Prevention and management of secondary central nervous system lymphoma

Prevention; LymphomaPrevenció; LimfomaPrevención; LinfomaSecondary central nervous system (CNS) lymphoma (SCNSL) is defined by the involvement of the CNS, either at the time of initial diagnosis of systemic lymphoma or in the setting of relapse, and can be either isolated or with synchronous systemic disease. The risk of CNS involvement in patients with diffuse large B-cell lymphoma is approximately 5%; however, certain clinical and biological features have been associated with a risk of up to 15%. There has been growing interest in improving the definition of patients at increased risk of CNS relapse, as well as identifying effective prophylactic strategies to prevent it. SCNSL often occurs within months of the initial diagnosis of lymphoma, suggesting the presence of occult disease at diagnosis in many cases. The differing presentations of SCNSL create the therapeutic challenge of controlling both the systemic disease and the CNS disease, which uniquely requires agents that penetrate the blood-brain barrier. Outcomes are generally poor with a median overall survival of approximately 6 months in retrospective series, particularly in those patients presenting with SCNSL after prior therapy. Prospective studies of intensive chemotherapy regimens containing high-dose methotrexate, followed by hematopoietic stem cell transplantation have shown the most favorable outcomes, especially for patients receiving thiotepa-based conditioning regimens. However, a proportion of patients will not respond to induction therapies or will subsequently relapse, indicating the need for more effective treatment strategies. In this review we focus on the identification of high-risk patients, prophylactic strategies and recent treatment approaches for SCNSL. The incorporation of novel agents in immunochemotherapy deserves further study in prospective trials

Prophylaxis with intrathecal or high-dose methotrexate in diffuse large B-cell lymphoma and high risk of CNS relapse

Limfoma de cèl·lules B; Supervivència lliure de malaltiaLinfoma de células B; Supervivencia libre de enfermedadB-cell lymphoma; Disease-free survivalAlthough methotrexate (MTX) is the most widely used therapy for central nervous system (CNS) prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the optimal regimen remains unclear. We examined the efficacy of different prophylactic regimens in 585 patients with newly diagnosed DLBCL and high-risk for CNS relapse, treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP-like regimens from 2001 to 2017, of whom 295 (50%) received prophylaxis. Intrathecal (IT) MTX was given to 253 (86%) and high-dose MTX (HD-MTX) to 42 (14%). After a median follow-up of 6.8 years, 36 of 585 patients relapsed in the CNS, of whom 14 had received prophylaxis. The CNS relapse risk at 1 year was lower for patients who received prophylaxis than patients who did not: 2% vs. 7.1%. However, the difference became less significant over time (5-year risk 5.6% vs. 7.5%), indicating prophylaxis tended to delay CNS relapse rather than prevent it. Furthermore, the CNS relapse risk was similar in patients who received IT and HD-MTX (5-year risk 5.6% vs. 5.2%). Collectively, our data indicate the benefit of MTX for CNS prophylaxis is transient, highlighting the need for more effective prophylactic regimens. In addition, our results failed to demonstrate a clinical advantage for the HD-MTX regimen.This work was supported in part by research funding from Fundación Alfonso Martín Escudero to SB. Data from this manuscript were presented at the 61st Annual Meeting of the American Society of Hematology, Orlando, FL, December 7th–10th, 2019

Comparative effectiveness of ZUMA-5 (axi-cel) vs SCHOLAR-5 external control in relapsed/refractory follicular lymphoma

