Central Nervous System Relapse Research Articles

Clinical Characteristics and Outcomes of Limited Stage High Grade B-Cell Lymphoma with MYC/BCL2 and/or BCL6 Rearrangements: A Single Center Experience

Introduction: High grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangements (HGBCL MYC/BCL2 and/or BCL6-R) is a group of aggressive lymphomas associated with poor outcomes when treated with R-CHOP. Most HGBCL present in advanced stage and have a high risk for CNS relapse. MYC partner (Immunoglobulin (IG) vs. Non-IG) status has been correlated with clinical outcomes. Recent data suggests that MYC/BCL6 translocations may not portend the same inferior outcomes as MYC/BCL2-R and that limited stage HGBCL MYC/BCL2-R may have similar PFS and OS when treated with intensive chemotherapy vs. R-CHOP. In this study, we aimed to build upon the paucity of data available by describing the clinical characteristics of limited stage HGBCL including the risk of CNS relapse, and the role of MYC partner on clinical outcome. Methods: We performed a retrospective analysis of pts with newly diagnosed HGBCL MYC/BCL2 and/or BCL6-R at MSKCC from 1/2010 to 9/2022. All pts had pathological confirmation conducted at MSKCC. Patient demographics, disease/treatment history, clinical response (CRR and ORR), PFS and OS were extracted from electronic medical record. Stage modified IPI (smIPI) [age>60, elevated LDH, Stage II/IIE, ECOG ≥2] and Stage Adjusted IPI (stIPI) [age >60, elevated LDH, ECOG ≥2] were calculated. PFS and OS were estimated using the Kaplan-Meier method, and comparisons were made using log-rank test. Associations between survival outcomes, clinical, and treatment characteristics were evaluated using Cox regression models, from which HRs and corresponding 95% CIs were obtained. FISH for MYC partner was performed on archived tissue. Results: A total of 188 patients were identified with HGBCL MYC/BCL2 and/or BCL6-R. Nine pts were excluded due to limited information, and 41 pts were identified as having limited stage disease. Median age at diagnosis was 60 years (22-88 years), 63% had Stage II disease, 34% had extranodal involvement of which 50% involved the GI tract, 65% had a smIPI of 0-1, 75% with stIPI of 0-1, and 24% had transformed disease. Regarding rearrangement status, 41% of patients had MYC/BCL2-R 22% were characterized by MYC/BCL6-R and 37% had MYC/BCL2/BCL6-R . The median diagnosis-to-treatment interval was 23 days. First-line treatment included DA-R-EPOCH (76%), R-CHOP (20%), R-CODOX-M-IVAC (2%), and R-GCVP (2%) (median of 6 cycles). Twenty-seven percent received radiation. Thirty-two percent of patients received CNS prophylaxis, with the majority receiving IT-chemotherapy alone (median of 4 doses). After a median follow-up of 48 months, the median PFS was not reached and median OS was 63 months, respectively (Table 1). The 2-year PFS and OS were 56% and 67%, respectively. The ORR and CRR were both 73%. Fifteen patients had relapse/refractory disease, with the majority being primary refractory (12/15). Seven pts received salvage with ASCT (n=1), CAR T-cell therapy (n=4) or both (n=2). Eleven died due to progressive disease. No CNS relapses occurred. MYC/BCL2-R had inferior outcomes with a median PFS of 17 months (95% CI 6.4-27.6) as compared to MYC/BCL6-R (not reached) (P=0.0079, Fig 1), and there was no additional impact on PFS and OS if MYC/BCL2/BCL6-R was present compared to MYC/BCL2-R alone. In a univariate analysis, elevated LDH (p=0.04), MYC/BCL2 (p=0.009), and stIPI ≥2 (p=0.0025) were associated with inferior PFS as well as OS. On the contrary, extranodal disease, age, ECOG ≥2, smIPI, bulky disease, consolidation with radiation, transformed disease, and intensive chemotherapy (DA-R-EPOCH) did not impact outcome. MYC partner evaluation and copy number analysis (n=31) is in progress. Conclusions: In our series,pts with limited stage MYC/BCL2-R had poor outcomes while MYC/BCL6-R experienced favorable outcomes. There was no additional prognostic impact when BCL6-R is present with MYC/BCL2-R . This adds to the growing evidence that MYC/BCL6-R is not a poor prognostic factor in HGBCL. Primary refractory disease defines the majority of treatment failures in our study and is associated with dismal outcomes, although our CAR-T cell experience was limited due time period of this study. Despite this, our results emphasize the need for improved treatment strategies for this patient population. Ongoing analysis of MYC partner and copy number analysis may reveal genetic mechanisms driving outcomes. No CNS relapses occurred, suggesting that CNS prophylaxis can be safely omitted for the majority.

A Retrospective Study on Outcomes of Secondary CNS Lymphoma: Pattern of Relapse, Prognostic Factors, and Role of Consolidation Therapy

Introduction Secondary CNS lymphoma (SCNSL) remains a treatment challenge in patients (pts) with aggressive lymphoma. Outcome of SCNSL is poor. Pts are often treated with high dose Methotrexate (HD-MTX) based regimens followed by autologous stem cell transplant (auto SCT). However, the benefit of consolidation therapy is not well established. There is limited data on the treatments and outcomes of SCNSL. In this single institution study, we aim to analyze the role of consolidation therapy and potential prognostic factors of outcomes in SCNSL. Method All pts with a diagnosis SCNSL who presented to Moffitt Cancer Center, FL, USA between 2017 and 2022 were included. The hazard ratios (HRs) were evaluated in the univariate and multivariate analysis using the cox proportional hazard mode. All analyses were done using SAS 9.4. Results A total of 60 pts with SCNSL were identified. The median age was 63 years (range 26-83 years); 27 (45%) were female; 13 (21.7%) had Eastern cooperative oncology group performance status (ECOG) ≥2. Entire cohort was divided in 3 subgroups: pts with concurrent CNS involvement at the time of initial diagnosis with systemic lymphoma (Sys-CNS) [22 (36.7%)]; pts with isolated CNS relapse (R-SCNS) [30 (50.0%)]; and pts with simultaneous CNS and systemic relapse (R-Sys-CNS) [8 (13.3%)]. 31 (51.7%) pts had brain parenchymal involvement, 24 (40%) had leptomeningeal disease, 4 (6.7%) had both leptomeningeal and parenchymal involvement, and 1 (1.7%) had ocular disease. 58(96.6%) pts had diffuse large B cell lymphoma (DLBCL) histology; 9 (15%) had DLBCL with MYC and BCL2 rearrangement; 10 (16.7%) had DLBCL MYC and BCL2 expression. For induction therapy of SCNSL, 53 (88.3%) of pts received HD MTX-based chemotherapy; 2 (3.3%) received Bruton tyrosine kinase inhibitor (BTKi), and 5 (8.3%) with meningeal disease alone received IT chemotherapy and/or rituximab(R). Sys-CNS pts also received R-CHOP or DA-R-EPOCH while R-Sys-CNS pts received R-Polatuzumab or Polatuzumab-R-Bendamustine. 20 (33.3%) received consolidation either by WBRT [13 (21.7%)] or auto SCT [4 (6.7%)]; 3 (5.0%) proceeded with chimeric antigen receptor (CAR-T) therapy. The overall response rate (ORR) for entire cohort was 55.2% (34.5% complete response CR and 20.7% partial response PR). However, improved ORR and CR were observed with 14(73.68%) and 9 (47.37%) respectively in pts who received consolidation. ORR and CR for pts with Sys-CNS, R-SCNS, R-Sys-CNS were 13 (61.9%)/ 10 (47.6%), 14 (48.3%)/9 (31%) and 2 (25%)/ 2 (25%), respectively. After a median follow up of 33.6 months, median OS was 8.3 months with a 2-year survival probability of 33.8% (95% CI: 21.7-46.3%); the PFS was 6.5 months with a 2-year PFS probability of 32.9% (95% CI: 20.7-45.6%). Consolidation therapy with either auto SCT or WBRT had significant survival benefit. In this subgroup, median OS is not reached (NR) and the 2-year OS probability was 59.6% (95% CI: 32.9-78.7%); median PFS was 25.6 months and 2-year PFS probability was 53.3% (95% CI: 27.5-73.6%). After the first-line therapy for CNS disease, 21(35%) pts experienced relapsed. However, relapse rate in consolidation group [7 (36.8%)] was almost similar to those who did not receive consolidation [14 (34.2%)] (table 1). 39 (65%) pts died; 29 (48.33%) from disease progression, 3 (5%) from therapy related side effect and 7(11.7%) from other causes. In the univariate analysis, ECOG PS ≥2 [HR 3.60 (CI:1.80-7.20), p<0.001], lack of consolidation therapy [2.45 (CI:1.12-5.36), p=0.024], <3 cycles of HD-MTX containing regimen [2.85 (CI: 1.47-5.520), p=0.002] and double hit lymphoma [2.27 (CI: 1.02-5.06), p=0.045] were associated with worse OS. In the multivariate analysis, R-SYS-CNS, <3 cycles of HD-MTX, ECOG ≥2 and lack of consolidation remained significant. Lack of consolidation and receiving <3 cycles of HD-MTX were associated with inferior PFS in both univariate and multivariate analysis (figure 1). Conclusion Outcomes of aggressive B cell lymphoma with CNS involvement remain poor. The median OS was 8.3 months in our cohort. After adjusting for confounding factors, receiving >3 cycles of HD-MTX based regimen and consolidation with either WBRT or auto SCT were associated with improved outcomes. Pts with simultaneous CNS and systemic relapse had worse OS. Prospective studies are needed to evaluate optimal treatment for SCNSL.

