patients died of toxicity (bacterial infections). Response after induction (median duration: 47 days; interquartile range 41-54), was complete in 13 patients and partial in five [overall response rate = 90%; 95% confidence interval (CI) = 77-100]. All responders received consolidation, and five required autologous stem cell transplant. At a median follow-up of 55 (41-89) months, 14 patients are relapse-free and 15 are alive, with a five-year progression-free survival and an overall survival of 70% (95% CI = 60-80%) and 75% (95% CI = 66-84) respectively. No patient with cerebrospinal fluid (CSF)/meningeal lymphoma experienced central nervous system recurrence. With respect to previously reported regimens, this programme was delivered in a shorter period, and achieved the main goal of maintaining efficacy and improving tolerability.

Mobilization characteristics, blood graft composition, and outcome in diffuse large B-cell lymphoma after autologous stem cell transplantation: Results from the prospective multicenter GOA study.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a common indication for autologous stem cell transplantation (auto-SCT). STUDY DESIGN AND METHODS: This prospective noninterventional study aimed to evaluate the impact of mobilization characteristics and graft cellular content on hematologic recovery and outcome after auto-SCT among 68 patients with DLBCL. RESULTS: Better mobilization capacity as manifested by blood CD34+ cell count >32 × 106 /L and CD34+ cell yield of the first apheresis >2.75 × 106 /kg correlated with faster neutrophil (P = .005 and P = .017) and platelet (P = .002 and P < .001) recovery. A higher number of infused CD34+ cells (> 2.65 × 106 /kg) was associated with better 5-year overall survival (OS; 95% vs 67%, P = .012). The graft CD34+ CD133+ CD38- cell count >0.07 × 106 /kg was predictive of better 5-year OS (87% vs 63%; P = .008) and higher graft CD3+ cell count (>23.1 × 106 /kg) correlated also with better 5-year OS (80% vs 40%, P = .008). In multivariate analysis only disease status of CR I at auto-SCT was associated with better progression-free survival (P = .014) and OS (P = .039). CONCLUSION: The mobilization capacity of CD34+ cells impacted on early hematologic recovery in patients with DLBCL after auto-SCT. Higher graft CD34+ cell count and both CD34+ CD133+ CD38- and CD3+ cells were also associated with better OS. The effect of optimal graft cellular composition on outcome in DLBCL should be evaluated in a randomized study.

Outcomes of rituximab-BEAM versus BEAM conditioning regimen in patients with diffuse large B cell lymphoma undergoing autologous transplantation.

BACKGROUND: Although rituximab-based high-dose therapy is frequently used in diffuse large B cell lymphoma (DLBCL) patients undergoing autologous hematopoietic cell transplantation (auto-HCT), data supporting the benefits are not available. Herein, we report the impact of rituximab-based conditioning on auto-HCT outcomes in patients who have DLBCL. METHODS: Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, 862 adult DLBCL patients undergoing auto-HCT between 2003 and 2017 using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning regimen were included. All patients received frontline rituximab-containing chemoimmunotherapy and had chemosensitive disease pre-HCT. Early chemoimmunotherapy failure was defined as not achieving complete remission (CR) after frontline chemoimmunotherapy or relapse within 1 year of initial diagnosis. The primary outcome was overall survival (OS). RESULTS: The study cohort was divided into 2 groups: BEAM (n = 667) and R-BEAM (n = 195). On multivariate analysis, no significant difference was seen in OS (P = .83) or progression-free survival (PFS) (P = .61) across the 2 cohorts. No significant association between the use of rituximab and risk of relapse (P = .15) or nonrelapse mortality (P = .12) was observed. Variables independently associated with lower OS included older age at auto-HCT (P < .001), absence of CR at auto-HCT (P < .001) and early chemoimmunotherapy failure (P < .001). Older age (P < .0002) and non-CR pre-HCT (P < .0001) were also associated with inferior PFS. There was no significant difference in early infectious complications between the 2 cohorts. CONCLUSION: In this large registry analysis of DLBCL patients undergoing auto-HCT, the addition of rituximab to the BEAM conditioning regimen had no impact on transplantation outcomes. Older age, absence of CR pre auto-HCT, and early chemoimmunotherapy failure were associated with inferior survival.

