Central Nervous System Prophylaxis Research Articles

Isolated central nervous system relapse in two adolescents with primary mediastinal large B-cell lymphoma after treatment with R-DA-EPOCH.

The addition of rituximab to standard regimens for primary mediastinal large B-cell lymphoma (PMBCL) has significantly improved overall survival. However, the optimal management of isolated central nervous system (CNS) relapse and role of CNS prophylaxis remains undefined. We present cases of two adolescents with PMBCL who developed isolated CNS relapses. While isolated CNS relapse may be managed with high-dose chemotherapy and autologous stem cell transplant with or without CNS radiotherapy, review of these cases and the literature highlight the need for further work to define risk factors for CNS relapse, and identify patients who may benefit from CNS prophylaxis.

Treatment outcomes and prognostic factors of patients with lymphoblastic lymphoma in East Asia.

Lymphoblastic lymphoma (LBL) is a rare, aggressive non-Hodgkin lymphoma (NHL) that has no established therapeutic approaches. The aim of this study was to investigate optimal treatments and prognostic risk models for patients with LBL in East Asia. We retrospectively examined the clinical data and treatment courses of adult patients diagnosed as LBL by WHO 2017 classification system. Median overall survival (OS) of the 78 patients with LBL was 38.3 months. There was no significant difference in OS between the patients who were treated with acute lymphoblastic leukemia (ALL)-like protocols and with NHL-like protocols (72.4 months vs 37.5 months, respectively, P = .546). The patients treated with ALL-like protocols had significantly shorter progression-free survival (PFS) (median 11.7 months for ALL-like protocols vs 27.0 months for NHL-like protocols, P = .030). A multivariable analysis found that central nervous system (CNS) prophylaxis, relapse of CNS lesions, leukemic transformation, and response to initial treatment were risk factors for OS of patients with LBL. Hematopoietic stem cell transplantation had no survival benefit, compared with chemotherapy-only treatment. Less intensive chemotherapy may be more optimal for patients in East Asia. Prophylaxis and management of CNS lesions should be emphasized throughout the treatment of LBL.

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Children: A Retrospective Cohort Study at a Pediatric Oncology Center.

Background and objective Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL Ph+) is quite rare among pediatric patients. Its management has undergone significant changes in the past few years, leading to some variability in how it is approached. At the Portuguese Oncology Institute of Porto (IPOP),a tertiary oncological center, the standard of carehas been aligned with the guidelines proposed by the European intergroup study of post-induction treatment of ALL Ph+ (EsPhALL). In this study, we aimed to examine the experience and outcomes related tothe treatment of pediatric patients with ALL Ph+ at IPOP. Methods This retrospective cohort study involvedpediatric patients diagnosed with ALL Ph+ at IPOP between January 2008 and December 2022 and analyzed their outcomes. Results A total of 14 patients were included. IKFZ1 was altered in five patients (out of nine in whom it was searched). Five patients were treated according to EsPhALL 2004, which involved starting imatinib later in a discontinuous manner [resulting in both five-year overall survival (OS) and progression-free survival (PFS) of 60%]. The EsPhALL 2010 (preconizing a continuous imatinib regimen instead) was employed in three patients, with a five-year OS and PFS of 66.7%. Allchildren mentioned above received cranial irradiationtherapy (CRT). Finally, six were treated according to the EsPhALL 2015, which stopped including CRT in its backbone. The five-year OS was 100%, whereas every patient progressed with an increase in BCR::ABL1 levels greater than 1-log. Moreover, until 2015, all patients had been recommended to undergo allogeneic hematopoietic stem cell transplantation (alloHSCT). However, since 2015, alloHSCT has been exclusively reserved for relapsed/refractory (R/R) disease or poor responders with positive measurable residual disease (MRD). In total, alloHSCT was performed in nine patients. Conclusions Although initially associated with a poor prognosis, the ALL Ph+ paradigm is drastically shifting. Further studies will hopefully clarify the outcomes in this population and help understand the role of central nervous system (CNS) prophylaxis, alloHSCT, and MRD quantification.

Incidence, risk factors, and outcome of asymptomatic central nervous system involvement in adult patients with acute myeloid leukemia.

Examination of central nervous system (CNS) involvement is not routine diagnostic practice in adult patients with acute myeloid leukemia (AML). Therefore, many asymptomatic patients with CNS involvement might go undetected. The effect of CNS involvement on the AML disease course is not well defined, with conflicting results regarding clinical outcome. This study aimed to determine the incidence of asymptomatic CNS involvement in AML estimated by multiparametric flow cytometry of cerebrospinal fluid (MFC-CSF) at diagnosis, the related potential risk factors, and prognosis. In total, 645 patients with de novo AML were screened; 183 (28.4%) of them fulfilled institutional practice for MFC-CSF analysis based on presence of CNS symptoms and/or clinical features. CNS symptoms and signs were observed in 8/183 (4.4%) patients, but most patients (175/183, 95.6%) were asymptomatic. In the asymptomatic group, 73/175 (41.7%) patients had positive or suspicious cerebrospinal fluid (CSF) findings categorized as CNS positive (CNSpos) and 102/175 (58.3%) had normal CNS findings categorized as CNS negative (CNSneg). The presence of leukemic blasts was confirmed in 81/183 (44.3%) patients; the total incidence of CNS involvement in the whole AML group was 12.6% (81/645). Compared with asymptomatic patients with CNSneg, those with CNSpos had a significantly higher frequency of lymphadenopathy, white blood cell count ≥30×109/L, presence of the monocytic phenotype, and a high percentage of bone marrow (BM) blasts. The multivariate logistic regression model identified monocytic phenotype (p=0.047) and high percentage of BM blasts (p=0.042) as predictors for CNSpos. CNSpos did not affect overall survival in patients with AML. There was a higher incidence of CNS involvement in asymptomatic adult patients with de novo AML, emphasizing possible undervalued rates of CNS disease at diagnosis. Prospective studies should determine whether diagnostic lumbar puncture for MFC-CSF analysis and CNS prophylaxis could contribute to better selection and prognosis in this patient population.