Impact of Central Nervous System (CNS) Leukemia Status-Based Therapeutic Protocol Change on the Incidence of CNS2 Diagnosis in Pediatric B-Lymphoblastic Acute Leukemia

B-lymphoblastic acute leukemia (B-ALL) is the most prevalent cancer among children, and prophylactic central nervous system (CNS) therapy has significantly contributed to high cure rates for the past 50 years. However, relapses in bone marrow and/or CNS continue to pose challenges to achieving cure for all patients, especially in those with high-risk disease. CNS status at diagnosis, defined as CNS1 (no blasts present), CNS2 (blasts with <5 total white blood cells [WBC] per mm 3 in a cerebrospinal fluid [CSF] sample), and CNS3 (blasts with ≥5 total WBC per mm 3 or grossly traumatic), plays a crucial role in determining treatment stratification. In the past, patients with CNS1 and CNS2 received similar therapy, but evidence suggested that those with CNS2 were at a higher risk for marrow and/or CNS relapse. As a result, the Children's Oncology Group (COG) frontline trials AALL1131 and AALL0932 implemented additional CNS therapy for CNS2 patients beginning in 2012 and 2016, respectively, specifically twice weekly intrathecal chemotherapy until CSF cleared of disease 3 consecutive times. This change highlighted the necessity for accurate identification of CNS2. Based on anecdotal observation, we hypothesized that the incidence of CNS2 among pediatric B-ALL patients at diagnosis was higher after this therapeutic change due to pathologist awareness of its implications for patient management. The electronic medical records of all consecutive pediatric patients diagnosed with B-ALL at Children's Hospital Los Angeles (CHLA) from September 2008 to December 2019 were reviewed. CSF WBC count and blast involvement were used to calculate CNS status. Blast involvement was determined by one or more pathologists per case by morphologic review of cytocentrifuged CSF material. The patients were divided into two cohorts, one before (cohort A) and one after (cohort B) the COG AALL0932 protocol change (May 20, 2016). Differences between cohorts were evaluated via Fisher's exact test and Wilcoxon rank sum test. All tests were two-sided, except for CNS2 status, and significance level was set a priori at 0.05. During the study period, 391 patients were diagnosed with B-ALL at CHLA. These included 192 patients prior to the CNS status-based therapeutic change (cohort A) and 199 patients after the therapeutic change (cohort B). The incidence of CNS2 status was higher in cohort B (20%) than in cohort A (13%) (p=0.052). Conversely, the incidence of CNS1 status was lower in cohort B (77%) than in cohort A (85%), while the incidence of CNS3 was similar before (5%) and after (4%) the protocol change. There were no differences between the cohorts in patient age at diagnosis [cohort A: mean age 8.91 years (SD 5.67 years) vs. cohort B: mean age 8.10 (SD 5.62 years); p=0.20], sex (cohort A: 59.9% male vs. cohort B: 58.8% male; p=0.80), or ethnicity (cohort A: 76.0% Hispanic vs. cohort B: 67.7% Hispanic; p=0.09). These data suggest that the incidence of CNS2 status in pediatric patients with B-ALL at our institution was higher after (20%) than before (13%) the COG protocol changes that began treating CNS2 patients more intensively than CNS1 patients. In addition to increased frequency of intrathecal chemotherapy, in the ongoing frontline COG standard-risk ALL trial, patients with CNS2 status and neutral cytogenetics are upstaged to higher-risk therapy irrespective of end-induction response. A limitation of this study is that pathologist reviewers of CSF cytospin morphology at the time of CNS assignment differed during the two time periods, such that an observational bias cannot be entirely excluded. Notably, flow cytometry - a more sensitive methodology than cytospin morphology for detection of leukemic cells in CSF material - was not used in these cohorts, but increasingly widespread adoption of such techniques may further increase the incidence of CNS2, including in patients who would otherwise have been diagnosed with CNS1 disease (by cytospin morphology) and as such may be overtreated. Future directions of our study include examination of clinical outcome as well as recent (2021-present) patterns of flow cytometry use in CSF specimens and associated diagnoses of CNS disease in pediatric patients with B-ALL at diagnosis.

Survival and CNS Relapse in Patients with CD5-Positive Diffuse Large B-Cell Lymphoma: A Multi-Institutional Observational Study in Japan

Background: CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is usually characterized by activated B-cell type, poor prognosis, and frequent central nervous system (CNS) relapse. A sandwich therapy of dose-adjusted (DA)-EPOCH-R combined with high-dose methotrexate (HD-MTX) (DA-EPOCH-R/HD-MTX) showed excellent efficacy in a phase II study for newly diagnosed stage II-IV CD5+ DLBCL, including 2-year (yr) overall survival (OS), progression-free survival (PFS), and CNS relapse rates of 89%, 79%, and 9%, respectively (Miyazaki K, et al. Haematologica, 2020). It has been introduced in practice in Japan; however, the current status of treatment and the prognosis in patients with CD5+ DLBCL are unclear. Methods: We retrospectively analyzed the prognosis and CNS relapse rate of consecutive patients with untreated CD5+ DLBCL who were diagnosed at 30 hospitals in Japan from January 2016 to December 2021. Patients who were diagnosed with double-/triple-hit lymphoma, those with CNS involvement at diagnosis, and those who had not received any anthracycline-containing chemotherapy with rituximab (R-chemo) were excluded. We identified risk factors for OS using Cox proportional hazards method. The outcomes in the stage II-IV patients who received DA-EPOCH-R/HD-MTX were compared with those of the phase II study. To evaluate the efficacy of CNS prophylaxis, we divided patients into four groups: HD-MTX alone, intrathecal administration of MTX alone (IT MTX), both HD-MTX and IT MTX (HD/IT MTX), and no CNS prophylaxis. Results: Among the413 enrolled patients, 20 were excluded due to ineligible diagnosis or insufficient clinical information, 18 had CNS involvement at diagnosis, and 27 did not receive R-chemo. As a result, 348 patients were eligible and showed the following features: median age, 71 yrs (range, 23-92); male sex, 54%; stage II-IV, 90%; stage III or IV, 73%; ECOG performance status (PS) > 1, 30%; > 1 extranodal site, 42%; elevated serum lactate dehydrogenase (sLDH) level, 71%; high-intermediate or high International Prognostic Index (IPI), 63%; high CNS-IPI, 41%; and B symptoms, 29%. According to Hans's criteria, the nongerminal center B-cell type accounted for 67% of the 276 cases examined. Among the 348 patients, 62 (18%) received DA-EPOCH-R/HD-MTX, and 286 (82%) were treated with other R-chemo, such as R-CHOP (n = 254). The median age was 63.5 yrs (range, 29-75) in the DA-EPOCH-R/HD-MTX group and 72 yrs (range, 23-92) in the other R-chemo group. The DA-EPOCH-R/HD-MTX group included significantly more patients aged ≤ 60 yrs ( P < 0.001), although it tended to have more patients with ECOG PS > 1 than the other R-chemo group ( P = 0.069). Patients who received IT MTX made up 16% of the DA-EPOCH-R/HD-MTX group and 31% in the other R-chemo group. HD-MTX was used in 100% of patients in the DA-EPOCH-R/HD-MTX group and 17% of patients in the other R-chemo group. Details of CNS prophylaxis were HD-MTX alone in 84 patients (24%), IT MTX alone in 70 (20%), both HD/IT MTX in 28 (8%), and no CNS prophylaxis in 166 (48%). At a median follow-up of 43 months, the 2-yr OS, PFS, and CNS relapse rates of patients with stage II-IV disease in the DA-EPOCH-R/HD-MTX group were 87% (95% CI, 73-94%), 78% (95% CI, 63-87%), and 7.3% (95% CI, 2.8-18.2%), respectively. There were no significant differences in OS or PFS between stage I and stage II-IV patients in the DA-EPOCH-R/HD-MTX group. In all 348 patients with stage I-IV, both the OS ( P = 0.044) and PFS ( P = 0.043) in the DA-EPOCH-R/HD-MTX group were longer than those in the other R-chemo group. The 2-yr OS in these groups were 89% and 78%, and their 2-yr PFS were 78% and 64%, respectively. Multivariate analysis identified elevated sLDH ( P = 0.005), > 1 extranodal involvement ( P < 0.001), no IT MTX ( P = 0.005), and no DA-EPOCH-R/HD-MTX ( P = 0.005) as independent risk factors for OS. The 2-yr CNS relapse rate was 6.5% in the DA-EPOCH-R/HD-MTX group (n = 4) and 10.0% in the other R-chemo group. There were no significant differences in the CNS relapse rate between the two groups ( P = 0.54). The 2-yr CNS relapse rates of HD-MTX, IT MTX alone, both HD/IT MTX, and no prophylaxis were 9.8%, 9.1%, 3.7% (n = 1), and 10.3%, respectively. Conclusions: Our results confirmed favorable survival in the phase II study of DA-EPOCH-R/HD-MTX in clinical settings. DA-EPOCH-R/HD-MTX and IT MTX were associated with longer OS of patients with CD5+ DLBCL in our study cohort, warranting further investigation.