Bortezomib maintenance after R-CHOP, cytarabine and autologous stem cell transplantation in newly diagnosed patients with mantle cell lymphoma, results of a randomised phase II HOVON trial.

Rituximab-containing induction followed by autologous stem cell transplantation (ASCT) is the standard first-line treatment for young mantle cell lymphoma patients. However, most patients relapse after ASCT. We investigated in a randomised phase II study the outcome of a chemo-immuno regimen and ASCT with or without maintenance therapy with bortezomib. Induction consisted of three cycles R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles high-dose cytarabine, BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT. Patients responding were randomised between bortezomib maintenance (1·3 mg/m2 intravenously once every 2 weeks, for 2 years) and observation. Of 135 eligible patients, 115 (85%) proceeded to ASCT, 60 (44%) were randomised. With a median follow-up of 77·5 months for patients still alive, 5-year event-free survival (EFS) was 51% (95% CI 42-59%); 5-year overall survival (OS) was 73% (95% CI 65-80%). The median follow-up of randomised patients still alive was 71·5 months. Patients with bortezomib maintenance had a 5-year EFS of 63% (95% CI 44-78%) and 5-year OS of 90% (95% CI 72-97%). The patients randomised to observation had 5-year PFS of 60% (95% CI, 40-75%) and OS of 90% (95% CI 72-97%). In conclusion, in this phase II study we found no indication of a positive effect of bortezomib maintenance after ASCT.

Implantation of carmustine wafers (Gliadel®) for high-grade glioma treatment. A 9-year nationwide retrospective study.

BACKGROUND: Carmustine wafers (CW) are approved to treat newly or recurrent high-grade gliomas (HGG). Widespread use has been limited regarding some doubtful uncertainties about their efficacy, related increased risk of infection and expensive cost. OBJECTIVE: To describe the epidemiology of CW implantation, search for related complications, long-term survival and associated prognostic factors. METHODS: We processed the French medico-administrative national database to retrieve appropriate cases operated between 2010 and 2018. A survival analysis was conducted. RESULTS: We identified 1659 patients treated in 39 institutions. Median age at CW implantation was 61 years and there was an over-representation of male (63.5%). 491 patients (29.6%) had previous diagnosis of glioma. Time between the first surgery and CW implantation was 0.9 years, IQR[0.6, 1.6]. The frontal lobe was the most frequently involved 29%. 131 patients (7.9%) had to be re operated on for a complication of which 121 for surgical site infection. At one year, 514 patients (31%) had died. Median overall survival (OS) was 1.4 years, 95% CI [1.3, 1.5]. OS at 1 and 2 year was 66%, 95%CI [63.7, 68.5], 32.3%, 95%CI [29.9, 35]. In the adjusted Cox regression, male gender & age at CW implantation were established as independent factors of OS in all three groups. Patients with recurrent HGG have a significant worse prognosis (HR = 0.71, 95% CI [0.62, 0.80] p < 0.001). A post-operative diagnosis of infection or intracranial bleeding eventually leading to a redo surgery was not associated with a decrease OS. CONCLUSION: Over the past 9 years, there is a significant decrease utilisation of CW in France. OS after CW implantation is significantly variable as influenced by many factors such as age, gender or recurrent disease but not by post-operative complications. Compare to previous results, CW may increase the OS and this effect seems more pronounced when adjuvant RT/TMZ is given.

Diagnostic delay and outcome in immunocompetent patients with primary central nervous system lymphoma in Spain: a multicentric study.