Follicular lymphomaLimfoma fol·licularLinfoma folicularIn the pivotal ZUMA-5 trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory (r/r) follicular lymphoma (FL) patients. Here, outcomes from ZUMA-5 are compared with the international SCHOLAR-5 cohort, which applied key ZUMA-5 trial eligibility criteria simulating randomized controlled trial conditions. SCHOLAR-5 data were extracted from institutions in 5 countries, and from 1 historical clinical trial, for r/r FL patients who initiated a third or higher line of therapy after July 2014. Patient characteristics were balanced through propensity scoring on prespecified prognostic factors using standardized mortality ratio (SMR) weighting. Time-to-event outcomes were evaluated using weighted Kaplan-Meier analysis. Overall response rate (ORR) and complete response (CR) rate were compared using weighted odds ratios. The 143 ScHOLAR-5 patients reduced to an effective sample of 85 patients after SMR weighting vs 86 patients in ZUMA-5. Median follow-up time was 25.4 and 23.3 months for SCHOLAR-5 and ZUMA-5. Median overall survival (OS) and progression-free survival (PFS) in SCHOLAR-5 were 59.8 months and 12.7 months and not reached in ZUMA-5. Hazard ratios for OS and PFS were 0.42 (95% confidence interval [CI], 0.21-0.83) and 0.30 (95% CI, 0.18-0.49). The ORR and CR rate were 49.9% and 29.9% in SCHOLAR-5 and 94.2% and 79.1% in ZUMA-5, for odds ratios of 16.2 (95% CI, 5.6-46.9) and 8.9 (95% CI, 4.3-18.3). Compared with available therapies, axi-cel demonstrated an improvement in meaningful clinical endpoints, suggesting axi-cel addresses an important unmet need for r/r FL patients. This trial was registered at www.clinicaltrials.gov as #NCT03105336.Was provided by Kite Pharma, a Gilead company, for this study

A 24-month updated analysis of the comparative effectiveness of ZUMA-5 (axi-cel) vs. SCHOLAR-5 external control in relapsed/refractory follicular lymphoma

Follicular lymphoma; Axicabtagene ciloleucel; Comparative effectivenessLimfoma fol·licular; Axicabtagene ciloleucel; Eficàcia comparativaLinfoma folicular; Axicabtagene ciloleucel; Eficacia comparativaBackground In the ZUMA-5 trial (Clinical trials identification: NCT03105336), axicabtagene ciloleucel (axi-cel; a chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory (r/r) follicular lymphoma (FL) patients and clear superiority relative to the SCHOLAR-5 external control cohort. We update this comparison using the ZUMA-5 24-month data. Research design and methods The SCHOLAR-5 cohort is comprised of r/r FL patients who initiated ≥3rd line of therapy after July 2014 and meeting ZUMA-5 eligibility criteria. Groups were balanced for patient characteristics through propensity scoring on prespecified prognostic factors using standardized mortality ratio (SMR) weighting. The overall response rate was compared using a weighted logistic regression. Time-to-event outcomes were evaluated using a Cox regression. Results For SCHOLAR-5, the sum of weights for the 143 patients was 85 after SMR weighting, versus 86 patients in ZUMA-5. The median follow-up was 29.4 months and 25.4 months for ZUMA-5 and SCHOLAR-5, respectively. The hazard ratios for overall survival and progression-free survival were 0.52 (95% confidence interval (CI): 0.28–0.95) and 0.28 (95% CI: 0.17–0.45), favoring axi-cel. Conclusion This updated analysis, using a longer minimum follow-up than a previously published analysis, shows that the improved efficacy of axi-cel, relative to available therapies, in r/r FL is durable.This manuscript was funded by Kite, a Gilead Company

Autologous stem-cell transplantation as consolidation of first-line chemotherapy in patients with peripheral T-cell lymphoma: a multicenter GELTAMO/FIL study