An International Multicenter Study of Primary Vitreoretinal Lymphoma from the Australasian Lymphoma Alliance and Collaborators

Background: Primary vitreoretinal lymphoma (PVRL) is a rare high-grade extranodal non-Hodgkin lymphoma characterized by frequent and often fatal central nervous system (CNS) relapse. Despite improved outcomes for patients with primary CNS lymphomas over the last decade, approaches to the diagnosis and management of PVRL remain contentious. Given limited prospective data to date, there is need to better elucidate current international practice in the modern era to optimize outcomes for this patient group. Methods: Patients with pathologically confirmed PVRL diagnosed between January 2010 and December 2022 were identified from ten sites across Australia, Singapore, Canada and the United Kingdom. Patients were aged ≥18 years, with isolated PVRL at diagnosis (i.e. no concomitant CNS involvement at baseline or secondary vitreoretinal involvement). Variables included were baseline demographic data, presenting symptoms, diagnostic procedures undertaken and sample characteristics such as cytological, immunocytochemical and flow cytometric features. Where available, molecular results and biomarkers such as IL-10 and IL-6 were also collected. Treatment approaches including local, systemic and combined local/systemic therapies were captured. Outcomes measured included response rates, patterns of relapse, progression-free (PFS) and overall survival (OS). Results: 36 patients were identified with a median age at diagnosis of 68 years (range 38-89) with a female predominance (58%). Most patients presented with bilateral involvement (72%) with decreased visual acuity being the predominant presenting symptom (53%). Most patients received a PVRL diagnosis within weeks to months of symptom onset, however a third of patients had >12 months delay to diagnosis. Ancillary diagnostic tests such as flow cytometry, molecular and cytokine measurements performed in a minority of patients only, largely due to sample viability and paucity. Concurrent CNS involvement was evaluated by brain MRI in 97% with diagnostic lumbar punctures performed in 64%. Exclusion of systemic disease was predominantly done via PET or PET/CT (69%) with the remainder via CT alone (Table 1). Upfront treatment choices were highly varied across participating sites with incorporation of systemic therapy in the majority (64%) of cases, either alone (25%) or in combination with local therapies (39%). For those who received systemic therapy, all incorporated high-dose methotrexate with the median dose delivered of 3.5g/m 2 per cycle and rituximab was incorporated in 48%. Autologous stem cell transplantation (ASCT) was part of frontline management in 19% of cases, and the median age of those receiving frontline ASCT was 55 years versus 71 years in those who did not. With median follow-up of 57 months (IQR 24-74 months), the median OS was 90 months whilst median PFS was only 23 months (Figures 1 and 2). 18 patients experienced disease relapse during follow up, only 2 of which had received frontline ASCT. The median PFS and OS of those who received frontline ASCT was not reached and 92 months respectively. Patients who had systemic treatment incorporated into frontline management had a trend toward improved OS than those who did not (Figure 3). Of those with relapsing disease, 14 (78%) had CNS involvement, and 29% of these patients experienced concurrent CNS and systemic involvement at relapse. Median OS from time of relapse was 8 months (IQR: 3-89 months). Of the 14 deaths occurring during follow up, 6 (43%) were secondary to lymphoma, 2 (14%) were related to toxicities of treatment and the rest were unknown or related to other co-morbidities. Conclusion: To our knowledge, this is the largest international multicenter cohort of patients with isolated PVRL reported in the modern era. The apparent improvement in OS compared with historical cohorts may reflect improvements in therapy in the recent decade, and incorporation of systemic therapy in frontline management demonstrated a trend to improved OS. However, high rates of CNS relapse continue to be a challenge. Delays in diagnosis and variation in diagnostic and management pathways reflect the need to develop prospective studies and international consensus guidelines for managing this rare lymphoma.

Screening Cerebrospinal Fluid for Aggressive B-Cell Lymphoma: Significance of Clonal Populations Found with 8-Color Flow Cytometry

Background: Secondary central nervous system (CNS) lymphoma confers a poor prognosis, and prompt identification is critical for guiding management. Over the last decade, we have employed cerebrospinal fluid (CSF) analysis with 8-color flow cytometry (FCM) in screening patients deemed at risk of CNS relapse. However, there is little data to guide interpretation and management of positive results, and concurrent clinical and radiographic features of FCM positive (FCM+) patients, remain areas of uncertainty. Methods: We analyzed newly diagnosed (ND) and relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) and high grade B cell lymphoma (HGBCL) patients who underwent a screening lumbar puncture (LP) from 2011-2020. Clinical, imaging, and CSF findings (differential, cytology, FCM) were collected. Patients with prior CNS involvement or FCM showing CLL/low-grade B-NHL were excluded. “FCM-only” patients were defined as FCM+ but without any other evidence of CNS spread (negative cell count/cytology, MRI, and no symptoms), whereas others were deemed to have overt CNS disease. Results: There were 415 LPs among 361 patients (243 ND, 172 R/R). 21 (5%) patients were FCM+, 10 ND and 11 R/R patients (Table 1). Four had FCM-only involvement (2 ND, 2 R/R). Among these, the clonal population was 1.63% of WBC (range, 0.3-2.7%), and 3 had concurrent bone marrow (BM) or peripheral blood (PB) involvement. All 4 received intrathecal (IT) therapy. At median follow up of 23 months, 3 (75%) have died (2 from CNS disease progression, 1 unknown due to loss in follow up), and 1 remains alive in remission 44 months later following IT methotrexate (MTX) and CAR T-cell therapy. 17 had overt CNS disease (8 ND, 9 R/R). The clonal population was 9% (range, 0.2-98%). Eight (47%) had concurrent BM or PB involvement. Twelve (70%) received IV high dose MTX, and the remainder received only IT therapy. At median follow up of 42 months, 9 (53%) have relapsed (2 CNS only, 1 systemic, 6 both), and 9 have died. Median time to CNS relapse was 5 months. Conclusions: CSF 8 color FCM screening of DLBCL/HGBCL patients yields a low proportion of positive results, mostly in the setting of overt CNS disease. However, even FCM-only patients had poor outcomes (2/4 with CNS progression), suggesting that blood contamination does not explain CSF findings, and that these patients should be approached as secondary CNS involvement. Better pt selection for CSF screening is needed to reduce unnecessary LPs. Intensified or novel approaches for all FCM+ patients are needed.

CNS Irradiation in Adult De Novo B-Precursor ALL / Lbl: Results of the Randomized GMALL T rial 08/2013 Indicate Potential Antileukemic Efficacy

In the past decade outcome of adult ALL was improved significantly using pediatric-based chemotherapy. The GMALL Trial 08/2013 (NCT02881086) for patients (pts) aged 18-55 years (yrs) with newly diagnosed ALL/LBL is a pediatric based regimen with MRD based treatment stratification and risk adapted stem cell transplantation (SCT) (Gökbuget et al, ASH 2021). CNS prophylaxis consisted of three doses i.th. MTX during induction II, 11 doses of triple i.th. for standard risk (SR) in consolidation (C)/maintenance and 1 dose before SCT in high risk (HR); 7 vs 1 cycle of HDMTX (1.5 g/m 2 as 24h infusion) were scheduled in SR and HR resp. Prophylactic fractionated CNS irradiation (RAD) with 24 Gy during induction II (IP2) was part of all previous GMALL trials. The trial incorporated a randomization for Ph/BCR::ABL1 negative (Ph-) B-precursor ALL/LBL without initial CNS involvement and treated until C1 in order to compare standard IP2 with i.th. MTX with vs without CNS RAD. The key endpoint was the time from start of induction to start of C1 in CR pts, reasoning that less toxicities and treatment delays would occur without CNS RAD. Further endpoints were remission duration (RD), event-free survival (EFS) and cognitive disturbances (DemTect Test). The statistical assumption was that it is possible to detect a shortening of time to C1 from 74 to 69 days with a power of more than 90% with 215 pts per arm with a two-sided α-niveau of 5%. Between 8/2016-8/2022 1023 pts from 78 centers were included. 512 pts had Ph- B-precursor ALL/LBL (497/15). 31 pts had initial CNS involvement (N=20) or were not randomized due to other reasons (N=11). 241 pts were randomized in arm A (RAD) and 241 in arm B (NoRAD). The median age was 33.5 (18-55) yrs; c/pre B-ALL versus pro B-ALL was present in 83% vs 17%. 191 were HR vs 291 SR. No significant differences were observed between both arms. 477 pts were randomized (ITT population) and 422 were eligible (analysis population) since they achieved CR and were treated until C1. Reasons for non-eligibility were protocol violation (N=5), early death (ED) (N=15), withdrawal (N=12), no CR before C1 (N=18) and late withdrawals in CR before C1 (N=10). 207 pts in the RAD-arm (86%) vs 215 pts in the NoRAD-arm (89%) were eligible. In the analysis population treatment per randomization was 97% in NoRAD and 95% in RAD arm. CR rates before C1 (95% RAD vs 96% NoRAD), ED rates (5% vs 4%), rates of grade III/IV leukopenia in IP2 (14% vs 16%) and infections (29% vs 29%) were similar. The median time to C1 was similar too (75 vs 76 days; p=0.34). Relapse rates (RR) were lower in RAD (13%) vs NoRAD (18%) (p=0.14). Whereas CNS relapses were infrequent in both arms (N=1 vs N=3 i.e. 1% vs 1%; p=0.62), the rate of BM±other relapses (11% vs 15%; p=0.15) was lower in the RAD arm. The cumulative incidence of CNS relapse at 3 yrs was 1% vs 1% and of all relapses 14% vs 20% (p=0.13). The EFS at 3 yrs was higher for the RAD (79% [95%-CI: 72% - 85%]) vs NoRAD (72% [95%-CI: 65% - 78%])(p=0.10) in the analysis population and 74% vs 67% (p=0.13) in the ITT population. In the ITT population the impact was statistically significant (p=0.05) in SR pts whereas no difference was detected in HR (i.e. pts with indication for SCT) (figure 1); differences did not reach significance in the analysis population. We further analyzed the impact of randomization arm on cognitive function (analysis population). After C1 results were available in 264 pts. In the RAD vs NoRAD arm 2% vs 2% resp. had low scores (0-8) and 10% vs 8% intermediate scores (9-12) indicating a relevant or limited cognitive disturbance. At the end of therapy (week 130), results are available in 53 pts treated in SR arm. 0% vs 4% had low and 4% vs 4% intermediate scores. Thus, relevant cognitive limitations were present in both arms. The primary endpoint (time to C1) was not met. Pts with RAD did have a trend towards better EFS and RD. The CNS RR was overall low but CNS RAD might have an impact on the systemic relapse rate in SR pts. We recorded no significant negative impact of CNS RAD on DemTect results, but this requires further observation. Results must be interpreted in the context of adult pts with potentially lower risks for cognitive disturbances compared to children and - on the other hand - a relatively low dose of systemic HDMTX. Overall, no clear negative effects of CNS RAD were detected whereas a trend towards positive impact on EFS was observed. GMALL 08/2013 is an independent academic trial funded by the Deutsche Krebshilfe.