INTRODUCTION: To assess the management of immunocompetent patients with primary central nervous system lymphomas (PCNSL) in Spain. METHODS: Retrospective analysis of 327 immunocompetent patients with histologically confirmed PCNSL diagnosed between 2005 and 2014 in 27 Spanish hospitals. RESULTS: Median age was 64 years (range: 19-84; 33% ≥ 70 years), 54% were men, and 59% had a performance status (PS) ≥ 2 at diagnosis. Median delay to diagnosis was 47 days (IQR 24-81). Diagnostic delay > 47 days was associated with PS ≥ 2 (OR 1.99; 95% CI 1.13-3.50; p = 0.016) and treatment with corticosteroids (OR 2.47; 95% CI 1.14-5.40; p = 0.023), and it did not improve over the years. Patients treated with corticosteroids (62%) had a higher risk of additional biopsies (11.7% vs 4.0%, p = 0.04) but corticosteroids withdrawal before surgery did not reduce this risk and increased the diagnostic delay (64 vs 40 days, p = 0.04). Median overall survival (OS) was 8.9 months [95% CI 5.9-11.7] for the whole series, including 52 (16%) patients that were not treated, and 14.1 months (95%CI 7.7-20.5) for the 240 (73.4%) patients that received high-dose methotrexate (HD-MTX)-based chemotherapy. Median OS was shorter in patients ≥ 70 years (4.1 vs. 13.4 months; p < 0.0001). Multivariate analysis identified age ≥ 65 years, PS ≥ 2, no treatment, and cognitive/psychiatric symptoms at diagnosis as independent predictors of short survival. CONCLUSIONS: Corticosteroids withdrawal before surgery does not decrease the risk of a negative biopsy but delays diagnosis. In this community-based study, only 73.4% of patients could receive HD-MTX-based chemotherapy and OS remains poor, particularly in elderly patients ≥ 70 years.

Bortezomib consolidation or maintenance following immunochemotherapy and autologous stem cell transplantation for mantle cell lymphoma: CALGB/Alliance 50403.

Immunochemotherapy followed by autologous transplant (ASCT) in CALGB/Alliance 59909 achieved a median progression-free survival (PFS) in mantle cell lymphoma (MCL) of 5 years, but late recurrences occurred. We evaluated tolerability and efficacy of adding post-transplant bortezomib consolidation (BC) or maintenance (BM) to this regimen in CALGB/Alliance 50403, a randomized phase II trial. Following augmented-dose R-CHOP/ methotrexate, high-dose cytarabine-based stem cell mobilization, cyclophosphamide/carmustine/etoposide (CBV) autotransplant, and rituximab, patients were randomized to BC (1.3 mg/m2 IV days 1, 4, 8, 11 of a 3-week cycle for four cycles) or BM (1.6 mg/m2 IV once weekly × 4 every 8 weeks for 18 months) beginning day 90. The primary endpoint was PFS, measured from randomization for each arm. Proliferation signature, Ki67, and postinduction minimal residual disease (MRD) in bone marrow were assessed. Of 151 patients enrolled; 118 (80%) underwent ASCT, and 102 (68%) were randomized. Both arms met the primary endpoint, with median PFS significantly greater than 4 years (P < .001). The 8-year PFS estimates in the BC and BM arms were 54.1% (95% CI 40.9%-71.5%) and 64.4% (95% 51.8%-79.0%), respectively. Progression-free survival was significantly longer for transplanted patients on 50403 compared with those on 59909. Both the PFS and OS were significantly better for those who were MRD-negative post-induction. The high risk proliferation signature was associated with adverse outcome. Both BM and BC were efficacious and tolerable, although toxicity was significant. The comparison between studies 50403 and 59909 with long-term follow up suggests a PFS benefit from the addition of BC or BM post- transplant.

Intravascular Large B-Cell Lymphoma: Clinical and Histopathologic Findings.

Intravascular large B-cell lymphoma (IVLBCL) is a rare subset of extranodal non-Hodgkin lymphoma characterized by neoplastic lymphocytes within the lumina of small to medium-sized blood vessels. IVLBCLs are B-cell tumors that can present in essentially any organ system, including the skin. Cutaneous manifestations vary greatly and can mimic other skin disease which may delay diagnosis; in the absence of skin lesions, blind skin biopsies can be utilized for diagnosis. Early studies suggested that IVLBCL is a very aggressive lymphoma with high overall mortality rate and short survival times. However, earlier diagnosis and use of new treatment modalities have shown promise in recent studies. This case series illustrates the heterogeneity of clinical and pathologic presentations of this uncommon lymphoma.