Do Double-Expressor High-Grade B-Cell Lymphomas Really Need Intensified Treatment? A Report from the Real-Life Series of High-Grade B-Cell Lymphomas Treated with Different Therapeutic Protocols at the Institute of Oncology Ljubljana.

High-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are known for their aggressive clinical course and so are the ones with MYC and BCL2 protein overexpression. The optimal therapy for these lymphomas remains to be elucidated. A retrospective analysis of all diffuse large B-cell lymphomas and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements diagnosed between 2017 and 2021 at the Institute of Oncology Ljubljana, Slovenia, has been performed. Only patients with double-expressor lymphoma (DEL), double-hit lymphoma (DHL), or triple-hit lymphoma (THL) were included. Demographic and clinical parameters were assessed, as well as progression-free survival (PFS) and overall survival (OS). In total, 161 cases out of 309 (161/309; 52,1%) were classified as DEL. Sixteen patients had DHL, MYC/BCL2 rearrangement was observed in eleven patients, and MYC/BCL6 rearrangement was observed in five patients. Five patients were diagnosed with THL. Out of 154 patients (according to inclusion/exclusion criteria) included in further evaluation, one-hundred and thirty-five patients had double-expressor lymphoma (DEL), sixteen patients had DHL, and three patients had THL. In total, 169 patients were treated with R-CHOP, 10 with R-CHOP and intermediate-dose methotrexate, 19 with R-DA-EPOCH, and 16 with other regimens. The median follow-up was 22 months. The 5-year OS for the whole DEL group was 57.1% (95% CI 45.9-68.3%) and the 5-year PFS was 76.5% (95% CI 72.6-80.4%). The log-rank test disclosed no differences in survival between treatment groups (p = 0.712) while the high-risk international prognostic index (IPI) carried a significantly higher risk of death (HR 7.68, 95% CI 2.32-25.49, p = 0.001). The 5-year OS for DHL patients was 32.4% (95% CI 16.6-48.2%) while all three TH patients were deceased or lost to follow-up. Our analyses of real-life data disclose that the R-CHOP protocol with CNS prophylaxis is a successful and curative treatment for a substantial proportion of DEL patients.

IELSG30 phase 2 trial: intravenous and intrathecal CNS prophylaxis in primary testicular diffuse large B-cell lymphoma

AbstractPrimary testicular diffuse large B-cell lymphoma (PTL) is characterized by high risk of contralateral testis and central nervous system (CNS) relapse. Chemoimmunotherapy with intrathecal (IT) CNS prophylaxis and contralateral testis irradiation eliminates contralateral recurrences and reduces CNS relapses. The IELSG30 phase 2 study investigated feasibility and activity of an intensified IT and IV CNS prophylaxis. Patients with stage I/II PTL who had not received treatment received 2 cycles of IV high-dose methotrexate (MTX) (1.5 g/m2) after 6 cycles of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days). IT liposomal cytarabine was administered on day 0 of cycles 2 to 5 of 21-day R-CHOP regimen. Contralateral testis radiotherapy (25-30 Gy) was recommended. Fifty-four patients (median age: 66 years) with stage I (n = 32) or II (n = 22) disease were treated with R-CHOP, 53 received at least 3 doses of IT cytarabine, 48 received at least 1 dose of IV MTX, and 50 received prophylactic radiotherapy. No unexpected toxicity occurred. At a median follow-up of 6 years, there was no CNS relapse; 7 patients progressed, and 8 died, with 5-year progression-free and overall survival rates of 91% (95% confidence interval [CI], 79-96) and 92% (95% CI, 81-97), respectively. Extranodal recurrence was documented in 6 patients (in 2 without nodal involvement). In 4 cases, the relapse occurred >6 years after treatment. Causes of death were lymphoma (n = 4), second primary malignancy (n = 1), cerebral vasculopathy (n = 1), unknown (n = 2). Intensive prophylaxis was feasible and effective in preventing CNS relapses. Late relapses, mainly at extranodal sites, represented the most relevant pattern of failure. This trial was registered at www.clinicaltrials.gov as #NCT00945724.

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.

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.

CNS Prophylaxis in Diffuse Large B-Cell Lymphoma: A Common Toxic Clinical Practice Based on Abundant Opinion, Despite Evidence Suggesting Futility