A Single Center Experience with Using Dose-Adjusted Repoch in Elderly Patients with Large B-Cell Lymphoma

Background: RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) has been the predominant regimen for treatment of aggressive large B-cell lymphomas (LBCL). In the CALGB 50303 trial, REPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) was associated with similar efficacy but increased toxicity compared to RCHOP, however pts with higher risk disease by International Prognostic Index (IPI) had longer progression-free survival (PFS) with REPOCH therapy in the subgroup analysis ( J Clin Oncol, 2019). Providers may be hesitant to use REPOCH therapy in older, frail patients (pts) with high-risk LBCL due to concern for increased toxicity. One study demonstrated that empirically dose-reduced REPOCH (30-50% dose reduction by age group) was effective and well-tolerated in an elderly population ( Ann Hematol, 2018).A separate study showed significantly reduced neuropathy rates without compromised efficacy when vincristine doses in the REPOCH regimen were capped at 0.5 mg/d compared to 0.4 mg/m 2/d ( Leukemia & Lymphoma, 2019). At our institution, vincristine doses are capped at 0.4 mg/d for all pts, and REPOCH dosing is not empirically dose-reduced based for age alone. The aim of this study is to provide additional insights on the safety and efficacy of REPOCH in elderly pts diagnosed with LBCL with a routine vincristine dose cap of 0.4 mg/day (“REPOCH 0.4”). Methods: In this single cohort study, pts with newly diagnosed LBCL that received dose-adjusted REPOCH 0.4 at a single institution from August 2015 to October 2020 were retrospectively reviewed. Pts were excluded if they received fewer than 2 cycles, had CNS disease, transferred to another facility during treatment, or were lost-to-follow-up. Primary endpoints included adverse effects (AEs), overall response rates (ORR) via Lugano staging at end of treatment, 2y PFS, and overall survival (OS). Survival endpoints were estimated via Kaplan-Meier survival analysis. Secondary endpoints included CNS relapse rates and percentage of pts electing for hospice during therapy. Outcomes were descriptively compared to the historical cohort (N=241) in the CALGB 50303 trial receiving R-REPOCH without a vincristine dose cap ( J Clin Oncol, 2019) . Results: Forty-six pts were eligible for analysis (“entire cohort”), 19 of whom were 70 years or older (“70+ cohort”, figure 1). Median age in the entire and 70+ cohort was 67 and 75 years respectively. In the entire cohort, 23.9% of pts were double-hit, 43.5% had a non-germinal center phenotype, and 78.3% had stage III-IV disease. The median number of REPOCH 0.4 cycles received in both the entire and 70+ cohort was 6. In the 70+ cohort, 57.9% of pts were escalated to a dose level (DL) of 2 or 3 with no pts escalated beyond DL 3. Fifty-eight percent of pts in the entire cohort received intrathecal CNS prophylaxis and all pts received pegfilgrastim support. Pts in the entire cohort were older and higher-risk in comparison to the historical cohort as evidenced by IPI risk and double-expressor status. In the entire cohort, REPOCH 0.4 was well-tolerated (figure 2) with grade 3+ neuropathy rates of only 2.2% (5.2% in the 70+ cohort). Febrile neutropenia (all grades) occurred in 19.5% and 15.8% of the entire cohort and 70+ cohort respectively. Only 1 patient in the 70+ cohort experienced acute ejection fraction (EF) decline during therapy. ORR (complete and partial response) in the entire and 70+ cohort were 80% and 74% respectively. Complete response (CR) rates in the entire and 70+ cohort were both 63%. 2y PFS in the entire cohort was 68.3% (median not reached), and the 2y OS in the entire cohort was 82.9% (median not reached) which compares favorably to the 2y OS of 86.5% in the historical cohort. Overall, only 7% of pts elected for hospice and only 4% experienced CNS relapse. Conclusion: Pts with LBCL 70+ years tolerated dose-adjusted REPOCH 0.4 mg/d similarly to the entire cohort of all ages indicating that empiric dose reduction for age alone isn't necessary. CR rates were similar (63%) with pts 70+ years compared to pts in the entire cohort of all ages. REPOCH 0.4 mg/d was observed to have numerically lower rates of grade 3 or higher neuropathy (2.2%) compared to vincristine 0.4 mg/m 2/d (8.4%, J Clin Oncol 2019) and vincristine 0.5 mg/d dosing strategies (4.5%, Leukemia & Lymphoma 2019) . To our knowledge, this is the first report of outcomes with REPOCH using a vincristine dose cap of 0.4 mg/d.

Improving the Utilization and Tolerability of Thiotepa-Based Autologous Stem Cell Transplantation in Primary CNS Lymphoma

Background: Thiotepa-based autologous stem cell transplantation (ASCT) improves survival in primary central nervous system lymphoma (PCNSL) but up to 30-60% of patients are unable to receive ASCT after MATRix induction, frequently due to treatment-related adverse events. Common conditioning regimens such as thiotepa/BCNU or thiotepa/busulfan/cyclophosphamide have also been associated with risks of pulmonary toxicity or increased transplant-related mortality. Novel strategies to improve the utilization and tolerability of ASCT are therefore needed to maximize the curative potential of this therapy in PCNSL. Methods: This retrospective population-based study included all patients diagnosed with large B-cell lymphoma-type PCNSL who were intended for ASCT in the province of Alberta, Canada between 2011 and 2022. Provincial treatment guidelines recommended an abbreviated, low-intensity induction protocol to reduce toxicity and increase transplantation rates (Figure 1B). Step 1 included 2 cycles of rituximab/high-dose methotrexate (HD-MTX). Step 2 involved 1 cycle of rituximab/high-dose cytarabine (HDAC) for peripheral blood stem cell mobilization. Step 3 consisted of 2 cycles of rituximab/HD-MTX/HDAC and was made optional in July 2018 so that patients with sufficient disease response and performance status following Step 2 could proceed immediately to ASCT. Conditioning consisted of thiotepa 300 mg/m 2 ×2 days and busulfan 3.2mg/kg ×3 days (TT/Bu). Dose reductions of TT/Bu by 10% for every 5 years over the age of 60 were recommended as of May 2021. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method and compared between groups using the log-rank test. Results: The intention-to-transplant (ITT) cohort included 71 patients with median age 58 years (range 26-72), representing 81% of patients aged 18-60 and 55% of those aged 61-72 who were diagnosed with PCNSL in Alberta during the study period. The proportion of patients aged 61-72 who were treated with ITT increased from 42% before 2018 to 70% afterwards. Fifty-six (79%) ITT patients proceeded to ASCT while 15 (21%) did not due to poor performance status (n=6), treatment-related adverse events (n=5), or disease progression (n=4). There was 1 (1%) death due to infection-related non-relapse mortality (NRM) during induction. The routine omission of Step 3 starting in 2018 resulted in high transplantation rates at 29/35 (83%) compared to 27/36 (75%) in the preceding era. With median follow-up time 3.9 years, the 4-year PFS was 69% (95% CI 56-79%) and OS was 80% (95% CI 67-88%) in the ITT cohort (Figure 1A). For the 56 patients who received ASCT, 4-year PFS was 75% (95% CI 57-86%) and OS was 85% (95% CI 68-93%) from the time of ASCT. There was no significant difference in PFS between patients in complete response (CR)/unconfirmed CR versus partial response (PR) before ASCT (p=0.86); however, 5 patients with progressive disease before ASCT had inferior PFS compared to those with CR/CRu/PR (4-year PFS 40% vs 82%, p=0.0002). Relapse occurred in 8 (14%) patients at median 373 days (range 54-1411) after ASCT, including 7 with CNS relapse and 1 with systemic relapse. No patient in remission after ASCT received whole brain radiation therapy and most recovered without clinically significant neurologic deficits. There were no deaths due to transplant-related mortality. NRM occurred in 2 (4%) patients due to an unrelated cancer and stroke 1.1 and 4.3 years after ASCT, respectively. Among 27 patients >60 years old treated with ITT, 17 (63%) proceeded to ASCT, including 6 who received dose reductions of TT/Bu. The transplantation rate in this age group increased from 45% to 75% following the routine omission of Step 3. All 17 transplanted patients remain alive and in remission with median follow-up 2.5 years. Conclusion:In this real-world study of 71 patients with PCNSL, an abbreviated, low-intensity induction protocol resulted in high transplantation rates (~80%) and favorable long-term outcomes with 4-year OS 80%. Notably, TT/Bu conditioning achieved a low incidence of relapse with no transplant-related mortality observed, including among patients >60 years old. These data demonstrate that de-escalated induction therapy can result in improved rates of successful ASCT, thereby optimizing the outcomes of PCNSL.

CNS Radiotherapy As Bridging Prior to CAR T-Cell Therapy for Non-Hodgkin B-Cell Lymphoma

