Incidence Of Central Nervous System Relapse Research Articles

Predicting central nervous system relapse in primary breast diffuse large B-cell lymphoma using the stage-modified IPI score: A retrospective cohort study

ObjectiveThe existing Central Nervous System-International Prognostic Index (CNS-IPI) provides insufficient guidance for predicting central nervous system (CNS) relapse in individuals with primary breast diffuse large B-cell lymphoma (DLBCL). This retrospective cohort study sought to examine the potential of the stage-modified IPI in predicting CNS relapse within this specific patient population. Patients and methodsWe examined the baseline characteristics of 76 consecutive patients diagnosed with primary breast DLBCL, calculating the stage-modified IPI score for each individual. Utilizing a competing risk regression (CRR) model, we conducted both univariate and multivariate analyses to explore the relationship between potential prognostic factors and the occurrence of CNS relapse. ResultsIn our cohort, the rates of CNS disease at 2 and 5 years since the diagnosis of primary breast DLBCL are 3.9% and 7.8%, respectively. Among patients experiencing CNS relapse, 80% presented with a parenchymal brain mass. Individuals with a high stage-modified IPI score (1–3 points) had a significantly higher incidence of CNS relapse (p = 0.031), a shorter time from the initial diagnosis of primary breast DLBCL to the first CNS relapse (p = 0.010), as well as relapse at any site (p = 0.012), compared to those with a low score (0 points). Univariate analysis identified stage (Hazard Ratio (HR): 4.098, p = 0.024), stage-modified IPI score (HR: 11.582, p = 0.012), and radiation therapy (HR: 5.784, p = 0.026) as significant risk factors. In multivariate analysis, in addition to radiation therapy (HR: 7.258, p = 0.012), the stage-modified IPI score (1–3 points versus 0 points) emerged as an independent and reliable predictor for CNS relapse (HR: 12.945, p = 0.016). ConclusionOur study underscores the significance of stage-modified IPI scores in predicting CNS relapse for patients with primary breast DLBCL. Validation of these findings through further research is essential, along with exploring potential prevention and intervention approaches.

Risk of Central Nervous System Vs. Systemic Relapse in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP: What Should We Focus on?

Background: Clinical outcome of patients (pts) with diffuse large B-cell lymphoma (DLBCL) has improved during the last two decades. However, a significant proportion of DLBCL pts is still at risk of lymphoma relapse (REL)/progression or death due to progression. DLBCL pts with adverse clinical features, i.e., those with high IPI or CNS IPI scores are at the highest risk of lymphoma REL, systemic (S) or central nervous system (CNS) REL. CNS prophylaxis is questionable based on retrospective analyses. Moreover, the risk of S-REL should be discussed in those pts as well. However, the comparison of the risks of CNS vs S-REL within the different CNS IPI risk groups has not been shown. Methods: Using the prospective observational NiHiL project (NCT03199066), we identified pts ≥ 18 years of age with histologically confirmed DLBCL or high-grade B-cell lymphoma (diagnosed 2011-2021), who received R-CHOP as frontline treatment in 2 centres in Czech Republic. Pts with CNS involvement at diagnosis were excluded. Cumulative incidence of CNS (± S) REL was calculated using Kaplan-Meier statistics treating S-REL and death as competing events. Results: A total of 1242 pts were included; according to CNS IPI score (available in 1225 out of 1242 pts), 344 (28.1%), 539 (44.0%) and 342 (27.9%) pts were categorized as being at low (0-1, LR), intermediate (2-3, IR), and high risk (4-6, HiR) resp. Overall, 308 (24.8%) pts received CNS prophylaxis with either high-dose(HD) Methotrexate (MTX), HD-AraC, intrathecal chemotherapy or combination. By CNS IPI, 150 (43.9%) out of 342 pts with HiR CNS IPI received CNS prophylaxis. CNS prophylaxis was given less frequently in the IR (n 111[20.6%] out of 539 pts) or LR (n 45 [13.1%] out of 344 pts) CNS IPI groups. At a median follow up of 5.3 years (range; 0.1 - 13.3), 307 (24.7%) out of 1242 pts developed lymphoma REL, out of which 45 occurred in CNS (35 isolated CNS REL, 10 simultaneous CNS+S-REL) and 262 lymphoma RELs occurred systemically. CNS prophylaxis had no impact on the incidence of CNS REL in pts with HiR CNS IPI. Median time to CNS (± S) and S-REL was 11.5 months (range; 2.7-116.8) and 11.8 months (range; 0.8 - 144.3), resp. Occurrence of RELs within the first 6, 12 and 24 months after lymphoma diagnosis was as follows: 20%, 53.3% and 80% for CNS (± S) RELs and 21%, 50.4% and 67.2% for S-RELs. In the entire cohort, the 7-year cumulative incidence of CNS (± S) and S-REL were 4.4% and 23.7%, resp. Across all CNS IPI risk groups, there was significantly higher risk of S-REL as compared to CNS (± S) REL. The 7-year cumulative incidence of S-REL vs CNS (± S) REL and the respective HRs were 10.5% vs 1.9%, HR 6.2 (95% CI 3.4-11.2) in the LR-, 25.2% vs 2%, HR 11.7 (95% CI 8.3-16.6) in the IR-, and 35.8% vs. 12.4 %, HR 3.6 (95% CI 2.5-4.9) in the HiR CNS IPI ( Fig1), resp. At the time of analysis, 417 (33.6%) out of 1242 pts were dead. CNS (± S) REL was associated with shorter post-REL overall survival (OS) as compared to S-REL (HR 1.8, p=0.001, median OS 0.38 vs 1.04 years, resp). In the entire cohort, the 7-year cumulative incidence of death due to lymphoma was 19.3% (16.7% and 3.1% due to S-REL and CNS (± S) REL, resp). The 7-year cumulative incidence of death due to R-CHOP-related toxicity, unrelated to lymphoma and unknown causes were 2.5%, 4.2% and 9.8%, resp. In HiR CNS IPI, the 7-year cumulative incidence of death due to lymphoma was 34.9% (28.3% and 9.2% due to S-REL and CNS (± S) REL, resp), while the 7-year cumulative incidence of death due to R-CHOP-related toxicity, unrelated to lymphoma and unknown causes were 5.1%, 5.1% and 14.9%, resp ( Fig2). Conclusion: DLBCL pts are at significantly higher risk of S-REL as compared to CNS (± S) REL overall and across all CNS IPI risk groups. In addition, death due to S-REL is the leading cause of death overall and across all CNS IPI risk groups. However, CNS (± S) REL represents remarkable portion of all lymphoma RELs occurring in the HiR CNS IPI group and non-negligible cause of death in DLBCL. Our results support the conclusion that R-CHOP + HD MTX is not sufficient to reduce the risk of S-REL as well as CNS REL especially in pts with HiR CNS IPI. New 1 st line treatment options able to reduce simultaneously the risk of S-REL as well as CNS REL are needed to improve the outcome of DLBCL pts especially in the subgroup with HiR CNS IPI. Grant support: AZV NU23-03-00127, NU21-03-00411, Charles University Hematology-Oncology Cooperatio Program