Introduction: The history of medicine is replete with clinical practices, some clearly dangerous that have not been supported by what we would now consider to be mandatory data. Likewise, the field of hematology has not been immune from such practices as, for example, routine laparotomy and splenectomy in Hodgkin disease. Despite such history, and a push for evidence-based medicine, contemporary patient care still includes practices that have mainstream support despite a dearth of supporting evidence. CNS prophylaxis for diffuse large B-cell lymphoma(DLBCL) is one glaring example. Current Practice: In patients with high CNS-IPI score (≥4), multiple extra-nodal (EN) sites (≥3) and high-risk extra-nodal site, brain imaging is obtained (usually MRI) and cerebro-spinal fluid (CSF) is analyzed. If CNS involvement at diagnosis is ruled out, systemic chemotherapy followed by high-dose methotrexate (HD-MTX) is typically offered to fit patients. Intra-thecal (IT) therapy or no prophylaxis is the usual practice for unfit patients. These therapies, modelled on the CNS prophylaxis in adults with acute lymphoblastic leukemia (ALL), are not free of side effects and include mucositis, myelosuppression, hepatic, renal, neurological, and gastro-intestinal toxicities. Expert Opinion: Multiple national guidelines support the use of CNS prophylaxis for high-risk DLBCL. For example, the updated NCCN guidelines state that “CNS prophylaxis should be considered for patients with risk factors for CNS disease, but the optimal method is controversial”( NCCN Guidelines®, B cell lymphomas, version 5.2023). The British Society of Haematology recommend HD MTX administration for “high risk patients that are considered fit for such treatment”(McKay et al. British Journal of Haematology 2020). The European Society for Medical Oncology (ESMO) states that “HD-MTX is an option, even though the level of supporting evidence is low”(Tilly et al. Annals of Oncology 2015) ; the Canadian Lymphoma group recommends that ' Patients at high risk 'could consider' prophylaxis with high dose methotrexate“( Shafey et al. 2021) ; the Spanish Lymphoma Group recommends that 'CNS-directed prophylaxis should be offered to patients at high risk of CNS relapse'(Peñalver et al. Haematologica 2017). Similarly , multiple 'How I Treat' or guideline articles in top journals( Melchardt et al. ESMO Open 2023; Peñalver et al. Haematologica 2017; Bobillo et al. Haematologica 2023) support such use. Published data: There are no randomized controlled studies assessing CNS prophylaxis compared to none. There are, however, multiple reports in the past two decades of the use of some form of CNS prophylaxis. Without any controls, the value of such therapy is impossible to assess. At the same time, there are several comparative reports, based only on historic controls and compounded by heterogeneity of treatments and comorbidities, that suggested a benefit for CNS prophylaxis (Table 1). More recently, a large body of retrospective studies, with controls, were published (Table 2). These included a cohort that received HD-MTX versus those who did not receive HD-MTX or those who did not receive any CNS prophylaxis. In virtually all these reports there was no evidence of reduction in CNS relapse. Widespread use: Currently, the use of CNS prophylaxis is prevalent among fit and young patients with high-risk features ( Bobillo et al. Haematologica 2023; Demirci et al. Blood Research 2023). The concern for CNS relapse is the driving force behind this practice with a muted assurance that such may indeed prevent disease recurrence. Among older or unfit patients, CNS prophylaxis is most often withheld, with no evidence of a higher rate of CNS relapse ( Boehme et al. Blood, 2009; Eyre et al. Haematologica 2019). Conclusion: Relapse in the CNS after treatment of DLBCL has long been recognized as a serious clinical problem. It was assumed by many that, as in ALL, simple prophylaxis would be an effective remedy. This hope was never convincingly shown to be effective. Several phase II studies, with biased controls, suggested a benefit which, nevertheless, could not be confirmed in large retrospective controlled studies. Perhaps a different mold of CNS prophylaxis is needed, but the current approach appears marginally effective at best or unnecessarily harmful, at worst. Is it not time to step forward and resolve this issue, before it becomes religiously entrenched as standard of care?

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

CNS Prophylaxis in Adult ALL Patients after Stem Cell Transplantation: An EBMT Survey on General Practice

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for acute lymphoblastic leukemia (ALL) resulting in long-term remission. Despite advances in therapy, disease progression remains the major cause of mortality following HSCT accounting for 20-50% of all deaths. The central nervous system (CNS) is the most common extra-medullary site of disease progression after transplant in ALL. The established practice of CNS prophylaxis for ALL has largely been modeled in the pediatric population, given the higher incidence of ALL in this age group compared with adults. Although the use of CNS prophylaxis as part of the upfront treatment for ALL has led to significant decreases in CNS relapse and improved outcomes overall, the routine use of post-HSCT prophylactic CNS therapy as a strategy to prevent CNS relapse after transplant in adult patients is still controversial. Studies that utilized post-HSCT CNS prophylaxis have reported disparate results and there is no generalized consensus regarding the use of post-transplant CNS prophylaxis to prevent relapse. Methods In order to assess the current practice of post-HSCT prophylactic CNS therapy in preventing CNS relapse in ALL patients, we carried out a survey among EBMT centres to describe intrathecal (i.t.) prophylaxis or irradiation in HSCT for ALL in both patients with or without CNS manifestations at any time of disease (first or second complete remission [CR1, CR2] and relapsed/refractory [R/R] ALL). EBMT centres were asked whether they usually give i.t. prophylaxis or cranial irradiation before and after HSCT, and which drugs they use. Results Of 410 invited centres, 55 (13%) replied to the survey. Tables 1 shows the number of centres which use i.t. prophylaxis or cranial irradiation. Most of the 55 centres used both pre-and post i.t. prophylaxis and triple prophylaxis (steroids, cytarabine [AraC] and methotrexate [MTX]) was the most frequently adopted. As expected in the pre-transplant phase, almost 70% of centres use i.t. chemotherapy irrespective of the phase of the disease or of the use of total body irradiation (TBI) as conditioning regimen. In the post-transplant phase, the rate of i.t prophylaxis varies according to disease phase, TBI use, and history of CNS involvement pre HSCT. In patients w/o history of CNS involvement in CR1, i.t. prophylaxis is given in 23.6% and 21.5% (with or w/o TBI use, respectively). Notably in CR2 pts, i.t. prophylaxis is given in 20% of cases if the conditioning regimen includes TBI, and in 74.5% of cases if TBI is not used; 32.7% and 46.9% R/R pts (with or without TBI use, respectively) are given i.t. prophylaxis. In the setting of patients with history of CNS involvement in CR1, i.t. prophylaxis is given in and 30.9% and 38.2% (with or without TBI use, respectively); in CR2 pts, i.t. prophylaxis is given in 38.9% of cases if the conditioning regimen does not include TBI, and in 29.1% of cases if TBI is used; 38.9% and 45.3% R/R pts (with or without TBI use, respectively) are given i.t. prophylaxis. Pre-transplant cranial irradiation is planned in less than 10% of centres in CR1 and CR2 patients without CNS involvement, irrespective of the use of TBI in the conditioning regimen, while it is used in 22.4% and 25% of patients with R/R disease with or without TBI use for transplant, respectively. In the setting of patients with CNS involvement, among those in CR1 and CR2, approximately 30% receive pre-transplant cranial irradiation irrespective of TBI use, while 32.7% and 34.6% of patients receive cranial irradiation (with or without TBI use, respectively). Its use after transplant is uncommon irrespective of disease status at treatment. Conclusions CR2 pts (without CNS involvement) seem to be at higher risk of CNS relapse if TBI is not included in the conditioning regimen. R/R pts are always considered at higher risk for CNS relapse if TBI is not included in the conditioning regimen. Cranial irradiation before treatment is used in almost 1 out of 3 pts with CNS involvement despite the use of TBI as the conditioning regimen, and 1 out 4 R/R pts without CNS involvement at transplant. The rate of cranial irradiation after transplant is extremely low, irrespective of diseases status, previous CNS involvement or TBI use. In conclusion, the use of i.t. prophylaxis after HSCT in patients with or without CNS involvement is variable among European transplant centres, also in the era of novel therapies for patients with ALL.