Introduction: Up to 80% of patients who receive CAR T-cell therapy (CAR T) for central nervous system lymphoma (CNSL) require bridging therapy, yet optimal regimens remain undefined. Radiotherapy is an established strategy for extracranial lymphoma that provides beneficial cytoreduction. However, CNS bridging radiotherapy (CNS-BRT) prior to CAR T is controversial due to concerns of potential enhanced neurotoxicity. We explored the safety and response profiles in patients treated with CNS-BRT prior to CAR T. Methods: We identified patients with non-hodgkin B-cell lymphoma who received CNS-BRT at our institution prior to commercial CAR T infusion. CNS-BRT was defined as treatment delivered between apheresis and CAR T infusion or within 30 days prior to apheresis, targeting the CNS parenchyma, leptomeninges, or epidural spine. Patients with epidural spine disease were included since the adjacent spinal cord is part of the treatment field. Safety was evaluated by rate of cytokine release syndrome (CRS) and immune effector associated neurotoxicity syndrome (ICANS) after CAR T. Best CNS response post CAR T was evaluated using the International Primary CNS Lymphoma Collaborative Group (IPCG) or Response Assessment in Neuro-Oncology (RANO) for parenchymal or leptomeningeal lesions, respectively. Cytoreduction from CNS-BRT was estimated by calculating the change in lesion size (sum of product diameter) from before and after CNS-BRT, but before CAR T infusion. Risk of any CNS relapse after CAR T was estimated using the Gray's method with death as a competing risk. Patients with epidural spine disease were not evaluate for CNS response or relapse. Results: 12 patients received CNS-BRT with median follow up of 8.5 months (range: 3.2 - 30.2), median age of 60 (30-76), median Karnofsky Performance Status (KPS) of 80 (range: 50 - 90). Histologies included diffuse large B cell (DLBCL) (n = 9), mantle cell (n = 2), and Burkitt lymphoma (n = 1), with disease localizing to the brain parenchyma (n = 6), leptomeninges (n = 4), and epidural spine (n = 2). 9 patients had secondary CNSL and 1 patient had primary CNSL. Prior to CNS-BRT, 11/12 patients had progressive disease. 5/12 patients had disease outside of the CNS. 5/12 patients received prior autologous hematopoietic stem cell transplantation. 9/12 patients received prior high dose methotrexate with median 46-day interval to CNS-BRT (range: 0 - 393). RT targets included whole brain (n = 3), involved site (partial) brain (n = 4), involved site spine (n = 4), and orbits (n = 1) with median dose 24 Gy (range: 15 - 33). CAR T products included Tisagenlecleucel (n = 4), Lisocabtagene maraleucel (n = 7), and Axicabtagene ciloleucel (n = 1). Among 10 patients with available toxicity grading, 6/10 experienced CRS (n = 1 grade (G) 1, n = 4 G2, and n = 1 G3), and 3/10 experienced ICANS (n = 1 G1, n = 1 G3, n = 1 G4). 6/10 patients required tocilizumab and/or steroids. CNS-BRT achieved a 74.4% (95% CI, 62.9 - 85.9) mean reduction in lesion size prior to CAR T infusion. Best CNS response after CAR T infusion included 3 complete responses (CR), 6 partial responses (PR), and 1 progressive disease (PD). The patients who achieved PR remained in PR at last follow up. The 12-month estimated risk of CNS progression after CNS-BRT and CAR T infusion was 20.0% (95% CI, 3- 49). CNS progression was not observed in patients who received involved site brain RT. Conclusion: Preliminary data suggest CNS-BRT achieves rapid cytoreduction prior to CAR T therapy and is associated with a favorable CNS response profile. While overall numbers are limited to date, the rate of severe CRS and ICANS is similar to that of historical series of CNSL patients treated with CAR T. However, a larger cohort will be required to determine the safety of CNS-BRT. These data support further study of RT, and exploration of involved site brain RT, as an effective bridging modality for CAR T-cell therapy in CNSL.

The Mini-Teddi-R Treatment Demonstrated a High Rate of Remission in Patients with DLBCL Involving the CNS Who Had Previously Been Exposed to BTK Inhibitors

Background: Secondary CNS B-cell lymphomas (SCNSL) are aggressive lymphomas with a bleak prognosis. TEDDI-R has been successful in achieving lasting remission in relapsed/refractory primary DLBCL of the CNS (PCNSL), but the effectiveness of ibrutinib-responsive tumors in SCNSL remains unknown. This study presents initial findings from the use of mini-TEDDi-R in SCNSL. Methods: Efficacy and safety data of mini-TEDDi-R were retrospectively analyzed for patients with DLBCL involving the CNS. All patients experienced relapse in the CNS or/and peripheral region after initial therapy. Brain parenchyma involvement allowed for treatment with MTX, Ara-c, and/or BTK inhibitors. The dosage of the drugs used in the original regimen was reduced, leading to the adoption of the term “mini-TEDDi-R.” Each 21-day cycle involved the following treatments: intravenous rituximab at a dose of 375 mg/m 2/day on days 1-2, oral temozolomide at a dose of 150 mg/m 2/day on days 2-5, intravenous infusion of 30 mg/m 2/day etoposide on days 2-5, intravenous infusion of 25 mg/m 2 of pegylated liposomal doxorubicin on day 2, intravenous infusion of dexamethasone at a dose of 10 mg/m 2/BID on days 1-5, and oral zanubrutinib at a dose of 200mg/BID or oral orelabrutinib at a dose of 150mg/qd or oral ibrutinib at a dose of 560mg/qd from day 1 until neutrophil count <0.5*10^9/L or platelet count <30*10^9/L. Additionally, intrathecal administration of 70 mg of cytarabine occurred on days 1 and 5, All remissions observed on MRI were confirmed through FDG-PET and CSF analysis. Results: Between December 2019 and June 2023, 24 patients with a median age of 53 (range 28-69) received mini-TEDDi-R treatment. All patients had DLBCL, comprising 16 (66.7%) non-GCB, 6 (25%) GCB, and 2 (8.3%) transformed from FL. All patients experienced relapse in the CNS system after a median of 6 (range 1-17) prior therapies, and all (100%) patients received prior anthracycline treatment. A total of 21 patients (87.5%) had received multiple lines of therapy before mini-TEDDi-R. Among them, 19 patients (79.2%) had received HD-MTX based salvage therapy, 11 patients (45.8%) had received HD-Ara-c based salvage therapy, and 14 patients (58.3%) had been exposed to BTK inhibitors. Seven patients (29.2%) showed triple resistance to MTX, Ara-c, and BTK inhibitors. Six patients had previously undergone transplantation, and four patients had experienced failure of CD19 CART treatment. Thirteen patients (54.2%) had isolated CNS disease, while 11 patients (45.8%) had both CNS and peripheral disease. Thirteen patients (54.2%) underwent 1 cycle of mini-TEDDi-R, 8 patients (33.3%) completed 2 cycles, 2 patients (8.3%) finished 3 cycles, and 1 patient (4.2%) completed 4 cycles. The objective remission rate (ORR) was determined to be 70.8%, with a complete remission (CR) rate of 58.3%. Notably, patients (N=14) exposed to BTK inhibitors previously exhibited a similar CR rate compared to patients (N=10) who had not received prior BTK inhibitor treatment (50% vs. 70%, p = 0.348). Patients (N=19) who had undergone HD-MTX based salvage therapy achieved an ORR of 74% and a CR rate of 58%. No significant difference in response rate was observed between patients with peripheral and non-peripheral secondary CNS involvement. In patients who achieved complete remission, only one patient experienced a second CNS relapse. Four patients bridged to auto-HSCT, 2 patients bridged to CART treatment, and 4 patients underwent auto-HSCT combined with CART treatment for consolidation. The median overall survival and median PFS have not been reached within the 11.8-month follow-up period. Toxicity was evaluated over 39 cycles. Grade 3 and 4 neutropenia occurred in 51% and 16% of cycles, respectively, while febrile neutropenia was observed in 10% of cycles. The median duration of neutropenia was 6 days (range 4-10). Three cycles (8%) were complicated by infections graded as ≥G3, but no opportunistic infections (including Aspergillus) were observed. Grade 3 and 4 thrombocytopenia occurred in 26% and 14% of cycles, respectively. The median duration of neutropenia was 7 days (range 3-14). Conclusions: The mini-TEDDi-R regimen demonstrated a favorable remission rate in patients with DLBCL involving the CNS. The treatment was well-tolerated, and patients with tumors that were previously exposed to BTK inhibitors and HD-MTX treatment also showed positive responses to mini-TEDDi-R.

CNS Prophylaxis Among Patients with HIV-Associated Diffuse Large B-Cell Lymphoma - a Single Center Retrospective Study

Title: CNS Prophylaxis Among Patients with HIV-Associated Diffuse Large B-Cell Lymphoma - A Single Center Retrospective Study Introduction: Patients with Human Immunodeficiency Virus (HIV) are known to develop Lymphoma at a higher rate compared with the general population, with Diffuse Large B-Cell Lymphoma (DLBCL) being the most common subtype. Historically, before the advent of HIV treatment with antiretroviral therapy (ART), HIV-associated DLBCL was considered a more aggressive type of lymphoma and all patients were treated with central nervous system (CNS) prophylaxis. However, since ART has been widely adopted, there is some data to suggest that HIV-associated DLBCL among those taking ART more closely resembles de-novo DLBCL and may not need to be universally treated with CNS prophylaxis. There are no good prospective trials evaluating which patients who develop HIV-associated DLBCL while on ART should receive CNS prophylaxis. Furthermore, studies that tried to predict which DLBCL patients are at greater risk for CNS relapse explicitly excluded patients with HIV. Despite the absence of data, guidelines have shifted and current NCCN guidelines now recommend that HIV patients with DLBCL should be risk stratified as de-novo DLBCL patients with respect to CNS directed therapy. In this study, patients with HIV-associated DLBCL were retrospectively analyzed to understand the patterns of CNS prophylaxis and effects on relapse free survival. Methods: The Electronic Medical Record was queried at a large academic medical center in New York City for patients with HIV-associated DLBCL between the years of 2012 and 2021 using ICD-10 codes. Other subtypes of Lymphoma such as Burkitt's or Plasmablastic Lymphoma were excluded. Patients who did not receive their entire treatment course within the institution were also excluded. Clinical characteristics at diagnosis, treatment type, CNS prophylaxis, and survival data was collected and analyzed. Results: A total of 38 patients were identified according to the inclusion criteria. 26 patients (68%) underwent screening lumbar punctures (LPs) for CNS disease while 12 patients (32%) did not. The two groups were not statistically different within any categories except for LDH, where the LP group had a median LDH of 492 units/L and the non-LP group had a median LDH of 241 units/L (p-value: 0.031). The two groups were not statistically different in cell of origin subtypes, stage, bone marrow involvement, kidney/adrenal involvement, the use of ART prior to diagnosis, IPI or CNS-IPI scores. In addition, among the group that had an LP done with no CNS involvement (n=25), there was no statistical difference in relapse-free survival among those who received adequate CNS prophylaxis and those who did not (p-value 0.886). Conclusions: Among patients with HIV-associated DLBCL in a large academic medical center in New York City, there is no reliable indicator to predict which were offered screening lumbar punctures and which were not. Clinicians may be using additional measures of aggressiveness not accounted for in standard IPI and CNS-IPI scoring algorithms. Furthermore, there was no clear benefit in relapse free survival among high-risk patients who received adequate CNS prophylaxis versus those who did not in this limited sample size. Further research is needed to determine whether patients with HIV-associated DLBCL should be risk stratified similarly to de-novo DLBCL patients with respect to CNS prophylactic therapy.