Incidence of Central Nervous System Relapse in Patients with Primary Mediastinal Large B-Cell Lymphoma: A Retrospective Study

Background Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of non-Hodgkin lymphoma. Clinicopathologic features are distinct from diffuse large B cell lymphoma, but it shares some clinical and biologic features with Nodular sclerosis classic Hodgkin lymphoma. Central nervous system (CNS) relapse appears to be rare in patients with PMBCL, with limited literature reporting a rate of approximately 1.5% to 4%. We examined the incidence of CNS relapse, treatment approaches and survival outcomes in patients with PMBCL. Methods Patients with newly diagnosed PMBCL seen at Mayo Clinic between 2002 and 2022 were identified using the prospective Mayo Clinic Lymphoma Database. Clinical features, treatment details and outcomes were abstracted from the medical record. Cumulative incidence of CNS relapse was analyzed with death as a competing risk. The association of CNS-IPI, systemic treatment, and CNS prophylaxis approach with CNS relapse rate was analyzed using competing risk models and descriptively. Event-free survival (EFS) for the cohort was defined as time from PMBCL diagnosis to first recorded CNS and/or systemic relapse or death from any cause. Overall survival (OS) was defined as time from PMBCL diagnosis (or CNS relapse) to death from any cause. Survival analysis was performed using the Kaplan-Meier method. Results A total of 124 PMBCL cases were identified. The median age at diagnosis was 37 years and 61% were female. The distribution of CNS-IPI was low-risk in 67 (61%), intermediate-risk in 41 (37%), and high-risk in 2 (2%). 64 patients (52%) received R-CHOP and 54 patients (44%) received R-DA-EPOCH as frontline therapy. High-dose methotrexate (HD-MTX) for CNS prophylaxis was administered to 6 patients (5%), 5 with R-CHOP and 1 with R-DA-EPOCH. 16 patients received intrathecal (IT) chemotherapy (methotrexate and/or cytarabine) for CNS prophylaxis, 3 with R-CHOP and 13 with R-DA-EPOCH. The median follow-up was 56.0 months. The 5-year EFS rate was 75.1% and the 5-year OS rate was 90.7% for the entire cohort. 20 patients had systemic relapse only and 3 had CNS relapse. The cumulative incidence of CNS relapse was 1.84% (95% CI 0.46%-7.17%) at 2 years and 2.92% (95% CI 0.50%-8.84%) at 5 years (Figure 1). No statistically significant association of CNS-IPI, systemic therapy or CNS prophylaxis regimen with CNS relapse rate was found in competing risk models; however, this analysis was limited by a small event number (n=3). Among the 3 patients with CNS relapse, 1 had high-risk CNS-IPI and 2 had intermediate risk. All 3 patients were treated initially with R-CHOP. Two patients did not receive any CNS prophylaxis and 1 patient received IT CNS prophylaxis. All three patients who had CNS relapse were female. Patient #1 was diagnosed at age 48 and had simultaneous CNS and systemic relapse 6 months later. The patient was treated with HD-MTX, temozolomide and rituximab for CNS relapse, and subsequently received multiple therapies for systemic disease including R-DHAP, R-ICE, and died 17 months after CNS relapse. Patient #2 was diagnosed at age 22 and had CNS relapse after 8.7 months, followed by systemic relapse 2 months later. The patient received HD-MTX, temozolomide and rituximab for CNS relapse, followed by systemic and whole-brain radiation therapy (RT) for both systemic and CNS relapse. Subsequently the patient received salvage chemotherapy, autologous and allogeneic stem cell transplant for systemic relapse. The patient died 26.8 months after CNS relapse. Patient #3 was diagnosed at age 24 and had systemic relapse after 20.7 months, followed by CNS relapse 5.4 months later. The patient received methotrexate and whole-brain RT following CNS relapse and died 1.2 months after CNS relapse. Besides these 3 patients, we identified 6 PMBCL patients with CNS relapse who were diagnosed at other medical centers and subsequently referred to our institution for management of refractory disease. The survival after CNS relapse was poor, with a median OS of 10.4 months (95% CI 5.6-15.2). Conclusion Our study showed that the CNS relapse rate (1.84% at 2 years and 2.92% at 5 years) was overall low in patients with PMBCL, consistent with previous reports. CNS relapse was associated with poor survival despite aggressive treatment approaches. Novel approaches utilizing biological risk factors for CNS relapse, such as circulating tumor DNA, are needed to identify patients with CNS relapse.

Incidence and Risk Factors for Central Nervous System Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Acute Lymphoblastic Leukemia

Background Acute lymphoblastic leukemia (ALL) is frequently accompanied with the involvement of the central nervous system (CNS). The clinical prognosis for ALL patients with CNS disease is generally unfavorable, and prophylactic measures such as intrathecal chemotherapy are highly recommended. In adult ALL patients, hematopoietic stem cell transplantation (HSCT) presents a potential curative approach. However, there are currently only a few reports available on the risk factors and epidemiology of CNS relapse after HSCT. Method We conducted a retrospective single-center cohort study involving 1043 patients diagnosed with either acute lymphoblastic leukemia (ALL) or mixed phenotype acute leukemia (MPAL). These patients were treated at our center using the same treatment protocol between 2009 and 2022. During the remission induction phase, we utilized a modified hyper-CVAD regimen, along with six rounds of prophylactic intrathecal (IT) chemotherapy. High-risk patients who had suitable donors underwent allogeneic hematopoietic stem cell transplantation (HSCT) as part of their post-remission therapy. Diagnosis of central nervous system (CNS) leukemia was established when neurologic symptoms were observed in correlation with CNS lesions on imaging studies, or when leukemic blasts were detected in the cerebrospinal fluid (CSF). In our study, we examined the incidence, risk factors, and survival outcomes of patients who experienced CNS relapse after transplantation. Results Among the entire cohort of 1043 patients, CNS involvement was observed in 3 (0.3%) patients at initial diagnosis and 12 (1.2%) during chemotherapy. We proceeded with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 755 consecutive patients. Among these 755 patients, 3 had CNS leukemia prior to transplantation. Among the group of 755 patients, a total of 224 (29.6%) experienced relapse. Of these relapses, 142 (18.8%) were bone marrow relapses alone, 54 (7.1%) were extramedullary relapses alone (with CNS involvement in 21 [38.8%]), and 28 (3.7%) had both bone marrow and extramedullary relapses (with CNS involvement in 13 [46.4%]). Overall, extramedullary relapse was observed in 82 (10.8%) patients, with CNS involvement in 34 (4.5%) cases, following allo-HSCT. The 5-year cumulative incidence of CNS relapse was 4.6%, which was significantly higher in patients with Philadelphia chromosome-positive (Ph-positive) ALL (9.4% vs. 1.0%, p <0.001), as well as those with a high leukocyte count at diagnosis (8.3% vs. 2.6%, p = 0.001). Among the Ph-positive ALL cases, a high leukocyte count (n=151) was associated with a higher prevalence of pre-HSCT minimal residual disease (MRD) > 0.1% (n=88), which exhibited a significantly increased incidence of CNS relapse (16.6% vs. 6.8%, p = 0.009). Factors such as age, number of intrathecal chemotherapy treatments, conditioning intensity, and dose of anti-thymocyte globulin did not have a significant impact. Among the 34 patients with CNS relapse, 21 (61.7%) had isolated CNS relapse, and 7 of them showed evidence of positive MRD. With the exception of one patient who refused further treatment, the remaining 33 patients received initial CNS local therapy, including intrathecal chemotherapy combined with radiotherapy in 27 (82.0%) cases, intrathecal chemotherapy alone in 6 cases, and radiotherapy alone in 4 cases. Out of these patients, 22 were treated with dasatinib or ponatinib, while 6 received salvage chemotherapy. The median overall survival for patients with CNS relapse was 11.2 months, which was 19.8 months for those with isolated CNS relapse and 10.9 months for those with CNS relapse accompanied by bone marrow relapse (p = 0.077). The subsequent 2-year cumulative incidence of CNS relapse was 30%. Conclusion Based on our findings, the current prophylaxis strategy employed for the prevention of post-HSCT CNS relapse in adult ALL appears to be effective. However, our data indicates that MRD-positive Ph-positive ALL requires distinct management due to its significantly elevated risk of CNS relapse. New strategies including prophylactic radiotherapy for this high-risk subgroup must be considered to prevent post-HSCT CNS disease.