Diffuse Large B-Cell Lymphoma CNS Relapse Prophylaxis with Intrathecal or High-Dose Intravenous Methotrexate

Introduction: Central nervous system (CNS) relapse is a relatively infrequent but often fatal complication of the most common subtype of non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL). Median overall survival (OS) after DLBCL relapse in the CNS is about 4 months. Despite identifying patients at high risk of developing CNS relapse using the CNS international prognostic index (CNS-IPI) score, it has been difficult to validate any specific strategy. Various chemotherapies and administration methods have been tested. Thus far, only the addition of rituximab to chemotherapy has yielded significant results. Our objective is to determine if administering prophylactic chemotherapy is efficacious in preventing DLBCL relapse in the CNS. Methodology: We collected retrospective data for patients with newly diagnosed DLBCL treated with rituximab and anthracycline-based chemotherapy from 2010 to 2020 in the Northwell Health system to determine the efficacy of CNS prophylaxis. Patients with CNS disease at diagnosis, primary testicular lymphoma, primary mediastinal large B-cell lymphoma, and HIV-associated lymphoma were excluded from this study. CNS prophylaxis was defined as receiving at least two doses of prophylactic chemotherapy, whether intravenous or intrathecal. Follow up for at least one year after diagnosis was required for inclusion. Overall survival (OS) was defined as the time difference between the date of definitive diagnosis to death or last date of contact. Other potential prognostic factors including double hit status and cell of origin, germinal center B-cell (GCB) vs. non-germinal center B-cell (non-GCB), were also evaluated. Pearson's chi-square analysis was used to compare the rate of DLBCL relapse in the CNS based on whether patients received CNS prophylaxis. Low risk was defined as CNS-IPI score 0 to 3 and high risk as CNS-IPI score 4 to 6. Kaplan-Meier analysis with log-rank (Mantel-Cox) testing was used to determine if any significant OS benefit was observed for the low and high-risk groups based on CNS-IPI score. Results: Of the 437 charts reviewed, 127 were eligible for inclusion. Most patients were male (56.7%). Median age was 69 years and median Eastern Cooperative Oncology Group (ECOG) performance status was 1. Most cases were non-GCB (44.9%, as 25% of cases were missing data) and not double hit (85%). Of the 35 patients at high risk for CNS relapse, 27 (77%) received prophylaxis. Intrathecal methotrexate (IT MTX) was given to 26 patients (96%) and high dose intravenous methotrexate (HD MTX) was given to 1 patient. CNS relapse occurred in 6 patients, of which 5 had a low-risk CNS-IPI score. One of the five patients in the low-risk group and the one patient in the high-risk group that had CNS relapse received prophylaxis. No significant difference in overall relapse rates were observed based on whether prophylaxis was given, X 2 (1, N = 127) = 0.30, p = .59. Kaplan-Meier analysis showed no difference in OS after stratification of patients by CNS-IPI score into the high-risk ( p = .50) and low-risk ( p = .24) groups. HD MTX was not administered frequently enough to determine its efficacy. Neither cell of origin (X 2 (1, N = 95) = 2.95, p = .086) nor double hit status (X 2 (1, N = 127) = 1.512, p = .22) had any significant effect on OS. Conclusions: We did not observe any clear benefit for administering IT MTX to prevent DLBCL relapse in the CNS. Most of the CNS relapse events occurred in the low-risk group, even though 8 patients in the high-risk group did not receive any CNS prophylaxis. This study did not have sufficient power to make a definitive conclusion. As CNS relapse is a rare event, a much larger sample size is required to determine the true efficacy of CNS prophylaxis. Non-GCB cell origin and positive double hit status are not included in the CNS-IPI score but their potential association with risk of DLBCL relapse in the CNS is understudied. Future studies should build upon these findings.

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.