Autologous stem-cell transplantation; Chemotherapy; T-cell lymphomaTrasplante autólogo de células madre; Quimioterapia; Linfoma de células TTrasplantament autòleg de cèl·lules mare; Quimioteràpia; Limfoma de cèl·lules TPeripheral T-cell lymphomas (PTCL) are a heterogeneous group of rare lymphoid malignancies that mostly have poor prognoses with currently available treatments. Upfront consolidation with autologous stem cell transplantation (ASCT) is frequently carried out, but its efficacy has never been investigated in randomized trials. We designed a multicenter, international, retrospective study with the main objective of comparing progression-free survival and overall survival of patients with PTCL who underwent ASCT in complete remission (CR) after first-line chemotherapy with a control group who did not undergo ASCT. From the initial population of 286 registered patients, 174 patients with PTCL other than anaplastic large cell lymphoma, ALK-positive, deemed fit for ASCT at the time of diagnosis, and who were in CR or uncertain CR after induction therapy (CR1) were included in our analysis. one hundred and three patients underwent ASCT, whereas 71 did not, in most cases (n=53) because the physician decided against it. With a median follow-up of 65.5 months, progression-free survival was significantly better in the transplanted patients than in the non-transplanted group: 63% versus 48% at 5 years (P=0.042). Overall survival was significantly longer for ASCT patients in the subgroup with advanced stage at diagnosis (5-year overall survival: 70% vs. 50%, P=0.028). In the multivariate analysis, first-line ASCT was associated with significantly prolonged progression-free survival (HR=0.57, 95% CI: 0.35-0.93) and overall survival (HR=0.57, 95% CI: 0.33-0.99). In conclusion, our study supports the use of ASCT as a consolidation strategy for patients with PTCL in CR1. These results should be confirmed in a prospective randomized study

A gene expression assay based on chronic lymphocytic leukemia activation in the microenvironment to predict progression

Several gene expression profiles with a strong correlation with patient outcome have been previously described in chronic lymphocytic leukemia (CLL), although their applicability in clinical practice as biomarkers has been particularly limited. Here we describe the training and validation of a gene expression signature for predicting early progression of patients with CLL based on the analysis of 200 genes related to microenvironment signaling on the NanoString platform. In the training cohort (n=154), the CLL15 assay containing a 15-gene signature was associated with time to first treatment (TtFT) (HR: 2.83, 95%CI 2.17-3.68; p<0.001). The prognostic value of the CLL15 score (HR 1.71, [95%CI 1.15-2.52]; p=0.007) was further confirmed in an external independent validation cohort (n=112). Of note, the CLL15 score improved the prognostic capacity over the IGHV mutational status and the International Prognostic Score for asymptomatic early-stage (IPS-E) CLL. In multivariate analysis, the CLL15 score (HR: 1.83, 95%CI 1.32-2.56; p<0.001) and the IPS-E CLL (HR: 2.23, 95%CI 1.59-3.12; p<0.001) were independently associated with TtFT. The newly developed and validated CLL15 assay successfully translates previous gene signatures, such as the microenvironment signaling, into a new gene expression-based assay with prognostic implications in CLL

Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition

Altres ajuts: This work was supported by research funding from the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias cofinanced by the European Regional Development Fund (ERDF); Fundación Asociación Española Contra el Cáncer (M.C. and P.A.) and Gilead Fellowships (GLD16/00144, GLD18/00047, F.B). M.C. holds a contract from Ministerio de Ciencia, Innovación y Universidades. S.B. is the recipient of a postdoctoral fellowship from Fundación Alfonso Martin Escudero.Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells frequently have deregulated B-cell receptor (BCR) signaling, but clinical responses to its inhibition using ibrutinib have been brief. In this regard, blocking nuclear export by using selinexor, which covalently binds to XPO1, can also inhibit BCR signaling. Selinexor crosses the blood-brain barrier and was recently shown to have clinical activity in a patient with refractory diffuse large B-cell lymphoma in the CNS. We studied selinexor alone or in combination with ibrutinib in pre-clinical mouse models of PCNSL. Orthotopic xenograft models were established by injecting lymphoma cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Malignant cells and macrophages were studied by immunohistochemistry and flow cytometry. Selinexor blocked tumor growth and prolonged survival in a bioluminescent mouse model, while its combination with ibrutinib further increased survival. CNS lymphoma in mice was infiltrated by tumor-promoting M2-like macrophages expressing PD-1 and SIRPα. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRPα expression in the remaining tumor-promoting M2-like macrophages. These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide pre-clinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential. The online version of this article (10.1007/s11060-020-03580-y) contains supplementary material, which is available to authorized users