The Outcome of Diffuse Large B-Cell Lymphoma Patients with Testicular Involvement - Real World Data

Introduction: Patients (pts) with testicular lymphoma (TL) have an increased risk of central nervous system (CNS) relapse. In rituximab era, the reported incidence vary from 10% (in limited disease) to 25% (advanced disease). More data is needed to guide the managment of TL pts in current era. Optimal strategy for CNS relapse prevention is uncertain. Methods: We studied consecutive pts diagnosed between 2000 and 2022 with testicular diffuse large B-cell lymphoma (DLBCL) prospectively observed in the Czech Lymphoma Study Group Project NiHiL (Clinical Trial gov. NCT03199066). Objectives were to analyze the cumulative incidence of CNS relapse, time to CNS relapse, PFS and OS. The impact of various treatment strategies on CNS relapse was analyzed. Results: We identified 229 pts with testicular involvement: 157 pts with primary testicular lymphoma (PTL) in clinical stage I or II and 72 pts in advanced stage (AD) III or IV. Median age was 70 years (range 33 - 87). Rituximab-based chemotherapy received 192 (83.8%) pts including 127 (81%) cases with PTL. Following localized treatments were used more often in PTL compared to AD: unilateral orchiectomy [148 (94.3%) vs. 47 (65.3%); p < 0.0001], testicular irradiation (RT) [116 (61.7%) vs. 40 (38.7%); p = 0.005]. Most patients (85%) received some form of CNS prophylaxis. There were similar rates in use of prophylactic methotrexate (MTX) between PTL and AD (p = 0.88): intrathecal (i.t.) MTX 64 (40.8%) vs. 29 (40.3%), intravenous (i.v.) MTX with or without cytarabine 20 (12.8%) vs. 7 (9.7%); combined i.t. and i.v. MTX 38 (24.2%) vs. 20 (27.8%). Out of 229 cases 25 (15.9%) PTL and 11 (15.3%) AD pts did not receive any CNS prophylaxis. Median follow-up was 51.8 months.Overall 63 (27.5%) pts relapsed including 14 (6.1%) relapses in CNS. Median time to CNS relapse was 21.9 months and to other systemic relapse was 14.7 months (p = 0.63). The 5-year cumulative incidence of CNS relapse in PTL was 4.55% (95% confidence interval [CI], 0.1 - 28.6) and in AD 12.07% (95% CI 0.8 - 39.6), respectively. In univariate analyses, MTX prophylaxis (i.v. and/or i.t.) and testicular RT had no impact on CNS relapse (p = 0.49 and p = 0.60, respectively). Orchiectomy was the single significant factor associated with lower risk of CNS relapse in PTL (hazard ratio [HR] = 0.11[95% CI 0 - 0.124]; p = 0.001). Rituximab significantly reduced CNS relapse in AD with testicular involvement (HR = 0.1002 [95% CI 0.0 - 0.45]; p = 0.0005). Out of 14 pts with CNS relapse 8 died due to lymphoma progression. Median progression-free survival (PFS) and overall survival (OS) in PTL was significantly better when compared to AD (PFS 92.9 vs. 28.1 months, p < 0.0006; OS 108.7 vs. 56.7 months, p = 0.0002). Median PFS2 and OS2 since CNS relapse was dismal in AD compared to PTL (PFS2 1.6 vs. 37.8 months, p = 0.04 and OS2 2.3 vs. 37.8 months, p = 0.05). Conclusions: The rate of CNS relapses in PTL and advanced disease with testicular involvement is lower than previously reported. This study confirmed a significant favorable impact of rituximab in prevention of CNS relapse. Notably, methotrexate prophylaxis i.v. or i.t. did not alter the CNS relapse risk. Prognosis of CNS relapse is particularly poor in advanced disease. This work was supported by grant AZV NU21-03-00411 from the Ministry of Health of the Czech Republic and by the Cooperatio Program, research area “Oncology and Haematology”

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.

Incidence and risk factors for central nervous system relapse in patients with primary mediastinal large B-cell lymphoma in the rituximab era.

Central nervous system (CNS) involvement is rare in primary mediastinal large B-cell lymphoma (PMLBCL). We aimed to evaluate the incidence of CNS relapse as first treatment failure event and the effect of the induction chemotherapy regimen, central nervous system - international prognostic index (CNS-IPI) and other clinical and laboratory variables on the risk of CNS relapse in 564 PMLBCL patients treated with immunochemotherapy. Only 17 patients (3.0%) received CNS prophylaxis. During a 55-month median follow-up only 8 patients experienced CNS relapse as first event, always isolated. The 2-year cumulative incidence of CNS relapse (CI-CNSR) was 1.47% and remained unchanged thereafter. The CI-CNSR was not affected by the chemotherapy regimen (R-CHOP or R-da-EPOCH). None of the established International Prognostic Index factors for aggressive lymphomas predicted CNS relapse in PMLBCL. The 2-year CI-CNSR in patients with versus without kidney involvement was 13.3% versus 0.96% (p<0.001); 14.3% versus 1.13% with versus without adrenal involvement (p<0.001); and 10.2% versus 0.97% with versus without either kidney or adrenal involvement. CNS-IPI was also predictive (2-year CI-CNSR in high-risk vs. intermediate/low-risk: 10.37% vs. 0.84%, p<0.001). However, this association may be driven mainly by kidney and/or adrenal involvement. In conclusion, in PMLBCL, CNS relapse is rare and appears to be strongly associated with kidney and/or adrenal involvement.