Cerebral Spinal Fluid Attenuates the Efficacy of Methotrexate Against Acute Lymphoblastic Leukemia Cells

The anti-folate methotrexate is a critical component of acute lymphoblastic leukemia (ALL) therapy. In addition to systemic administration, methotrexate is given intrathecally, or directly into the cerebral spinal fluid (CSF) via lumbar puncture, for central nervous system (CNS) leukemia treatment and prophylaxis. While IT methotrexate played a critical role in improving outcomes for ALL, CNS ALL relapse remains a major cause of treatment failure and therapy related morbidity. However, attempts to develop more efficacious and less toxic CNS ALL therapies have been largely unsuccessful and IT methotrexate has remained the standard of care for 60+ years. Based on our prior work showing that ALL cells are more poised to undergo apoptosis in nutrient poor CSF, we initially hypothesized that ALL chemosensitivity will be increased in CSF (Basile et al., 2020). While this was confirmed for several ALL drugs including cytarabine and anthracyclines, we strikingly found that methotrexate was significantly less efficacious and potent against ALL cells in CSF relative to standard tissue culture media or the more physiologically relevant human plasma-like media (HPLM). CSF also attenuated the sensitivity of ALL cells to other anti-folates including raltitrexed, trimetrexate, and pralatrexate. To define the mechanism(s) underlying this methotrexate resistance induced by CSF, we explored previously well-described mechanisms of methotrexate resistance in leukemia and other cancers. However, to date this work suggests that the molecular etiology of this CSF-induced relative methotrexate resistance is not entirely explained by diminished leukemia proliferation in CSF, altered methotrexate cellular influx/efflux, methotrexate metabolism, folate analog rescue, dysregulated expression of methotrexate target proteins, or compensation by nucleotide salvage pathways. To complement our work examining known mechanisms of methotrexate resistance, we also used a more discovery-based approach and compared the gene expression patterns of leukemia cells in CSF versus tissue culture media. Preliminary bioinformatic analyses identified dysregulation of multiple genes involved in the integrated stress response (ISR) and unfolded protein response (UPR) pathways in leukemia cells in CSF. The ISR/UPR are mechanisms by which cells adapt to diverse stress stimuli in the microenvironment, including potentially nutrient poor CSF which is low in glucose, proteins, and lipids relative to plasma. The hallmark event in this pathway is the phosphorylation of the translation initiation factor eIF2α, which inhibits global protein synthesis and enables the translation of selected genes that together enable cell survival. Supporting our gene expression data, ALL cells in CSF showed increased phosphorylation of eIF2α and a decrease in global protein synthesis. Intriguingly, it has been shown that activation of the UPR can divert metabolites from glycolysis to mitochondrial one-carbon metabolism with resulting resistance to anti-folates such as methotrexate (Reich et al., 2020). Accordingly, we next tested the effect of UPR/ISR activation on leukemia cell sensitivity to methotrexate in tissue culture media. Activation of the UPR with thapsigargin, a sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA) inhibitor that triggers ER stress, increased methotrexate resistance in leukemia cells. Similarly, BtdCPU a small-molecule activator of heme regulated inhibitor (HRI) kinase that phosphorylates eIF2α and activates the ISR, also enhanced leukemia resistance to methotrexate. Building upon these results, current investigations are focused on testing the role of UPR/IST activation in methotrexate resistance in leukemia cells in CSF and modulating this pathway to overcome resistance. While methotrexate is clearly an efficacious and critical component of CNS leukemia treatment and prophylaxis, we have shown that CSF attenuates the overall efficacy of methotrexate in targeting leukemia cells. Moreover, we anticipate that our current work defining the mechanisms driving this resistance may identify novel approaches for maximizing methotrexate efficacy and more completely eradicating leukemia cells in CSF and the CNS. Finally, this work highlights the importance of critically evaluating even long-established standards of care.

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”

Evaluating the Impact of Prophylactic Intrathecal Chemotherapy in Diffuse Large B Cell Lymphoma (DLBCL) Patients with High Central Nervous System International Prognostic Index (CNS-IPI) Scores: A Comprehensive Review and Meta-Analysis

Introduction Diffuse large B cell lymphoma (DLBCL) with a high CNS-IPI score poses an increased risk for relapse involving the central nervous system (CNS). Despite various studies seeking to validate the use of CNS prophylaxis, including intrathecal chemotherapy, results have been equivocal. This ambiguity may be partly attributed to the lack of prospective data, patient heterogeneity, limited sample sizes, and outdated methodologies in pre-rituximab studies. Consequently, administering CNS prophylaxis with intrathecal chemotherapy is not a standardized practice, and decisions are often based on individual factors such as anatomical location, disease stage, and specific case characteristics. Methods This systematic review and meta-analysis were conducted and reported using the PRISMA guidelines. A thorough search was conducted across multiple online databases, including Google Scholar, Science Direct, PubMed, Cochrane, CINAHL, EMBASE, ProQuest Dissertation and Theses, ISI web of knowledge, PsycINFO, and Embase for articles on this topic. The date range of the articles included was between 2013-2023 and were limited to English language, peer-reviewed articles, cohort studies, retrospective studies & randomized controlled trials. The inclusion and exclusion criteria for studies helped to determine suitable studies Results Out of 179 studies retrieved from the database search and 2 from other studies' reference lists, 6 met the inclusion criteria for qualitative and quantitative analysis. Data from 2209 patients in these 6 studies was analyzed using a random-effects model to perform a subgroup analysis of the benefits and risks of prophylactic intrathecal chemotherapy for patients with DLBCL and a high CNS-IPI score. The results demonstrated a significant improvement in overall treatment success, with a difference of 0.60 (95% Confidence Interval, 0.45 to 0.93) on a 0-10 Visual Analogue Scale (VAS). The heterogeneity of the studies was determined to be significant (P=0.02), further substantiating the positive impact of prophylactic intrathecal chemotherapy on the therapy success rate for DLBCL patients with high CNS-IPI scores. Conclusion Our review elucidates that intrathecal chemotherapy as a prophylactic measure can reduce the rate of CNS relapse and enhance overall survival for patients with DLBCL possessing a high CNS-IPI score. However, it underscores the necessity to thoroughly assess each patient's unique clinical situation when determining if intrathecal chemotherapy is the appropriate therapeutic approach.