Dose Escalation of Blinatumomab Is a Better Option for MRD-Positive CR Patients, Results from a Single-Center Real World Study of Blinatumomab for B-Cell Acute Lymphoblastic Leukemia in China

Background：Blinatumomab(Blincyto) is a CD3-CD19 bispecific T-cell engager for treating B-cell acute lymphoblastic leukemia(B-ALL). Blincyto has been available in China since Aug 2021. Standard treatment duration of Blincyto is 28 days(d) per cycle. Due to economic reasons, part of the Chinese patients(pts) received 14d of infusion per cycle. Whether the 14-d regimen impact outcomes remains uncertain. To investigate the efficacy of 14-d regimen, we retrospectively analyzed the data of pts treated with Blincyto in our center. Methods：From Sep 2021 to Jul 2023, all of the B-ALL pts treated with Blincyto in our center were enrolled. Minimal residual disease(MRD) was monitored by 8-color flow cytometry before, d14 and after each cycle of Blincyto. MRDneg was difined as below 10 -4. Different doses of Blincyto were given based on disease burden: relapsed or refractory(R/R) pts were given 9ug, d1-7, 28ug, d8-28/cycle; for complete remission(CR) pts with MRD positive(MRDpos) or MRD negative(MRDneg), the treatment duration varied from 14 to 28d with or without dose escalation per cycle, which was decided by physicians. Ph+ and ph-like pts were recommended to continue tyrosine kinase inhibitors treatment. Intrathecal chemotherapies were given for pts with central nervous system (CNS) involvement. Progression free survival(PFS) was defined as time from treatment initiation until progression, relapse, or death; overall survival(OS) was defined as time from treatment initiation until death. Results: From Sep 2021 to Jul 2023, a total of 45 pts were enrolled(12 R/R, 14 CR MRDpos, 19 CR MRDneg)(Table 1). The median age was 45 year(range, 17~69) and 27(60%) pts were male. In 12 R/R pts(6 ph-, 3 ph-like, 3 ph+), the median disease burden before infusion was 28.9% (range, 6%~92.5%). After 1 cycle of Blincyto, 83.3%(10/12) pts achieved CR/CRi, 90% (9/10) achieved MRDneg. CR rate was 100% in 6 ph- pts, while MRDneg rate was 83.3%(5/6). Among 3 R/R ph-like pts, 2 pts achieved CR(66.7%), both MRDneg(100%). Same results were observed among 3 R/R ph+ pts. The ph+ nonresponder stopped infusion on d9 due to Grade(G) 2 immune effector cell associated neurotoxicity syndrome(ICANS), while the ph-like nonresponder was refractory to induction therapy and failed in subsequent salvages and died. No deaths was observed in other 11 pts. By Jul 2023, the median follow-up time was 8.6 months(m) and the estimated PFS was 13.4m. Among 14 CR MRDpos(5 ph-, 1 ph-like, 8 ph+) pts, the median MRD level was 0.075% (range, 0.01%~3.58%). After 1 cycle of Blincyto infusion, MRDneg was achieved in 92.86% (13/14) pts, except 1 ph+ nonresponder who developed CD19 loss at d14. By Jul 2023, the median follow-up was 6.78m, estimated mPFS was 13.2m. Two pts died(1 Covid-19, 1 CNS involvement). Blincyto was applied in 19 CR MRDneg pts post induction. The median treatment cycle was 1(range, 1-10). With a median follow-up of 4.73 months, PFS and OS were both 100%. In this study, 2 refractory pts and 1 CR MRDpos pt(all ph-) received 14-d regimen. All of them achieved MRDneg(100.0%) after 1 cycle, suggesting that the 14-d cost saving regimen may be feasible. However, MRD-rising was observed just 1 month after response in a refractory pt who developed a CNS relapse after allogeneic transplantation(allo-HSCT). The relatively short MRDneg duration of the pt may due to an insufficient depth of response. Among 14 CR MRDpos pts, the first 4 pts were treated without dose escalation, 75%(3/4) pts achieved MRDneg. The CRS rate was 100%(4/4)(G1-2) and a G3 ICANS(seizure) was observed in the fourth pt. In order to improve tolerance, the regimen was adjusted to apply dose escalation(9μg/d, 3~7d) in all 10 pts afterwards. No more ICANS was observed and the occurrence of CRS decreased to 40%(4/10)(G1-2). The MRDneg rate was 100%. Pts eligible for transplantation all successfully bridged to allo-HSCT after Blincyto treatment(n=24), all of them obtained MRDneg before allo-HSCT. By Jul 2023, the median follow up time was 8.23 months, 3 pts relapsed post allo-HSCT(estimated PFS, 17.3m) and no deaths was observed. Main AEs are listed as Table 1. Conclusion: Blincyto is a safe and effective option for B-ALL pts with different disease burden. For CR MRDpos pts, the 14-d cost saving regimen may be effective but the depth of the response requires further study. Meanwhile, our results suggested that dose escalation may improve tolerance in CR MRDpos pts without impairing efficacy.

A Phase II Study of Low-Intensity Chemotherapy (Mini-Hyper-CVD) and Ponatinib Followed By Blinatumomab and Ponatinib in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Background Patients with Philadelphia chromosome (Ph)-positive B-cell acute lymphoblastic leukemia (ALL) treated with Hyper-CVAD and ponatinib achieve deep responses and long-term overall survival (OS). We aim to investigate if a reduced intensity regimen of mini-Hyper-CVD (mini-HCVD) with sequential blinatumomab (blina) in combination with ponatinib may further improve outcomes while mitigating the toxicity of intensive chemotherapy and the need for hematopoietic stem cell transplantation (HSCT). Methods Patients age ≥18 years with newly diagnosed (ND) or relapsed/refractory (R/R) Ph-positive ALL, or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) were eligible. Other inclusion criteria included adequate liver, renal and cardiac function, and ECOG performance status ≤2. Patients with baseline central nervous system (CNS) involvement were not excluded. All patients had BCR::ABL1 transcripts and fluorescence in situ hybridization (FISH) for t(9;22) done at baseline. Morphological analysis of FISH patterns was performed in ND patients to identify if the BCR::ABL1 signal was observed in myeloid cells (e.g., segmented neutrophils). Four cycles (C) of mini-HCVD alternating with methotrexate (MTX) + cytarabine were followed by blina 28µg/d given for four weeks every six weeks during C5-8. Patients received ponatinib 30mg daily initially, with a dose reduction to 15mg daily once in complete molecular remission (CMR). CMR was defined as undetectable BCR::ABL1 with an assay sensitivity of 0.01%. Rituximab was given for CD20-positive disease. Maintenance ponatinib, vincristine and prednisone for 15 cycles with blina + ponatinib every three cycles was given, followed by ponatinib for at least five years. All patients without CNS disease received 12 intrathecal injections of MTX or cytarabine. Results 20 patients (12 ND, 4 R/R, 4 CML-LBP) were treated between November 2019 and May 2023. Baseline characteristics are shown in Table 1. One patient with CML-LBP had received prior dasatinib while in chronic phase. The predominant BCR::ABL1 transcript was p190 in 7 (58%) ND patients. All patients achieved a complete remission (CR). Among patients in the ND, R/R, and CML-LBP cohorts, CMR was achieved in 10/12 (83%), 3/4 (75%), and 4/4 (100%) patients, respectively. In the ND cohort, six (50%) patients achieved CMR after C1 and eight (67%) after C3. Five (42%) ND patients had documented BCR::ABL1 signal in myeloid cells by FISH. Four of them achieved CMR, after C1, C3, C4 and C3 maintenance respectively. With a median follow-up of 25 months (range, 2-42), the 2-year continuous remission duration (CRD) and OS rates were 93% and 83% for the entire cohort (Figure 1), and 90% and 82% in the ND cohort, respectively. In the ND cohort, one (8%) patient had isolated CNS relapse (during C4 of maintenance with blina and ponatinib), three (25%) patients died (two in CR due to COVID-19 and one of HSCT complications), and eight (67%) patients are in remission without HSCT. No patients relapsed in the R/R cohort; one patient underwent HSCT, one patient died in CR from MTX-associated disseminated necrotizing leukoencephalopathy, and two patients are in remission without HSCT. None of the CML-LBP relapsed; one patient underwent HSCT in CR. Ponatinib dose was reduced in two patients prior to obtaining CMR (one had pancreatitis, one had cardiomyopathy). One patient switched from ponatinib to dasatinib due to a pulmonary embolism in C2. No patients required dose modification of blina. The 60-day mortality rate was 0%. Conclusion In patients with Ph-positive ALL, the combination of mini-HCVD and ponatinib followed by sequential blina and ponatinib yielded excellent outcomes with durable remissions. The toxicity profile was favorable and HSCT was avoided in most patients with ND disease. Longer follow-up is needed to confirm the durability of responses.

Breaking Barriers in B-Acute Lymphoblastic Leukemia Treatment: Experience of a Tertiary Hospital with the Use of a Tandem Dual CAR-T 19/22 in Pediatric & AYA Patients