The Role of Prophylactic Chemotherapy for the Prevention of Central Nervous System Relapse in Patients with Large B Cell Lymphoma: A Meta-Analysis

Introduction: Central nervous system (CNS) relapse in large B cell lymphoma (LBCL) is a rare, but catastrophic event associated with poor prognosis without an effective standard prophylactic strategy. Intravenous and/or intrathecal chemotherapy have been proposed for patients at high risk for CNS relapse (i.e., CNS-IPI of 4 or greater) with mixed results due to the lack of prospective trials comparing different approaches. Large retrospective cohort studies have challenged the value of CNS prophylaxis. We performed a systematic review and meta-analysis (MA) assessing the role of chemoprophylaxis in preventing CNS relapse for LBCL patients treated with chemoimmunotherapy. Methods: A systematic literature review was conducted using the major online databases, including English language studies published from 2011 until 2022. Data were pooled from the studies with a comparator group using the random effects model to report odds ratio (OR) and 95% confidence intervals (95% CI). Data from single-arm studies were pooled using the random effects model to report the pooled proportion with 95% CIs. Results: There were 16 studies included in the MA (12 retrospective and 4 prospective) assessing the role of CNS prophylaxis in a total of 11,530 patients. The incidence of CNS relapse appeared to be higher among patients who received CNS chemoprophylaxis (n=2108) compared with patients without chemoprophylaxis(n=9422) (OR 1.70, 95% CI 1.10-2.61) (figure 1). Among the single-arm studies, the pooled proportion of the incidence of CNS relapse, isolated CNS relapse and secondary CNS relapse was 5% (95% CI 4%-7%), 5% (95% CI 4%-7%), and 1% (95% CI 0%-2%), respectively. Results are confounded by the retrospective design of most studies, different types of chemoprophylaxis and heterogeneous patient population. Discussion: This systematic review and MA demonstrated consistent rates of CNS relapse as seen in prior large cohorts, and did not show evidence for the use of chemoprophylaxis in patients with LBCL to prevent CNS relapse. Given the scarcity of high quality data due to the absence of prospective trials and the lack of motivation by multiple stakeholders to develop these type of studies, the totality of evidence grouped in this MA constitutes one of the most robust datasets arguing against chemoprophylaxis for prevention of CNS relapse in patients with LBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Low Incidence of Central Nervous System (CNS) Relapse of Diffuse Large B-Cell Lymphoma despite Limited Use of Intrathecal Prophylaxis

Diffuse large B cell lymphoma (DLBCL) is the commonest sub type of non-Hodgkin's lymphoma (NHL) accounting for 30–50 % of NHL cases. Around 2% to 10% of patients with diffuse large B-cell lymphoma (DLBCL) experience central nervous system (CNS) relapse after initial therapy which is associated with a poor prognosis and most often a fatal outcome. The incidence of CNS relapse can vary from <1% in younger, good-risk patients, to around 30% in patients with multiple risk factors, however, the relapse risk was reported to be lower in the rituximab era in some studies. Moreover, optimal modality of CNS prophylaxis remains to be defined, with both systemic and intrathecal (IT) chemotherapy being widely used. As the incidence of CNS relapse and type of prophylaxis used varies in different reports, it is important to study this risk in different populations to implement optimal prophylaxis strategies. The Objectives of this study was to evaluate the incidence of CNS relapse in DLBCL patients at our institution and to study risk factors and the type and role of CNS prophylaxis. We retrospectively analyzed patients diagnosed with DLBCL at King Khalid University Hospital, Riyadh, from January 2011 to June 2019. Data were collected from computerized hospital information system and from the files of the patients. Variables studied included age at diagnosis, stage at diagnosis, international prognostic index (IPI) and CNS-IPI score, site(s) of extra-nodal involvement, type of chemotherapy received, CNS prophylaxis and CNS relapse. CNS prophylaxis was administered on the basis of presence of high-risk features like presence of ≥2 extranodal sites, involvement of bone marrow, bone, testes, nasopharynx and paranasal sinuses. Patients with presence of CNS involvement at diagnosis and primary CNS lymphoma were excluded. A total of 101 patients were diagnosed with DLBCL during the study period. There were 58 males and 43 females with a median age of 56 (range: 16-87) years. Ann Arbor stage of I-IV was assigned in 9, 21, 17 and 50 patients, respectively. The lung was the most common extranodal site involved in 27 (26.7%) patients, and liver and bone marrow involved in 20 (19.8%) patients each. Gastrointestinal tract was involved in 9 (8.9%) patients, kidneys in 5 (4.95%), breast in 4 (4%), and testis and adrenal in 2 (2%) patients each. Twenty-five (24.75%) patients had high risk CNS-IPI score, 44 (43.5%) had intermediate risk score and 32 (31.7%) had low risk score. Ninety-four (93%) patients received R-CHOP chemotherapy while rest of the patients received other types of chemotherapy, mostly a milder regimen (R-CVP), because of comorbidities and poor performance status. Sixteen patients received CNS prophylaxis, which was IT methotrexate (MTX) ± cytarabine/hydrocortisone in all patients. Nine of 25 (36%) patients with high-risk CNS-IPI score did not receive CNS prophylaxis. After a median follow up of 36 months (range 4-114), 2 (2%) patients developed CNS relapse and died shortly after this diagnosis. Both the patients with CNS relapse had high risk CNS-IPI score and did not receive CNS prophylaxis. CNS relapse of DLBCL was uncommon in this patient population despite limited use of IT CNS prophylaxis in high-risk patients. Low incidence of CNS relapse in many high-risk patients despite limited use of IT prophylaxis may be related to rituximab use and/or other factors. Our data indicate that IT CNS prophylaxis may be adequate for DLBCL patients at high risk of CNS relapse.