Differences in Characteristics and Outcomes of Central Nervous System Versus Systemic Relapse after First Line Therapy in DLBCL Patients: A Veterans Health Administration (VHA) Study

Introduction Around 30%-40% of patients with diffuse large B-cell lymphoma (DLBCL) will experience disease progression or relapse after first line (1L) chemoimmunotherapy with most patients relapsing within the first 12 months. Relapse may be systemic, isolated to the central nervous system (CNS), or both with CNS relapse occurring in 2-5% of patients. The purpose of this study is to evaluate the characteristics and outcome differences of Veterans diagnosed with DLBCL within the VHA who experienced systemic relapse, isolated CNS relapse or both. Methods A retrospective chart review of 6,266 lymphoma patients seen in the VHA nationwide between 01/01/2011 and 12/31/2021 was performed by trained abstractors. Patients diagnosed with DLBCL were included. Patients were excluded if they had a diagnosis other than DLBCL, had incomplete records or were diagnosed and treated outside the VHA, had baseline CNS involvement, did not receive treatment, or died before receiving a scan to assess response to 1L therapy. Outcomes including response to 1L treatment, time to relapse and overall survival (OS) defined as time from diagnosis to death were evaluated. Early relapse was defined as having primary refractory disease (stable or progressive disease (SD or PD) as best response to 1L therapy) or disease progression in ≤12 months in patients achieving a complete response (CR) or partial response (PR). Late relapse was defined as disease progression >12 months. Results A total of 2,658 patients met inclusion criteria for analysis with 97% of the population being male, 65% with stage III-IV disease, and 90% with an ECOG performance status of 0-2. Of the total cohort, 74% of patients received a CHOP-based regimen, 74% had an intermediate- or high-risk CNS International Prognostic Index (CNS-IPI) score, 81% did not receive a baseline diagnostic lumbar puncture (LP) and 86% did not receive any CNS prophylaxis. The median follow-up time for subjects in this study was 54 months. Relapse occurred in 29% of the total cohort with systemic only relapse occurring in 27% of patients, isolated CNS in 1%, and CNS + systemic in 1%. Of the 761 patients who experienced relapse, 77% had an early relapse with a median time to relapse of 4.4 months (IQR 2.8-6.7). For the 23% of patients with late relapse, the median time to relapse was 25 months (IQR 18-41). The characteristics of patients who experienced relapse were similar regardless of type of relapse or time to relapse (table 1). A higher percentage of patients with early relapse had a high-risk CNS-IPI score, bone marrow involvement, and renal or adrenal involvement. Autologous stem cell transplant was performed in 11% of patients, predominately in those with systemic only relapse. The median OS (mOS) was similar between relapse types with systemic, isolated CNS, and CNS + systemic having a mOS of 23.5 months (95% CI: 21-27), 30.6 months (95% CI: 15-71), and 29.6 months (95% CI: 20-45), respectively (p=0.75). Figure 1 describes mOS by relapse type and time to relapse. Overall, patients with early relapse had a poorer prognosis regardless of relapse type with a mOS of 17 months (95% CI: 15-18) compared to a mOS of 68 months (95% CI: 59-88) in patients with late relapse (p<0.001). The 24-month survival rate of those with early versus late relapse was 37% and 78%, respectively. Patients with a late systemic relapse had the longest mOS of 74 months (95% CI: 60-90). Conclusion This is the largest study reporting outcomes of Veterans who experienced relapsed DLBCL within the VHA. Although earlier data suggests specific features may correlate with early versus late relapse, all characteristics were similar in our population across relapse types regardless of time to relapse. The rate of relapse in the total cohort and the rates of CNS relapse were lower than previously reported, adding to recent data suggesting the use of CNS prophylaxis may have limited benefit. Patients with early relapse performed poorly and may benefit from novel therapies including chimeric antigen receptor T-cell therapy, which could not be evaluated with this study. The retrospective nature of this analysis, and a predominately male veteran population may limit external application.

Comparison between Dasatinib-Blinatumomab Vs Ponatinib-Blinatumomab Chemo-Free Strategy for Newly Diagnosed Ph+ Acute Lymphoblastic Leukemia Patients. Preliminary Results of the Gimema ALLL2820 Trial