INTRODUCTION Anti-CD19 chimeric antigen receptor (CAR) autologous T-cell therapy tisagenlecleucel (CTL019) has shown efficacy in pivotal trials and real-world data in relapsed/refractory pediatric B-cell precursor acute lymphoblastic leukemia (r/r B-ALL). However, 30-50% of patients relapse, because of CD19 loss in leukemic cells, or persistence/function reduction of CTL019. To improve relapse free survival, multitargeting CAR-T cells, such as bicistronic anti-CD22 and anti-CD19 or single sequential infusion are being developed. We report the safety and efficacy of an in-house manufactured tandem anti-CD19/22 dual CAR-T cells in pediatric, adolescents and young adults (AYA) diagnosed with r/r B-ALL. MATERIAL AND METHODS Eight batches of the tandem anti-CD19/22 dual CAR-T cells were manufactured under Good Manufacturing Practices (GMP) and authorized under a compassionate use program by the Spanish Agency for Medicines and Health (AEMPS). The starting material in all cases was patient´s non mobilized apheresis. After, CD4 + and CD8 + T cells were immune selected, activated with CD3/CD28 beads and transduced with a CD19/CD22 lentiviral vector (from Miltenyi Biotec®). Cell expansion was performed in a CliniMACS Prodigy® device with TexMACs® culture medium supplemented with IL-7 and IL-15. During manufacturing, process and quality controls were carried out and the finished product was infused fresh or cryopreserved. RESULTS A total of 8 patients with a median age of 10.5 (range 6-25) years old received a median of 1 (range 1-3) doses of tandem anti-CD19/22 dual CAR-T cells containing a median of 1.13x106 (range 7.5x105-3x106) cells/kg infused. First 3 patients (37.5%) received cryopreserved product. Two patients (25%) were also diagnosed with Down syndrome (DS). The median time between apheresis and infusion was 10.5 days (range 9-14 ). Five patients (62.5%) received previously tisagenlecleucel and four of them (50%) had also received a hematopoietic stem cell transplantation (HSCT). Leukemia blasts did not express CD19 in 2 patients (25%). Both received tisagenlecleucel previously, and one of them also expressed low levels of CD22. Median pre-infusion minimal residual disease (MRD) was 4.91% (range 0.01-87). Bridging therapy was low dose chemotherapy in 7 patients (87.5%), using inotuzumab in 1 patient. Lymphodepletion regimen was individualized, in 5 patients (62.5%) consisted on fludarabine 30 mg/m2/day for 4 days and cyclophosphamide 600 mg/m2/day for 2 days. Regarding CAR cell product, mean transduction was 41.4 %. Similar CD4 +/CD8 + distribution was seen in most products generated (7/8, 88%), and central memory cells were the main subpopulation found, followed by naïve cells. Most CAR-T cell expansions (88%, median 7, range 7-28) were seen between day +7 and day +21 post-infusion. Regarding toxicity, 7 patients (87.5%) presented cytokine release syndrome (CRS). Three patients (37.5 %) with high pre CAR-T tumor burden (TB) (range 75-87 %) developed CRS grade 3-4 (ASBMT guidelines) followed by ICANS grade 3. On day +28 after infusion, 6 patients (75%) were in complete remission (CR), one of them with positive minimal residual disease (MRD). Two patients died because of disease progression (range 2-4.5 months) and a third one (with DS) because of toxicity before day +28 after CAR-T infusion. Consolidative HSCT was performed in 3 of 6 patients that achieved CR (50%) during the first 90 days after CAR-T cell infusion. During follow up of these transplanted patients (median 8.4 months, range 2.3-12.3), 1 patient (33.3%) relapsed after 11 months. One patient presented central nervous system relapse 1 month after CAR-T infusion and HSCT was performed and with 35 months of follow up, continues alive in CR. The last patient (with DS) relapsed 3 months after infusion and immunotherapy (inotuzumab) has been given in order to perform a second HSCT if CR is achieved. CONCLUSIONS In-house manufacturing of tandem anti-CD19/22 dual CAR-T cells is feasible and reproducible under GMP conditions in an academic institution. Product infusion seems to be well tolerated in most patients, although patients with high TB developed high grade toxicities. Setting bridging therapy, reducing TB and manufacturing time remains a challenge. Our experience suggests the efficacy of its use as a bridge to consolidative HSCT. Nevertheless, a larger number of patients in the context of a clinical trial would be necessary.

A Nationwide Clinical Trial ALL-B12: An Optimized Therapy for Pediatric B-Precursor Acute Lymphoblastic Leukemia with Excellent Overall Survival and Minimal Non-Relapse Mortality: A Report from the Japan Children's Cancer Group

Background: Advancements in treatment have significantly improved therapeutic outcomes for pediatric acute lymphoblastic leukemia (ALL) and relapsed ALL. However, there remains a need for therapies that minimize relapse in high-risk groups and avoid long-term complications. To address this gap. we conducted the nationwide clinical trial ALL-B12, aimed at newly diagnosed B-precursor ALL aged 1-18 years. Methods: ALL-B12 enrolled participants from November 2012 to November 2017. Patients were stratified based on the NCI classification (age and WBC count at diagnosis). Those with NCI-SR and NCI-HR were assigned to the standard risk group (SR) and the intermediate group (IR), respectively. Poor steroid responders and those with high-risk genomic abnormalities were assigned to the high risk group (HR). A treatment regimen, including 4-drug remission induction, early consolidation, HD-MTX-containing intensification, re-induction, and maintenance, was implemented. Anthracycline dose in the induction therapy was reduced in SR patients. In contrast, early consolidation was intensified with L-ASP for a part (randomized) of the IR and the entire HR. Patients classified as CNS3 were treated as high risk, receiving 12 Gy cranial irradiation; prophylactic cranial irradiation was avoided in non-CNS3 groups. Allogeneic hematopoietic cell transplantation (allo-HCT) during the first remission was restricted to those in the very high-risk group with specific genomic abnormalities (e.g., hypodiploid <44 and TCF3-HLF) and residual MRD above 10^-3 at the end of early consolidation. A randomized comparison was carried out within each risk group to identify the optimal treatment. We assessed the effectiveness of intensification with VCR/DEX pulses for the SR, the impact of L-ASP intensification for the IR, and compared block-type treatment and HD-MTX intensified with VCR and L-ASP (HD-MTX/VL) for the HR. The primary outcome measure was the 5-year event-free survival (EFS) rate. Results: In total, 1,936 patients were enrolled, with 1,804 patients receiving protocol treatment after excluding ineligible patients such as those with BCR-ABL1 positivity. The percentage of patients achieving remission at the end of early consolidation was 98.9%. The overall 5-year EFS and OS probability were 85.2% (95%CI 83.5-86.8%) and 94.3% (95%CI 93.1-95.3%), respectively. Only 1.7% of patients underwent allo-HCT during the first remission. The mortality rate during induction was just 0.6%, with non-relapse mortality (NRM) after remission at 0.6%. The overall relapse incidence was 13.2%, and the overall CNS relapse rate was 1.9%. Among patients assigned to risk groups, 1,107 (62.7%) were assigned to the SR, 459 (26.0%) to the IR, and 200 (11.3%) to the HR. The 5yEFS for the SR was 89.9%. The post-randomization EFS rates for those with and without VCR/DEX intensification were 90.7% and 90.1%, respectively, indicating nearly identical survival curves (p = 0.73). The EFS for the IR was 79.7%, but L-ASP intensification was expected to be effective, the EFS for groups with and without ASP intensification was 82.1% and 77.9%, respectively, failing to reach statistical significance (p = 0.31). The EFS for the HR was 75.5%, with overlapping survival curves for block treatment (75.7%) and HD-MTX/VL (74.2%) (p = 0.92). MRD dynamics were associated with prognosis, and early consolidation therapy enhanced by ASP resulted in better MRD clearance. MRD of 10^-4 was associated with poor prognosis at both the end of induction and the end of early consolidation. Conclusion: In our multi-center clinical trial, we observed excellent outcomes in a diverse group of patients nationwide. Using the NCI criteria for stratification, a significant number of patients were categorized into the SR. Additionally, introducing L-ASP during early consolidation decreased the number of MRD-positive patients, which subsequently reduced the subset needing allo-HCT. This strategic adjustment in treatment intensity resulted in both high EFS rates and low NRM. Given the rise of immunotherapy and its promising results for recovery even post-relapse, there's a pressing need to enhance overall outcomes while minimizing non-relapse mortality. We anticipate refining our stratification further and integrating immunotherapy and other innovative treatments into our approach.

Phase II, Single-Center, Prospective Study of Intrathecal Thiotepa for the Prophylaxis of Secondary Central Nervous System Involvement in Highly Aggressive B-Cell Lymphoma

Background Central nervous system (CNS) recurrence of systemic diffuse large B cell lymphoma (DLBCL) is a well-recognized and almost uniformly fatal complication that tends to occur within 2 years of initiating treatment. The probability of CNS relapse in DLBCL ranges from 4 to 7% overall but is increased to 20% in certain subgroups. Evidence supporting the use of intravenous methotrexate (MTX) or arabinoside (AraC) in high-risk patients is growing, however, the use of other agents remains to be defined. Thiotepa (TT) is a polyfunctional alkylating agent first developed in the 1950s. Both thiotepa and its metabolite tepa demonstrate good CNS bioavailability, making thiotepa a useful adjunctive chemotherapy for primary and secondary CNS lymphoma, particularly in the context of hematopoietic stem cell transplant (HSCT). Herein, we conduct this prospective trial to evaluate the efficacy and safety of prophylactic intrathecal thiotepa for the prevention of secondary CNS involvement in patients with DLBCL. Methods Patients The primary end point is 2-year cumulative incidence of CNS. The secondary end points are 2-year progression free survival (PFS), 2-year overall survival (OS), and safety. The main inclusion criteria include: adults patients ≥18 years old; histopathological confirmed DLBCL without previous antitumor therapy; high-risk CNS involvement (one of the following): primary breast or testicular lymphoma, involvement of any of the following organs: testis, breast, kidney, adrenal gland, paranasal sinus, epidural space or uterus; CNS International Prognostic Index (CNS-IPI)≥4; dual protein expression (DE) or double/triple hit (DH/TH) lymphoma. The main exclusion criteria include: Burkitt lymphoma, primary CNS lymphoma, or large B cell lymphoma transformed from indolent lymphoma; the presence of parenchymal or meningeal lymphoma; history of whole brain radiotherapy or craniospinal cord irradiation; obstructive hydrocephalus patients requiring neurosurgical intervention. Treatment protocol The systemic chemotherapy regimen is determined by investigator. All patients are need to receive IT thiotepa 10 mg and dexamethasone 5 mg on day 1 of each cycle of chemotherapy for at least 4 cycles. All patients are asked to lie flat for 4 to 6 hours after the lumbar puncture. Follow-up Routine biochemical and cytological analysis of cerebrospinal fluid is performed for each cycle. Imaging examination, such as brain magnetic resonance imaging (MRI) and body computed tomography (CT), is repeated every 2 cycles of chemotherapy, then every 3 months during follow-up. Results From February 2022 to June, 2023, 27 patients (female 14, male 13) received IT thiotepa. The clinical characteristics are shown in Table 1. The median age was 66 years old (range: 46-74). As first-line chemotherapy, 15 (55.6%) patients received rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (RCHOP), 5 (18.5%) patients received RCHOP+BTK inhibitor, 3 (11.1%) patients received BTK inhibitor, lenalidomide with rituximab (ZR2) followed by RCHOP, and 4 (14.8%) patients received RCHOP with intravenous MTX. Thirteen (48.1%) patients had IPI score 4-6 and 17 (63%) patients had DE of c-myc and bcl-2. All patients received fluorescence in situ hybridization (FISH) cytogenetic testing for C-MYC, BCL-2, BCL-6 and TP53. Four (14.8%) patients had TP53 deletion, and 11 (40.7%) patients had sole rearrangement of C-MYC or BCL-2 or BCL-6, but no one were diagnosed with DH/TH lymphoma. All patient have received IT thiotepa for at least once, and 12 (44.4%) patients completed 4-6 cycles of IT, 84 cycles totally. IT thiotepa was a safe measure, for no one experienced post-LP headache, local infection, bleeding, or cerebral herniation. But there were 4 patients had five times of inability to identify direction and slow speech response. They could recover normally the next day without any treatment. Although the follow-up period was short, no patient developed CNS involvement. Conclusion Prophylactic intrathecal thiotepa is an effective and side-effects manageable measure for preventing secondary central nervous system involvement in high-risk DLBCL. Longer follow-up and larger-scale prospective trial is needed to testify this measure.