P1217: INTRATHECAL METHOTREXATE PROPHYLAXIS AND CENTRAL NERVOUS SYSTEM RELAPSE IN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH INTENSIFIED R-ACVBP STRATEGY

Background: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma is relatively uncommon (2-5%) and remains catastrophic with a median survival of 2 to 5 months. Intrathecal (IT) or intravenous high-dose methotrexate (HD MTX) have limited if any prophylactic impact on CNS relapse. We recently demonstrated in a cohort of 2203 patients included in multicenter clinical trials conducted by LYSA and GLA/ DSHNHL, that only 4 (1.6%) CNS relapses were seen with the R-ACVBP strategy in pts with aaIPI 2, 3 (and intermediate/high CNS-IPI), while 15 (3.9%) relapses did occur after R-(Mega)CHO(E)P. Aims: To address the role of IT in this intensified strategy R-ACVBP, we took the advantage of real world data of patients treated in four centers, and compared CNS relapses occurring in patients treated with R-ACVBP strategy with or without IT. Methods: The LYSA R-ACVBP strategy include four cycles of R-ACVBP (75 mg/m2 doxorubicin, and 1200 mg/m2 cyclophosphamide; 2 mg/m2 vindesine and 10 mg bleomycin on days 1 and 5) with four IT, two cycles of high dose methotrexate (3g/m2), four cycles of R-etoposide (300 mg/m2) and ifosfamide (1500 mg/m2) and 2 cycles of cytarabine(100 mg/m2) given sub cutaneously for 4 days. 233 patients with previously untreated diffuse large B-cell lymphoma (DLBCL) aged 18 to 59 years old received this intensified strategy between 2010 and 2020. We excluded 30 patients who received ASCT in first line and 10 others who received less than four cycles of R-ACVBP. We assessed the risk for of relapse and CNS-relapse. We also assesed the impact of the 2 courses of subcutaneous aracytine on overall survival (OS) and progression free survival (PFS). Results: A total of 193 pts were included. Median age was 44.4 years (IQR, 30.8-53, range: 17-62). Distribution of CNS IPI was not significantly different comparing IT (n=132) vs non-IT (n=61) groups within aaIPI categories (Table 1). 92 patients did not receive the two courses of subcutaneous Aracytine (no AraC group) for consolidation and 101 patients received the two courses (AraC group). With a median follow-up at 57.2 months, the 3 year OS and 3 year PFS of the whole cohort was 93.6% and 86.2%, respectively, without significant difference between IT and non IT groups in terms of OS (3yr-OS, = 92.3% versus 95.1%, HR= 1.29 (95%CI, 0.41 to 4.04, p=0.67) and PFS (3yr-PFS, 84.4% versus 90.1%, HR= 1.26 (95%CI, 0.59 to 2.72, p=0.55). The 3y-cumulative incidence of CNS relapse for pts treated IT group was 3.2% (95%CI, 1.0 to 7.4), and 3.3% (95%CI, 0.6 to 10.2) in the non-IT group (p= 0.93). In pts with aaIPI 1, two patients experienced a CNS relapse, one in the IT group and one in the non-IT group. In pts with aaIPI 2,3 and intermediate/high CNS IPI, 4 patients experienced a CNS relapse, three out of four in the IT group. 92 patients did not receive the two courses of subcutaneous Aracytine (no AraC group) for consolidation and 101 patients received the two courses (AraC group). Receiving or not AraC did not have any impact on the CNS relapse with a risk of CNS relapse at 4.1% (95%CI, 1.3 to 9.5) for patients receiving AraC and 2.2% (95%CI, 0.4 to 6.9) for patients not receiving AraC (p= 0.48). Image:Summary/Conclusion: CNS relapse was rare in younger DLBCL treated with this intensified strategy. Only 6 CNS relapses were observed without difference between IT and non-IT groups. The results presented at the EHA will included the total cohort of more than 600 patients.

Cerebrospinal fluid flow cytometry and risk of central nervous system relapse after hyperCVAD in adults with acute lymphoblastic leukemia.

Potential involvement of the central nervous system (CNS) by acute lymphoblastic leukemia is typically evaluated by a conventional cytospin (CC) of cerebrospinal fluid (CSF). Multiparameter flow cytometry (MFC) is generally more sensitive and specific than morphology, but data to guide its use versus CC are limited. This study identified 92 patients who had MFC performed on their initial CSF specimen and received at least 4 cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (hyperCVAD) as their initial treatment. Eighteen (20%) were CSF+ by MFC at the baseline, and only 6 of these patients were positive by CC. In contrast, 0 of 51 patients who were negative by MFC and had CC available were positive by CC. Despite the receipt of significantly more intra-CSF chemotherapy (P < .001), the cumulative incidence of CNS relapse by MFC was 22% among CSF+ patients versus 5% among those who were CSF- (P = .044). No such association was observed between CNS relapse and CC results (P = .42). None of the 74 CSF- patients became CSF+ during their initial treatment despite being tested a median of 5 times (range, 2-10). CSF positivity by MFC was the factor most strongly associated with CNS relapse in a series of univariate Cox models (hazard ratio, 3.7; P = .067). The initial CSF status by MFC had no significant impact on overall or event-free survival. MFC of CSF is superior to CC of CSF in identifying adults at high risk for CNS relapse after treatment with hyperCVAD. Surveillance of CSF by MFC has limited utility.

Impact of Double Hit Lymphoma and Cell of Origin in the Risk of Central Nervous System Relapse in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma

Introduction: Central nervous system (CNS) relapse is an uncommon but devastating complication occurring in about 2-10% of patients with diffuse large B-cell lymphoma (DLBCL). The CNS-IPI is a validated prognostic tool used to identify patients at high risk of CNS relapse. MYC and BCL2/BCL6 rearrangements (double-hit lymphoma- DHL) and non-GCB (NGCB) cell of origin may be at higher risk of CNS relapse. However, the ability of these molecular data to refine CNS-IPI risk prediction has not been assessed. In this study, we aimed to describe the impact of DHL and NGCB cell of origin in the incidence of CNS relapse in patients with newly diagnosed DLBCL.Methods: A retrospective review was conducted to identify patients with newly diagnosed DLBCL from 01/01/2002 - 06/30/2015 using the University of Iowa/Mayo Clinic Lymphoma Molecular Epidemiology Resource database. Patients with primary CNS lymphoma or with CNS involvement at diagnosis were excluded. All patients received chemoimmunotherapy. Clinical, biological, laboratory and radiological data were abstracted including the occurrence of CNS relapse. CNS IPI risk score categories were defined as low- (≤1) intermediate- (2-3) and high-risk (≥4) as originally described (Schmitz et al, JCO 2016). Cell of origin (COO) classification into GCB and non-GCB subtypes was performed using Hans algorithm and/or NanoString data. Characteristics between groups were compared using Kruskal-Wallis or Chi-squared test as appropriate. Survival analysis was performed using Cox proportional hazards model and the Kaplan Meier method. Statistical analysis was performed using SAS version 9.4M5 and R version 4.0.3.Results: We identified a total of 1,360 patients with newly diagnosed DLBCL. Patients had a median age of 62 years (range 18-93 years), were predominantly male (56%), had a performance status <2 (84%), had stage III/IV disease (61%) and an elevated LDH (56%) at diagnosis. Fluorescent in situ hybridization data was present for 65% of patients. Among patients with available data, DHL and NGCG COO represented 2.8% and 36% of the cohort, respectively. CNS IPI high- and intermediate-risk categories were present in 12.4% and 52% of the patients, respectively. R-CHOP was the most common upfront chemotherapy (n=980, 72%).The median follow-up for the entire cohort was 84.9 months (IQR: 58.9-120.9). Overall, 50 patients (3.6%) had a CNS relapse during the study period. Lymphoma relapsed in the CNS in 3.0% (95% CI:2.1-4.4), 4.7% (95% CI: 3.4-6.3) and 4.9% (95% CI: 3.7-6.6)% of patients with CNS-IPI score of intermediate/high risk at 1, 3 and 5 years following the diagnosis of DLBCL. In patients with low risk CNS-IPI, 1.1% (95% CI: 0.4-2.5), 1.7% (95% CI: 0.9-3.4) and 1.7% (95% CI: 0.9-3.4) had a CNS relapse at 1, 3 and 5 years following DLBC diagnosis. Patients with CNS relapse were more likely to have elevated LDH (76% vs 56%, p=0.008), advanced stage (78% vs 61%, p=0.01), adrenal involvement (8% vs 2.4%, p=0.014) and have a CNS IPI intermediate risk (68% vs 51%), and high risk (16% vs 12.3%, p=0.014) at the time of initial diagnosis compared to patients without CNS relapse. Patients with CNS relapse had similar rates of DHL (4% vs 2.7%, p=0.17) and NGCB cell of origin (42% vs 36.2%, p=0.52) compared to patients without CNS relapse.In the multivariable analysis, the strongest predictors for CNS relapse were CNS IPI high risk (Hazard Ratio [HR]= 3.6, 95%CI= 1.4-9.7) and CNS IPI intermediate risk (HR= 3.15, 95%CI= 1.46-6.81). DHL and NGCB cell of origin were not associated with a significantly higher risk of CNS relapse (HR= 1.79, [95%CI=0.42-7.59] and HR= 1.26, [95%CI=0.62-2.57], respectively).Conclusion: CNS relapse was an uncommon occurrence in patients with DLBCL who were treated with chemoimmunotherapy. CNS IPI intermediate- and high-risk scores remain the strongest predictors of CNS relapse in patients with DLBCL after adjusting to biological high-risk variables including DHL and NGCB cell of origin. Larger studies are required to validate our findings due to the low incidence of CNS relapse in our cohort. [Display omitted] DisclosuresFarooq: Kite, a Gilead Company: Honoraria. Maurer: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Habermann: Tess Therapeutics: Other: Data Monitoring Committee; Seagen: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Novak: Celgene/BMS: Research Funding.