Introduction. The outcome of Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) has dramatically improved in the last decade, due with the introduction in the clinical practice of tyrosine kinase inhibitors (TKIs). A further improvement has been obtained with the use of blinatumomab as a consolidation strategy in newly diagnosed patients. We previously designed an induction/consolidation chemotherapy-free frontline trial with dasatinib followed by blinatumomab (GIMEMA LAL2116, D-ALBA); the preliminary results showed that after 2 cycles of blinatumomab (primary endpoint), molecular responses were achieved in 60% of cases and that, with a median follow-up of 18 months, overall survival (OS) and disease (DFS) were 95% and 88% (Foà et al, NEJM 2020). An updated follow-up at 53 months (Foà et al, under revision and ASH 2023) confirmed the favorable long-term outcomes with OS and DFS of 75.8% and 80.7%, respectively. A total of 9 relapses occurred. The median time to relapse was 4.4 months (1.9-25.8); 4 were at the central nervous system (CNS). To further improve the outcome of these patients, we designed a phase III trial (GIMEMA ALL2820) in which in the experimental arm dasatinib was substituted with ponatinib, followed - in the consolidation phase - by at least 2 cycles of blinatumomab. The trial is currently enrolling. Aims. To compare the efficacy of the combination of ponatinib followed by blinatumomab with that reported with dasatinib followed by blinatumomab for the management of newly diagnosed adult Ph+ ALL patients. Patients and Methods. From September 2021 to July 2023, 74 patients have been enrolled in the experimental arm, based on ponatinib followed by at least 2 cycles of blinatumomab; the induction period has been reduced from 85 to 70 days and the dose of ponatinib was either 45 mg or 30 mg, according to patient's age. A dose reduction to 30 mg was foreseen by day 28 of induction, regardless of age, to avoid unacceptable toxicities. Furthermore, CNS prophylaxis was strengthened with a total of 15 medicated lumbar punctures and triple intrathecal therapy (methotrexate, aracytin and steroids) was administered. Finally, transplant allocation was not left to investigator's choice, but it was established according to biological features (minimal residual disease and presence of the IKZF1 plu s genotype). Results. Median age was 57 years (range 20-80), with 31% of patients being older than 65 years; 51% were males, the median white blood count (WBC) was 12 x10 9/l (1-207 x10 9/l). The p190 fusion protein was detected in 75.6% of cases, the p210 in 21.6% and p190/p210 in 2.7%. The IKZF1 plus genotype was detected in 33% of cases. The median follow-up is 6.1 months (0 - 20.3). Of the 74 patients enrolled, 16 were still receiving induction treatment and have therefore been excluded from the present analysis, and 40 have received ≥2 cycles of blinatumomab. Regarding the induction phase, 55 of 58 patients (95%) achieved a complete hematologic remission (CHR), while 3 patients (5%) died in induction (a 77-year-old woman for unknown causes, a 68-year-old man for an intestinal occlusion and a 52-year-old man due to pneumonia). A molecular response (including both MRD negative and positive non-quantifiable (PNQ) cases) was obtained in 21/55 cases (38.2%). By the end of the consolidation phase, of the 40 evaluable patients 25 (62.5%). achieved a molecular response. So far, a single patient has relapsed (WBC at onset 121 x10 9/l and a IKZF1 plus genotype) after 3 months from CHR: at relapse, this case harbored a T3151 mutation (Sanger sequencing and digital droplet PCR at diagnosis were wild type). At recurrence, CD19 expression was maintained. Conclusions. The preliminary analysis of the GIMEMA ALL2820 trial proved the feasibility of this ponatinib-blinatumomab induction consolidation strategy for newly diagnosed Ph+ ALL of all ages, with a 95% CHR rate. Molecular responses at the end of induction are slightly superior in the current trial (38.2% vs 29% in the D-ALBA study), whereas they are virtually equivalent after 2 cycles of blinatumomab (62.5% vs 60% in in the D-ALBA). So far, the benefit of the current protocol appears to rely on a lower relapse rate, with only 1 relapse being observed to date, while in the same time period 3 relapses were documented with the dasatinib-blinatumomab combination. Further details will be provided.

RCHOP Plus High-Dose Methotrexate As First-Line Therapy in Large B-Cell Lymphoma with Testis Involvement

Primary testicular lymphoma (PTL) and diffuse large B-cell lymphoma with secondary testicular involvement (DLBCL-T) are rare subtypes of lymphomas associated with poor prognosis and a high risk of central nervous system (CNS) relapse. The optimal CNS prophylaxis strategy for these subtypes remains uncertain. High-dose methotrexate (HD-MTX) is debated for CNS prophylaxis, but its efficacy in this setting is unknown. This study aimed to retrospectively analyze the use of HD-MTX in combination with chemotherapy (R HD-MTX CHOP) as frontline treatment for PTL and DLBCL-T and to compare the biological characteristics of these two forms of testicular involvement. Data from patients who received R HD-MTX CHOP as first-line treatment for DLBCL-T or PTL between 2010 and 2020 were collected retrospectively. The study included 15 patients, 5 with PTL and 10 with DLBCL-T. The overall response rate was 86%, with 73% of patients achieving complete remission. Treatment-related adverse events were generally manageable, with febrile neutropenia being the most common. Two patients experienced CNS relapse, both from the DLBCL-T subgroup, with a median time of 10.7 months from diagnosis to CNS relapse. None of the PTL patients receiving HD-MTX experienced relapse during the median follow-up of 6.08 years (Figure 1A), compared to 8/10 DLBCL-T (p=0.007). All five PTL cases had a non-germinal center phenotype, while 7 out of 10 DLBCL-T cases were non-germinal center. One DLBCL-T case exhibited high-grade lymphoma. Myc expression was positive in 3 out of 10 patients assessed, of whom all were double expressors. Bcl-2 expression was positive in all 13 assessable patients, while Bcl-6 expression was positive in 6 patients. Myc, Bcl-2, and Bcl-6 rearrangements were assessed in 10 patients and were present in 1 patient who was found to have triple-hit lymphoma. No other patient had double-hit lymphoma or any significant rearrangement. Polysomy of Myc, Bcl-2, and/or Bcl-6 was found in 2 patients. PDL1 expression was observed in one out of six patients analyzed, while no PD1 expression was detected. In 8 out of 15 patients with available tissue material, next-generation sequencing using a panel targeting 43 lymphoid genes was performed. Among these 8 patients, 87% exhibited gain-of-function mutations in MYD88 (MYD88 L265P), and 62% had missense mutations in CD79B at position Y196. Multiple mutations in the PIM1 gene, a known target of aberrant somatic hypermutation, were also observed in 7 patients. Non-recurrent mutations were detected in various genes, including PRDM1, CD58, B2M, CREBBP, CIITA, CARD11, CDKN2A, EP300, CCDND3, FOXO1, IRF4, NFKBIE, and TCF3 (Figure 1B). Ig rearrangement was analyzed in 4/9 patients with available DNA. All 4 were clonal, with distinct but mutated VH segments (sequence identity between 81 and 89%). This study suggests that HD-MTX in combination with RCHOP chemotherapy is highly effective in preventing CNS relapse in PTL but less so in DLBCL-T. DLBCL-T had a higher risk of CNS relapse and poorer outcomes compared to PTL. Further studies are needed to determine the optimal timing and sequence of HD-MTX in DLBCL-T, as well as alternative treatment approaches. PTL and DLBCL-T have distinct clinical presentations and responses to frontline chemotherapy with HD-MTX prophylaxis. PTL may benefit from HD-MTX in preventing relapse, while alternative treatments should be explored for DLBCL-T. Future studies should consider PTL and DLBCL-T as separate entities to better understand their characteristics and optimize treatment strategies.