Outcomes of Patients with Recurrent and Refractory Lymphoma Undergoing Allogeneic Hematopoietic Cell Transplantation with BEAM Conditioning and Sirolimus- and Tacrolimus-Based GVHD Prophylaxis.

The current standard of care for patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is high-dose conditioning followed by autologous stem cell transplantation (ASCT). For some patients (ie, those with highest-risk disease, insufficient stem cell numbers after mobilization, or bone marrow involvement) allogeneic hematopoietic cell transplantation (alloHCT) offers the potential for cure. However, the majority of patients undergoing alloHCT receive reduced-intensity conditioning as a preparative regimen, and studies assessing outcomes of patients after alloHCT with myeloablative conditioning are limited. In this retrospective study, we reviewed outcomes of 22 patients with recurrent and refractory NHL who underwent alloHCT with myeloablative BEAM conditioning and received tacrolimus/sirolimus as graft-versus-host disease (GVHD) prophylaxis at City of Hope between 2005 and 2018. With a median follow-up of 2.6 years (range, 1.0 to 11.2 years), the probabilities of 2-year overall survival and event-free survival were 58.3% (95% confidence interval [CI], 35.0% to 75.8%) and 45.5% (95% CI, 24.4% to 64.3%), respectively. The cumulative incidence of grade II to IV acute GVHD was 45.5% (95% CI, 23.8% to 64.9%), with only 1 patient developing grade IV acute GVHD. However, chronic GVHD was seen in 55% of the patients (n = 12). Of the 22 eligible patients, 2 had undergone previous ASCT and 2 had undergone previous alloHCT. Both patients with previous ASCT developed severe regimen-related toxicity. Patients who underwent alloHCT with chemorefractory disease had lower survival rates, with 1-year OS and EFS of 44.4% and 33.0%, respectively. In conclusion, alloHCT with a BEAM preparative regimen and tacrolimus/sirolimus-based GVHD should be considered as an alternative option for patients with highest-risk lymphoma whose outcomes are expectedly poor after ASCT.

Allogeneic Transplantation after Myeloablative Rituximab/BEAM ± Bortezomib for Patients with Relapsed/Refractory Lymphoid Malignancies: 5-Year Follow-Up Results.

Although bortezomib and rituximab have synergistic activity in patients with lymphoma and both can attenuate graft-versus-host disease (GVHD), the drugs have not been used together in patients undergoing allogeneic stem cell transplantation (alloSCT). In this phase I/II trial, we assessed the safety and activity of bortezomib added to the rituximab (R) plus BEAM (carmustine, etoposide, cytarabine, melphalan) regimen in patients with relapsed lymphoma undergoing alloSCT. Primary GVHD prophylaxis consisted of tacrolimus and methotrexate. Bortezomib (1 to 1.3 mg/m2 per dose) was administered i.v. on days -13, -6, -1, and +2. We performed inverse probability weighting analysis to compare GVHD and survival results with an historical control group that received R-BEAM without bortezomib. Thirty-nine patients were assessable for toxic effects and response. The median age was 54 years. The most common diagnosis was diffuse large B cell lymphoma (41%). Twenty-two patients (56%) and 17 patients (44%) received their transplants from matched related and matched unrelated donors, respectively. The maximum tolerated bortezomib dose was 1 mg/m2. The weighted cumulative incidences of grades II to IV and III or IV acute GVHD were 50% and 34%, respectively; these incidences and survival rates were not significantly different from those of the control group. Median survival was not reached in patients age ≤ 50 years and with a long follow-up time of 60.7 months. The R-BEAM regimen has a survival benefit in lymphoma patients age ≤ 50 years undergoing alloSCT. The addition of bortezomib has no impact on survival or incidence of GVHD.

Bendamustine as part of conditioning of autologous stem cell transplantation in patients with aggressive lymphoma: a phase 2 study from the GELTAMO group.