Impact of Choice of Platinum-Based Salvage Therapy on CNS Relapse in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Impact of Choice of Platinum-Based Salvage Therapy on CNS Relapse in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

High Frequency of CNS Involvement in Transformed Waldenström Macroglobulinemia

INTRODUCTIONCentral nervous system (CNS) relapse is a challenging situation in diffuse large B-cell lymphoma (DLBCL). High CNS-International Prognostic Index (IPI), activated B-cell (ABC) subtype and MYD88 L265P mutation, features often found in transformed Waldenström macroglobulinemia (WM), are associated with a higher risk for developing CNS relapse. This study was aimed to describe CNS involvement in a large cohort of transformed WM.METHODSThis international multicenter retrospective study included patients with a diagnosis of WM and a concurrent or sequential histological diagnosis of DLBCL. CNS disease was diagnosed by detection of DLBCL cells in the cerebrospinal fluid and/or by brain biopsy. Patients with CNS involvement by lymphoplasmacytic cells (Bing-Neel syndrome) were excluded. Of 254 identified patients with a diagnosis of histological transformation (HT) between 1988 and 2020, 19 were excluded due to lack of data on extranodal involvement. The first part of the analysis focused on baseline CNS involvement. Clinicobiological characteristics were compared between groups using Chi-square or Fisher's exact tests or Mann Whitney tests as appropriate. We analyzed CNS recurrence in the second part of the study. Forty-eight additional patients were excluded due to baseline CNS involvement (n = 25), absence of treatment at HT (n = 14) and lack of details on follow-up (n = 9). Cumulative incidence of CNS relapse was analyzed using competing-risk models that accounted for other events like systemic relapse or death from any cause, reporting sub-hazard ratio (SHR).RESULTSBaseline CNS involvement was present in 25 patients (11%) with transformed WM, including 10 (4%) with parenchymal disease, 10 with leptomeningeal, 4 (2%) with both, and 1 with unspecified CNS involvement. Characteristics associated with baseline CNS involvement were performance status 2-4 (P=0.03) and ≥2 extranodal sites (P=0.02). Median survival after HT was 1 year [0.7-2.5], comparable to the one of patients without CNS disease (1.8 year [1.2-2.6], P=0.74). We observed no difference in survival based on isolated CNS involvement (n = 10) compared to CNS and systemic involvement (n = 15) (P=0.94).Twenty-three CNS relapses occurred (12%). The 2-year and 3-year rates of CNS relapse were 9% (95% CI, 6-14) and 11% (95% CI, 7-16) (Figure 1). The median time to relapse in the CNS was 11 months (95% CI, 7-25). Thirteen CNS recurrences (57%) occurred during the first year of follow-up. Seventy percent were isolated CNS relapses. The location was leptomeningeal in 43% of cases, parenchymal in 35%, both in 17%, and unspecified in 4%. According to CNS-IPI risk groups (data available for 20 patients), 9 patients (45%) belonged to the high-risk group, 10 (50%) to the intermediate-risk group and 1 (5%) to the low-risk group. Prior to CNS relapse, 87% of patients had received rituximab, and 39% had received CNS prophylaxis (30% intrathecal chemotherapy, 4% high-dose methotrexate (HD-MTX), and 4% both). After CNS recurrence, 96% of patients received salvage treatment: combination of HD-MTX and HD-cytarabine (48%), HD-MTX alone (30%), or HD-cytarabine alone (9%). Four patients underwent consolidative autologous stem cell transplantation. The median survival after CNS relapse was 5.6 months. Factors associated with 3-year cumulative incidence of CNS recurrence in univariate analysis were involvement of kidney/adrenal glands (HR, 4.4; P=0.01) and MYD88 L265P mutation (P=0.01) (Figure 2A and B). Of note, among 74 patients (over 187, 40%) with data available for MYD88 mutation status, 11 CNS relapses occurred in patients with MYD88 L265P mutation (n = 54, 20%) whereas no relapse were observed in MYD88 WT cohort (n = 20). A trend toward higher risk of CNS relapse for ≥2 extranodal sites (HR, 2.3, 95% CI 0.98-5.3; P=0.06) was observed. Cumulative incidence according to CNS-IPI risk groups (0% in the low-risk, 9% in the intermediate-risk and 14% in the high-risk group) was not statistically significant (P=0.47).CONCLUSIONCNS involvement occurs frequently in transformed WM. Rate of CNS relapse seems similar to DLBCL patients belonged to the CNS-IPI high-risk group. Special attention should be paid to patients with kidney/adrenal involvement and MYD88 L265P mutation. [Display omitted] DisclosuresVos: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Travel reimbursement. Treon: X4: Research Funding; Janssen: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; BMS: Consultancy, Research Funding; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Dimopoulos: Janssen: Honoraria; Beigene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria. Kapoor: Cellectar: Consultancy; Karyopharm: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.