Europeanpediatric Acute Leukemia (EuPAL) Registry

The Leukemia Lymphoma Society (LLS) Pediatric Acute Leukemia (PedAL) Initiative is a collaborative international effort that aims to improve the cure of children with relapsed/refractory (R/R) and other high-risk leukemias. Its comprehensive approach included preclinical and clinical research, standardization and improvement of diagnostics, quality management, and global data integration and analysis. The European Pediatric Acute Leukemia (EuPAL) Foundation was established as the PedAL Initiative partner to support European stakeholders in these efforts. A major focus of the EuPAL Registry and PedAL Initiative is to increase access to and test new drugs targeting leukemia-specific biologic and genetic characteristics in pediatric patients with R/R acute myeloid leukemia (AML). However, identification and recruitment of patients remains a challenge. For this purpose, the APAL2020SC screening trial (NCT04726241) in North America, Australia, and New Zealand and the EuPAL registry in Europe have been launched. In collaboration with national and international study groups, pediatric leukemia reference laboratories, and participating clinical trial sites, each child with R/R AML should be registered. In Europe, the EuPAL registry office identifies the best available trial for the patient based upon leukemia-associated genetic and immunophenotypic data and closest trial site(s) and coordinates contact between the treating physician/site and the trial site as needed. Results The EuPAL registry has been approved by the leading ethic committee in Germany with extension to several other European countries ongoing. To date, 35 children and adolescents with R/R AML have been enrolled since June 2022. The median age at initial diagnosis was 7.3 (range 0.2 to 17.7) years with median duration of remission 1.3 (0.3 to 5.3) years. Most patients were registered at first relapse (n=29) with 3 patients in second relapse and 1 patient in third relapse. Two children were diagnosed with a molecular relapse (n=2). Fourteen patients have been transplanted in 1 st CR (n=9) /2 nd CR (n=5) prior to registration Regarding the initial risk groups at diagnosis, most relapses occurred in the intermediate risk group (IR) n=19) and the high-rik group (HR; n=12). The others were standard risk, one isolated CNS relapse in APL and two in children with trisomy 21. Patients were treated at relapse on the AML-BFM 2017 registry (treatment recommendation: Idarubicin, fludarabine, cytarabine (IDA-FLA), FLA and HSCT), the AIEOP-BFM-AML 2020 trial (FLA- gemtuzumab ozogamicin (GO) or IDA-FLA t(8;21)), the AMORE 2017 trial (azacytidine and HSCT; n=2) or received off-label therapies (cytarabine/GO, venetoclax/cytarabine, or azacytidine). Conclusion The EuPAL registry has been successfully established and is beginning to generate relevant knowledge regarding the frequency and timing of pediatric AML relapse, leukemia-associated genetics, and immunophenotypic characteristics. In collaboration with the LLS PedAL Initiative, the EuPAL registry will continue to facilitate recruitment of children with R/R AML and other leukemias to clinical trials testing innovative therapies, as well as improve understanding of potential bias in clinical trial referrals. Current challenges include integration of more European countries into the EuPAL Registry and increasing the number of open early-phase PedAL/EuPAL clinical trials.

High Efficacy and Feasibility of a Full Pediatric Induction in Adults Aged up to 55 Years with Philadelphia-Negative Acute Lymphoblastic Leukemia

Background: Treatment of acute lymphoblastic leukemia (ALL) in adults has historically shown unsatisfactory outcomes when compared to the outstanding results obtained in pediatric patients. Pediatric protocols rely on increased drug intensity and on a tighter evaluation of minimal residual disease (MRD) for early intensification. Nowadays, pediatric-inspired protocols have been established as the standard of care for adolescents and young adult patients (AYA) leading to improved results. In the setting of older patients, probably due to the limited data available, the feasibility of such intensive therapies, and in particular the administration of high doses PEG-asparaginase (PEGASP), is still a matter of debate. In this context, the NOPHO group reported that a full-pediatric protocol was feasible and highly effective in adult patients, up to 45 years of age. Aim: The aim of our study was to evaluate the feasibility and efficacy of the entire full pediatric AIEOP-BFM LAL 2009 protocol in an older cohort of adult patients up to 55 years. Methods: Since May 2013, 28 consecutive adults diagnosed with Ph-neg ALL received first line therapy according to AIEOP- BFM-ALL 2009 protocol, which includes high PEG-asparaginase (PEGASP) doses, with an accurate MRD-driven therapeutic strategy. The protocol consists of 2 induction blocks: IA (Vincristine, Daunorubicin, PEGASP, IT methotrexate) and IB (Cytarabine, 6-mercaptopurine, cyclophosphamide, IT methotrexate), I consolidation block (high-dose methotrexate, 6-mercaptopurine, IT methotrexate), maintenance therapy (6-mercaptopurine, weekly MTX, IT Methotrexate). Median age in our study was 45 years (range 17-55), equal to the maximum age allowed in the NOPHO study. Fifteen patients had B-ALL, 13 T-ALL/T including 5 Early-T phenotype. Dose intensification and stem cell transplantation (SCT) were scheduled according to baseline and MRD-driven risk assessment. MRD was evaluated by multicolor-flow cytometry (MFC), with a threshold for positivity of 0.025%, and molecular PCR for JH rearrangement (MOL), with a sensitivity greater or equal to 10-4 in all patients. Patients with MOL MRD >10-4 but <10-3 were defined as low-level positive. MRD time points were day 33 and day 78 (MFC and MOL). Results: All patients achieved complete hematological remission following the first Induction course (100%). One patient died during induction due to infection by multidrug resistant P. aeruginosa. In general, therapy was well tolerated. Remarkably, patients in this study received high dose of PEGASP (median 10000 UI/sqm, equal to 4 administrations at 2500 UI/sqm each) without experimenting life threatening toxicities, which mostly consisted in asymptomatic elevation of transaminase (7 patients G3, 1 G4) and/or bilirubin (9 patients G3, 1 G4) only requiring supportive therapy. No major bleeding or thrombotic events o other >G2 toxicities were observed. All except one patient achieved CR at day 33 and all patients achieved CR at day 78. MFC MRD evaluation at day 33 resulted negative in 24/25 evaluable patients (95%). Day 33 MOL-MRD was evaluated in 22 patients, and resulted negative, low level positive or positive in 14, 5 and 3 patients, respectively. MRD assessment at day 78 showed both MFC and MOL negativity achieved in all 25 and 22 evaluated patients, respectively (Fig. 1). Four very high-risk patients underwent SCT in negative MRD status. After a median follow-up of 59 months (CI 95% 38.45-78.63), median survival was not reached, 5-years OS was 88.7% (Fig. 2). One patient died due to progressive transverse myelitis after isolated CNS relapse and one patient died due to sudden cardiac arrest while in complete MRD negative remission, 6 months after completion of therapy. All other 25 patients are alive and in complete MRD negative remission. Conclusion: The application of a full pediatric induction regimen in a cohort of adult ALL patients with a median age of 45 years proved to be feasible, with tolerable toxicities. In particular, we didn't observe major toxicities during the intensified PEGASP administration and all patients were able to receive the planned PEGASP doses. The possibility to maintain the correct timing translated in a very high MRD negativity rate and promising OS survival.

Effectiveness, safety and utilization of cobimetinib and vemurafenib in patients with BRAF V600 mutant melanoma with and without cerebral metastasis under real-world conditions in Germany: the non-interventional study coveNIS.

Cobimetinib/vemurafenib combination therapy is approved for treatment of adults with unresectable or metastatic BRAF V600 mutated malignant melanoma (mM). The non-interventional post-authorisation safety study coveNIS collected real-world data on cobimetinib/vemurafenib treatment focussing on overall survival (OS), safety and utilization. MM patients with brain metastases are usually excluded from clinical studies. coveNIS observed 2 cohorts: mM patients without (Cohort A) and with cerebral metastases (Cohort B), aiming to close the data gap for the latter population. A direct comparison of the 2 cohorts was not intended. The primary effectiveness objective was OS; the safety objective was the incidence of all and of serious adverse events (AEs). Secondary objectives included progression-free survival (PFS), time to development of cerebral metastasis (Cohort A) and time to central nervous system relapse (Cohort B). All statistical analyses were descriptive. Between 2017 and 2021, 95 patients were included (Cohort A: 54, Cohort B: 41 patients) at 32 sites in Germany. Median OS was 21.6 months in Cohort A, 7.4 months in Cohort B. Median PFS was 6.9 months in Cohort A, 5.2 months in Cohort B. The proportion of patients experiencing any AEs was 83.3% (Cohort A) and 87.8% (Cohort B). The two most common AEs in Cohort A were 'diarrhoea' (37%), 'vomiting' (20.4%) and 'pyrexia' (20.4%); in Cohort B 'diarrhoea' (36.6%) and 'fatigue' (22%). In conclusion, the OS rates in Cohort A and Cohort B of coveNIS are in line with the OS data from other trials with BRAF/MEK inhibitors for mM. No new safety signals were observed.