We conducted a phase 2 trial to evaluate the safety and efficacy of bendamustine instead of BCNU (carmustine) in the BEAM (BCNU, etoposide, cytarabine and melphalan) regimen (BendaEAM) as conditioning for autologous stem-cell transplantation (ASCT) in patients with aggressive lymphomas. The primary endpoint was 3-year progression-free survival (PFS). Sixty patients (median age 55 [28-71] years) were included. All patients (except one who died early) engrafted after a median of 11 (9-72) and 14 (4-53) days to achieve neutrophil and platelet counts of >0.5 × 109 /l and >20 × 109 /l, respectively. Non-relapse mortality at 100 days and 1 year were 3.3% and 6.7%, respectively. With a median follow-up of 67 (40-77) months, the estimated 3-year PFS and overall survival (OS) were 58% and 75%, respectively. Patients in partial response at study entry had significantly worse PFS and OS than patients who underwent ASCT in complete metabolic remission, and this was the only prognostic factor associated with both PFS (Relative risk [RR], 0.27 [95% confidence interval {CI} [0.12-0.56]) and OS (RR, 0.40 [95% CI 0.17-0.97]) in the multivariate analysis. BendaEAM conditioning is therefore a feasible and effective regimen in patients with aggressive lymphomas. However, patients not in complete metabolic remission at the time of transplant had poorer survival and so should be considered for alternative treatment strategies.

Rituximab-PECC induction followed by 90 Y-ibritumomab tiuxetan consolidation in relapsed or refractory DLBCL patients who are ineligible for or have failed ASCT: results from a phase II HOVON study.

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after, or ineligible for, autologous stem cell transplantation (ASCT) have a dismal prognosis. This phase II study evaluated treatment with R-PECC (rituximab, prednisolone, etoposide, chlorambucil, lomustine), every 28 days for 4 cycles in 62 patients, followed by radio-immunotherapy consolidation with 90 Y-ibritumomab tiuxetan in responsive patients. Primary endpoints were failure-free survival (FFS) and incidence of grade ≥3 adverse events from start of 90 Y-ibritumomab tiuxetan. The overall response rate after R-PECC was 50%. Twenty-nine of 31 responsive patients proceeded to 90 Y-ibritumomab tiuxetan. Five out of 15 partial remission patients converted to complete remission after 90 Y-ibritumomab tiuxetan. One-year FFS and overall survival (OS) from start of 90 Y-ibritumomab tiuxetan was 52% (95% confidence interval [CI], 33-68%) and 62% (95% CI, 42-77%), respectively. One-year FFS and OS from start of R-PECC was 28% (95% CI, 17-39%) and 49% (95% CI, 36-61%), respectively. Toxicities of R-PECC and 90 Y-ibritumomab tiuxetan were mainly haematological. In conclusion, for relapsed DLBCL patients the largely oral R-PECC regimen achieves promising response rates, combined with an acceptable safety profile. Consolidation with 90 Y-ibritumomab tiuxetan resulted in long-term response durations in approximately one third of the patients that received it.

Evaluation of toxicity of carmustine with or without bevacizumab in patients with recurrent or progressive high grade gliomas.

PURPOSE: An increased incidence in hematologic toxicity has been reported with the addition of bevacizumab to lomustine for patients with recurrent or progressive high grade gliomas (HGG). Data regarding incidence of toxicity with combination bevacizumab and carmustine is limited. The purpose of this study is to compare toxicity of single agent carmustine and carmustine plus bevacizumab for patients with HGGs. METHODS: This single center retrospective study at Memorial Sloan Kettering Cancer Center included pathologically confirmed HGG with age ≥ 18 years who received carmustine between January 2003 and May 2017. RESULTS: Sixty-five patients with HGGs collectively received 110 doses of BCNU during the specified time period. Sixteen patients received single agent BCNU (30 doses); 49 patients received combination bevacizumab with BCNU (80 doses). There was no significant difference in incidence or grade of toxicity between single agent and combination therapy with respect to hepatotoxicity, leukopenia, lymphopenia, neutropenia, anemia, and thrombocytopenia. Rates of grade 3 and 4 neutropenia (20% vs 13.8%, p = 0.55) and thrombocytopenia (23.3% vs 23.8%, p = 1) did not differ between single agent BCNU versus combination therapy. When stratified based on dose ( < 150 mg/m2, 150 mg/m2, > 150 mg/m2), there was no statistically significant difference between the two groups with respect to grade 3 and 4 neutropenia or thrombocytopenia. CONCLUSIONS: This is the first study to report the toxicity of carmustine with or without bevacizumab for the treatment of recurrent and refractory HGG. The addition of bevacizumab to carmustine did not increase incidence or grade of hematologic toxicity when compared to single agent carmustine.