High-Dose Methotrexate Is Not Associated with Reduction in CNS Relapse in Patients with Aggressive B-Cell Lymphoma: An International Retrospective Study of 2300 High-Risk Patients

High-Dose Methotrexate Is Not Associated with Reduction in CNS Relapse in Patients with Aggressive B-Cell Lymphoma: An International Retrospective Study of 2300 High-Risk Patients

Impact of Central Nervous System International Prognostic Index on the Treatment of Diffuse Large B Cell Lymphoma.

BackgroundThe central nervous system international prognostic index (CNS-IPI) is being used widely for the identification of patients with diffuse large B cell lymphoma (DLBCL) with a high risk of central nervous system (CNS) relapse. The aim of our study is to confirm the value of the CNS-IPI in predicting CNS relapse in our young study population and to evaluate its impact on the selection of patients for CNS prophylaxis.MethodsWe retrospectively reviewed patients diagnosed with DLBCL who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) regimen from January 2010 till December 2018. Correlation between CNS-IPI and cumulative incidence of CNS relapse and time to CNS relapse was examined through Kaplan-Meier plots. Median time to CNS relapse and median overall survival after CNS relapse were also estimated using the Kaplan-Meier plots. ResultsA total of 354 patients were included. The median age was 46 years. Overall, 5% of the patients developed CNS relapse. Median survival after CNS relapse was seven months. Two-year CNS relapse rates according to CNS-IPI were 0.7%, 5.1%, and 26% for low, intermediate, and high-risk, groups respectively.On multivariate analysis, poor performance status (p=0.045), involvement of two or more extranodal sites (p= 0.021), involvement of bone marrow (p= 0.029), and renal or adrenal glands (p= 0.006) significantly correlated with CNS relapse. Considering the CNS-IPI and high-risk anatomical sites (breast, uterus, testis, and epidural space), 26% of our patients with DLBCL would have needed prophylaxis.ConclusionAlthough CNS-IPI helps in better selection of DLBCL patients for CNS prophylaxis, it can possibly increase the number of patients exposed to unnecessary prophylaxis. More investigational biomarkers are needed to better refining high-risk patients.

Central nervous system relapse in diffuse large B lymphoma: a retrospective cohort study

CNS relapse in patients with LDCGB is a poor prognosis event. The incidence of relapse is variable according to the literature. Data in Latin America is lacking. In order to establish the incidence of CNS relapse in our cohort, time to CNS relapse and the impact of CNS relapse risk factors, a retrospective cohort study was performed, from January 2012 to June 2017. One hundred and forty seven patients were analyzed. The median age was 66 years (ICR 56-76); 76 patients (51.70%) were men. The IPI was low or intermediate/low in 115 (78.2%) cases. The CNS IPI was intermediate in 77 (52.4%) and high in 14 (9.5%) of cases. Thirty-five (23.81%) patients received intrathecal prophylaxis. No patient received systemic prophylaxis. During the follow-up, 8 (4.59%) patients had CNS relapse, none of them with high IPI. The median time to relapse was 6.5 months (ICR 5.5-10). Seven (87.5%) patients relapsed within the year of diagnosis. We found no risk factors for CNS involvement in the bivariate analysis. The incidence of relapse was 2.7% (CI 0.2% -4.6%), 4.8% (CI 1.8% -8.9%) and 5.4% (CI 4.5- 8.9%) at 6, 12 and 24 months, respectively. The incidence of CNS relapse was similar to that described in the international series. Our study confirms that the majority of patients relapse during the first year of follow up. We must carry out broader collaborative work to better establish the risk factor for CNS relapse.

Incidence of Central Nervous System (CNS) Relapse in MYC Rearranged Diffuse Large B-Cell Lymphoma: Does CNS Prophylaxis Improve Outcome?

Introduction:Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is rare and associated with poor outcome. The presence of MYC rearrangement (MYC -R)with or without BCL2 and/or BCL6 rearrangement (high-grade B-cell lymphomas, or HGBCL, per 2016 WHO revision) has been associated with inferior survival with traditional R-CHOP chemotherapy and a higher incidence of CNS relapse. The incidence of CNS relapse and patient outcome in patients with HGBCL and MYC -R with increasing use of aggressive CNS directed chemotherapy or CNS prophylaxis is unknown.Methods:In this single-center retrospective cohort study we compared the incidence of CNS relapse in HGBCL with at least MYC -R (MYC- R group) with DLBCL not otherwise specified (DLBCL NOS, non- MYC -R group). Differences between groups were analyzed using Chi-square, Fisher's exact and t-Student tests. Statistical significance was set at P<0.05. Kaplan Meier method was used to calculate progression-free survival (PFS) and overall survival (OS). Log-rank test was used to determine differences in survival. Statistical analyses were performed using SPSS.24 software.Results:Of 205 patients, 72 (35%) were MYC -R and 133 (65%) were non- MYC -RDLBCL. The median age at diagnosis was 62 (range 18-70 years), and 126 patients were male (61%). The MYC -R (HGBCL) group included 58 (80%) patients with concurrent BCL2 and/or BCL6 rearrangement. Among MYC -R patients, 42 (58%) had a high-intermediate or high international prognostic score (IPI) score, 61 (of 68; 90%) were of germinal center B-cell (GCB) type, and 56 (of 69; 81%) presented with advanced stage disease. Among non- MYC -R patients, 49 (of 121; 40%) had high-intermediate or high IPI, and 90 (of 132; 68%) had advanced stage disease. For treatment, 28 (of 66; 42%) MYC -R and 31 (of 120; 25%) non- MYC -R patients received CNS prophylaxis either as intrathecal methotrexate or cytarabine or as systemic therapy with high-dose methotrexate. One MYC -R patient had CNS involvement at presentation. Chemotherapy among MYC -R patients included R-CHOP (23 patients), R-HyperCVAD (8), DA-R-EPOCH (27), R-CHOEP (4) and other diverse regimens including clinical trials (6). Among non- MYC -R patients, regimens included R-CHOP (102), R-HyperCVAD (3), DA-REPOCH (9), and R-CHOEP (13). CNS relapse was seen in 4 patients in the MYC -R group (5.6%) and 1 patient (0.7%) in the non- MYC -R group (P=0.053). Three of the 4 MYC -R patients with CNS relapse had received CNS prophylaxis. The non- MYC -R patient who had CNS relapse initially presented with CNS involvement and had been treated with high dose methotrexate. Twenty-six (26) MYC -R patients and 24 non- MYC -Rpatients had primary refractory disease. Median PFS was 15.9 months in MYC- R vs. not reached in non- MYC- R (HR 2.835; 95% CI 2.291 to 6.757, P<0.0001), and median OS was 30 months in MYC- R vs. not reached in non- MYC- R (HR 4.179; 95% CI 2.945 to 10.55, P<0.0001).Conclusion:The incidence of CNS relapse among both MYC -R (HGBCL) and non- MYC -R (DLBCL NOS) cohorts was overall low and may have been mitigated with the use of prophylaxis. Although, CNS relapse occurred despite CNS prophylaxis in both groups. Both the PFS and OS among MYC -R patients were significantly worse compared to non- MYC -R patients despite the use of more aggressive therapy in a majority of MYC- R patients. Larger studies are needed to confirm these findings and determine optimal strategies for CNS prophylaxis and therapy in HGBCL and DLBCL NOS. [Display omitted] DisclosuresReddy:BMS: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Gilead: Speakers Bureau.