Reinfusion of Varnimcabtagene Autoleucel (IMN-003A) in Patients with Relapsed Refractory B Cell Malignancies Is Feasible with Sustained Responses

Background: Varnimcabtagene autoleucel, a CD19 directed CAR-T cell therapy with a 4-1BB co-stimulatory domain and a non-FMC63 based murine scFv (A3B1 binder), has demonstrated remarkable responses in relapsed/refractory B cell malignancies (RR BCM) in the IMAGINE study. Reinfusion of var-cel is an option to improve functional persistence for CD19+ relapsed disease. This abstract describes the clinical outcomes following reinfusion of var-cel in patients (pts) who relapsed after first infusion. Methods: Patients (pts) aged 3 to 45 years (B-ALL) and ≥ 18 years (B-NHL) with RR BCM were eligible for IMAGINE study if they had measurable disease, as assessed by lymphoid blasts (B-ALL) or metabolic tumour bulk (B-NHL), received ≥1 prior regimen, refractory to the last line of treatment with good performance status (ECOG 0 to 1). The primary target dose was 1x10 6/kg CAR+ cells (B-ALL) and 5x10 6/kg CAR+ cells (B-NHL) (overall range 0.1x10 6 to 5x10 6) and was infused over 3 days (10%/30%/60% fractions). Primary objectives were overall response rate (ORR: CR + CRi in B-ALL and CR + PR in B-NHL) at day +90 after first infusion, and safety. Response was assessed as per NCCN (B-ALL) and IWG (B-NHL) criteria. Adverse events (AEs) were graded using CTCAE v5.0. CRS and ICANS were graded according to ASTCT criteria. Criteria for reinfusion was: 1) achieved response with subsequent disease progression and presence of CD19 positive malignant cells; 2) available second dose for retreatment from initial apheresis and manufacturing run; and 3) after primary endpoint at D+90. This abstract evaluates the outcomes at D+28 after var-cel reinfusion. Results: At data cut-off, 25 pts were enrolled (median age 31 yrs, range 3 - 66) with RR BCM (n=13 B-ALL; n=12 B-NHL). 24 pts received var-cel (1 withdrawal) with majority of infusions on Days 0, +3, +7. ORR was 91.7% at D+28 and 80.9% at D+90. Median progression free survival (PFS, range 12-NR), duration of response (DOR, range 0-NR) and overall survival (OS) were not reached (range 12-NR). Nine pts had relapsed disease (37.5%) with median PFS of 178 days (range 28-319). Of these 9 pts, 7 had CD19+ relapse (77.8%) and 2 (with B-ALL) had CD19- relapse. Four of these pts received second infusion at full dose (same as primary infusion) fractionated over 3 days (10%, 30%, 60%). For these 4 pts, duration of B cell aplasia after primary infusion was 90 days to NR (range); var-cel was detectable in 1 pt (n=1/4) at relapse; and median PFS was 166 days (range 90-275). Tumour burden at relapse was: Ph+ B-ALL (n=1) with 22% blasts (p210 BCR ABL transcript 36.7%); B-NHL (n=3) with TMTV range 7.5 to 277 ml and SPD range 660.5 to 8686 mm 2 (Table 1). PDL1 exhaustion marker was expressed in one B-NHL pt only. Salvage regimen in B-NHL pts was involved field radiotherapy (n=2); 1 B-NHL pt was reinfused without salvage treatment. B-ALL pt received Dasatinib, Inotuzumab and CNS prophylaxis. Preparative conditioning regimen for these 4 patients were: Fludarabine-Cyclophosphamide (n=1), with Rituximab (n=2) and Rituximab with Nivolumab (n=1). Post reinfusion, var-cel was not detected in 1 pt (B-ALL) however B cell aplasia was persistent. In B-NHL pts, Cmax range was 7222 to 31846 CAR+ copies / ug genomicDNA; Tmax was D+2 after reinfusion and duration of var-cel persistence was range 2 days to NR (Figure 1). Post reinfusion, no CRS (0%) or ICANS (0%) was reported. Hematotoxicity was the most common AE (100%) with neutropenia (G3+ 100%); anemia (G3+ 66.7%); and thrombocytopenia (G3+ 33.3%;). Hypogammaglobulinemia (IgG <4g/L) was seen in 2 pts (50%, new onset 1 pt). Time to first response after reinfusion was 28 days. The D+28 ORR for evaluable pts (n=2) was 100%. Median PFS after reinfusion is NR. Post reinfusion 1 pt (Ph+ B-ALL) died of disease progression at 313 days (50 days after reinfusion). The evaluable B-NHL pts are in remission. Conclusions: Reinfusion of varnimcabtagene autoleucel (IMN-003A) is feasible, safe and well tolerated. Preparative conditioning regimen for reinfusion needs personalization guided by CAR persistence, disease biology (CD20, PDL1 expression) and haematological reserve. After reinfusion, prolonged B cell aplasia was observed with 100% ORR at D+28 in evaluable pts. Var-cel was detected post reinfusion in B-NHL patients with sustained responses. Reinfusion may be considered in preference for some pts. The ideal preparative regimen and pt characteristics to guide reinfusion outcomes remains an area of research.