A multicenter randomized phase III study for newly diagnosed maximally resected glioblastoma comparing carmustine wafer implantation followed by chemoradiotherapy with temozolomide with chemoradiotherapy alone; Japan Clinical Oncology Group Study JCOG1703 (MACS study).

A randomized phase III trial in Japan commenced in June 2019. The present standard treatment for newly diagnosed glioblastoma is maximal resection followed by chemoradiotherapy with temozolomide. The purpose of this study is to confirm the superiority of maximal resection with carmustine wafer implantation followed by chemoradiotherapy with temozolomide over the standard maximal resection followed by chemoradiotherapy with temozolomide in terms of overall survival for newly diagnosed glioblastoma. A total of 250 patients will be accrued from 35 Japanese institutions in 5.5 years. Patients with >90% surgical resection will be registered and randomly assigned to each group with 1:1 allocation. The primary endpoint is overall survival and the secondary endpoints are progression-free survival, loco-regional progression-free survival and incidence of adverse events. This trial has been registered in the Japan Registry of Clinical Trial, as jRCT1031190035 [https://jrct.niph.go.jp/en-latest-detail/jRCT1031190035].

miRNA-26a expression influences the therapy response to carmustine wafer implantation in patients with glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme is the most frequent malignant brain tumor in adults being marked with a very poor prognosis. Therapy concept implies concomitant radio-chemotherapy and facultative implantation of carmustine-eluted wafer. Current literature suggests microRNA 26a expression in glioblastoma to interact with alkylating chemotherapy. Subsequently, the aim of this study was to investigate the correlation of miRNA-26a expression and carmustine wafer implantation and its potential usefulness as a predictive marker for therapy response. METHODS: In total, 229 patients with glioblastoma multiforme were included into the final analysis. Of them, 80 cases were recruited from the Saarland University Medical Center for a retrospective matched-pair analysis stratified after therapy regime: One group (carmustine wafer group; n=40) received concomitant radio-chemotherapy with carmustine wafer implantation. The other group (control group; n=40) only received concomitant radio-chemotherapy. The results were confirmed by comparing them with an independent dataset of 149 patients from the TCGA database. All tumor specimens were evaluated for miRNA-26a expression, MGMT promoter methylation, and IDH1 R132H mutation status, and the results were correlated with the clinical data. RESULTS: Twenty-three patients in the carmustine wafer group showed low expression of miRNA-26a, while 17 patients showed a high expression. In the control group, 28 patients showed low expression, while 12 patients showed a high expression. The patients with high miRNA-26a expression in the carmustine wafer group were characterized by a significantly longer overall (hazard ratio [HR] 2.750 [95% CI 1.352-5.593]; p=0.004) and progression-free survival (HR 3.091 [95% CI 1.436-6.657]; p=0.003) than patients with low miRNA-26a expression. The 17 patients in the carmustine wafer group with high miRNA-26a expression showed a significantly longer progression-free survival (p=0.013) and overall survival (p=0.007) compared with the control group. There were no such correlations identified within the control group. TCGA datasets supported these findings. CONCLUSIONS: MiRNA-26a expression turned out to be a promising predictor of therapy response and clinical outcome in glioblastoma patients treated with carmustine wafer implantation. For evaluation of the role of miRNA-26a in a combined therapy setting, further studies are needed in order to translate general findings to the patient's individual situation.