Central Nervous System Relapse in Diffuse Large B Cell Lymphoma—Predictors at Diagnosis

Background Central nervous system (CNS) relapse of diffuse large B cell lymphoma (DLBCL) is an infrequent outcome with very poor prognosis. Initial studies have identified risk factors for CNS relapse and the CNS international prognostic score ((CNS-IPI) (Schmitz et al, JCO 2016) has been validated in various cohorts. Biologic characteristics of the disease are not included in the derivation of this model. We sought to validate this risk factor model in our single center DLBCL population in search for additional disease - specific factors that could further improve prediction of CNS relapse.Methods The hematologic malignancies database of the University Hospitals Seidman Cancer Center was accessed to identify newly diagnosed DLBCL patients between 2002 and 2014. Patients with extra-nodal CNS involvement at diagnosis were excluded. Through retrospective chart review data, we identified patient and disease characteristics, and outcomes data including response, relapse and death was collected. Patients who underwent therapy and had follow up data were included for final analysis. Univariate Cox proportional hazards analysis was conducted on the risk factors and those reaching statistical significance (p < 0.05) were selected for inclusion in multivariate proportional hazards model to help identify predictors for CNS relapse. CNS IPI score was applied to our population and cumulative incidence (with death as competing risk) was used to estimate the incidence of CNS relapse with the Gray test performed for comparisons between groups.Results: Five hundred and twenty-four patients were included for final analysis. Median age in our cohort was 64 years, with 312 (59.5 %) patients above the age of 60 years. 322 (63 %) patients had stage (III-IV), and 220 patients (37%) had elevated LDH at diagnosis. Two hundred and eighty five patients had extra-nodal disease involvement at the time of diagnosis with 88 patients involving more than one site. Baseline patient and disease characteristics are listed in Table 1. Four hundred (76%) patients received R CHOP as first line therapy, 395 patients achieved complete remission with first line therapy. At a median follow up of 64 months, 187 patients died and 171 patients had relapsed.Twenty-one patients developed CNS relapse in the follow up period, at median of 8.2 months after treatment initiation (95% CI 6.2-9.6) months. Applying the CNS-IPI risk scoring among the evaluable patients, 149 patients (36%) were found to be low risk (0-1 factors), 222 patients (53%) were intermediate risk (2-3 factors) and 47 patients (9%) were high risk (4-6 factors) for CNS relapse. Univariate analysis showed advanced stage (stage III-IV), number of extra-nodal sites involved, liver involvement, non- GCB subtype, translocation t (14; 18) and body mass index were significantly associated with CNS relapse (p<0.05). In multivariate analysis, only non- GCB subtype and translocation t (14; 18) (p = 0.023 and 0.028 respectively) were significant. Table 2 summarizes the results of Cox proportional hazards analysis.We evaluated the cumulative incidence of CNS relapse in the high-risk group, defined as CNS-IPI >1, (n=269, 64%). The 2-year CNS relapse cumulative incidence was at 5.1 % (95% CI: 2.8- 9%) compared to 0% for patients with CNS IPI ≤ 1 (p=0.027) (Figure 1).Median survival after CNS relapse was 3.6 months (0 - 150.2 months). Overall survival from start of initial therapy was 16 months (95% CI 9.5 -81.9 months) for patients with CNS relapse vs 170 months (95% CI 120.3 months - not reached), p<0.001]. (Figure 2)SummaryPrognosis of CNS relapsed of DLBCL is very poor. CNS IPI score helps identify a cohort that may benefit from CNS prophylaxis, and may help avoid unnecessary diagnostic and therapeutic intervention in the low risk cohort, i.e., CNS- IPI score <1. Hepatic involvement at diagnosis may be an additional clinical characteristic associated with high risk of CNS relapse. Biological features including non-GCB subtype and translocation t (14; 18) are novel risk factors that should be considered in the development of future risk models. [Display omitted] DisclosuresMalek:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau. Cooper:Novartis: Research Funding. de Lima:Celgene Corporation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Caimi:Seattle Genetics: Equity Ownership; Abbvie: Equity Ownership; Incyte: Equity Ownership; Celgene: Speakers Bureau.

CNS relapse in DLBCL patients below 60 years treated with R-ACVBP, R-CHOEP, or R-CHOP: A joint analysis of LYSA and GLA/DSHNHL.

7543 Background: Central nervous system (CNS) relapse occurs in 2-6% of DLBCL patients (pts) increasing to 10% or more in high-risk groups. Intrathecal (IT) or intravenous high-dose methotrexate (HD MTX) have limited if any prophylactic impact on CNS relapse. To address the role of systemic first-line therapy in pts tolerating intensified strategies (R-ACVBP, R-(Mega)CHOEP, R-CHO(E)P), we compared CNS relapses occurring in a large cohort of pts ≤60 years. Methods: We conducted a retrospective analysis including previously untreated pts with DLBCL by central review, age 18-60 years, from multicenter clinical trials conducted by LYSA and GLA/DSHNHL (Table). We assessed the risk of CNS relapse in matched cohorts based on the aaIPI. Results: A total of 2203 pts were included. Median age was 47 years (18-60). 455 pts were treated with R-ACVBP, 444 with R-(Mega)CHOEP, 1304 with R-CHOP. Distribution of CNS IPI was not significantly different comparing R-ACVBP to R-CHO(E)P groups within aaIPI categories (Table). PFS and OS were comparable according to treatment within aaIPI groups, also adjusted for prognostic factors. No CNS events occured during observation time of 3 years in pts with aaIPI 0. In pts with aaIPI 1, no CNS event occured in the R-ACVPB arm, the 3y-cumulative incidence of CNS relapse for pts treated with R-CHO(E)P group was 1.0% (95%CI 0.3-1.7). In pts with aaIPI 2,3 and intermediate/high CNS IPI, four (1.6%) treated with R-ACVBP experienced relapse in the CNS compared to 15 (3.9%) pts treated with R-(Mega)CHO(E)P (3y-cumulative incidence 1.6% (95%CI 0-3.2) vs. 4.0% (95%CI 2.0-6.0). Conclusions: CNS relapse was extremely rare in younger DLBCL pts with aaIPI 0 or 1; prophylactic measures are not warranted. In pts with aaIPI 2,3 (and intermediate/high CNS-IPI), only 4 (1.6%) CNS relapses were seen with the R-ACVBP while 15 (3.9%) relapses did occur after R-(Mega)CHO(E)P. This analysis underlines the important role of the systemic therapy in controling CNS relapse.[Table: see text]