Treatment patterns and outcomes in relapsed/refractory follicular lymphoma: results from the international SCHOLAR-5 study

The SCHOLAR-5 study examines treatment patterns and outcomes of real-world follicular lymphoma (FL) patients on 3rd line of treatment (LoT) or higher, for whom existing data are limited. SCHOLAR-5 is a retrospective cohort study using data from adults (≥ 18 years) with grade 1-3a FL, initiating ≥3rd LoT after June 2014 at major lymphoma centers in the United States (US) and Europe. Objective response rate (ORR), complete response (CR), progression free survival (PFS) and overall survival (OS) were analyzed by LoT. Time-to-event outcomes were assessed using Kaplan-Meier methods. Of 128 patients, 87 initiated 3rd LoT, 63 initiated 4th LoT, and 47 initiated 5th LoT. At 1st eligible LoT, 31% progressed within 24-months of 1st LoT anti-CD20 combination therapy, 28% had prior autologous stem-cell transplantation, and 31% were refractory to the previous LoT. The most common regimen in each LoT was chemoimmunotherapy; however, experimental drugs were increasingly used at later LoTs. In the US, anti-CD20 monotherapy was more common at ≥3rd LoT compared to Europe, where stem cell transplants were more common. ORR at 3rd LoT was 68% (CR 44%), but decreased after each LoT to 37% (CR 22%) in ≥5 LoT. Median OS and PFS at 3rd LoT were 68 and 11 months, respectively, and reduced to 43 and 4 months at ≥5 LoT. Treatments were heterogenous at each LoT in both the US and Europe. Few FL patients achieved complete response in later LoT, and duration of response and survival diminished with each subsequent line

Immunological and genetic kinetics from diagnosis to clinical progression in chronic lymphocytic leukemia

Progressió clínica; Evasió immuneProgresión clínica; Evasión inmuneClinical progression; Immune evasionBackground Mechanisms driving the progression of chronic lymphocytic leukemia (CLL) from its early stages are not fully understood. The acquisition of molecular changes at the time of progression has been observed in a small fraction of patients, suggesting that CLL progression is not mainly driven by dynamic clonal evolution. In order to shed light on mechanisms that lead to CLL progression, we investigated longitudinal changes in both the genetic and immunological scenarios. Methods We performed genetic and immunological longitudinal analysis using paired primary samples from untreated CLL patients that underwent clinical progression (sampling at diagnosis and progression) and from patients with stable disease (sampling at diagnosis and at long-term asymptomatic follow-up). Results Molecular analysis showed limited and non-recurrent molecular changes at progression, indicating that clonal evolution is not the main driver of clinical progression. Our analysis of the immune kinetics found an increasingly dysfunctional CD8+ T cell compartment in progressing patients that was not observed in those patients that remained asymptomatic. Specifically, terminally exhausted effector CD8+ T cells (T-betdim/−EomeshiPD1hi) accumulated, while the the co-expression of inhibitory receptors (PD1, CD244 and CD160) increased, along with an altered gene expression profile in T cells only in those patients that progressed. In addition, malignant cells from patients at clinical progression showed enhanced capacity to induce exhaustion-related markers in CD8+ T cells ex vivo mainly through a mechanism dependent on soluble factors including IL-10. Conclusions Altogether, we demonstrate that the interaction with the immune microenvironment plays a key role in clinical progression in CLL, thereby providing a rationale for the use of early immunotherapeutic intervention.This work was supported by the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI17/00950, M.C., PI18/01392, P.A. and PI17/00943, F.B.) and co-financed by the European Regional Development Fund (ERDF) and Fundación Asociación Española Contra el Cáncer (M.C. and P.A.), Gilead Fellowships (GLD16/00144, GLD18/00047, F.B.) and Fundació la Marató de TV3 (201905–30-31 F.B). S.B. is the recipient of a postdoctoral fellowship from Fundación Alfonso Martin Escudero. R.V-M. is supported by a Torres Quevedo fellowship from the Spanish Ministry of Science and Innovation (PTQ-16-08623). A.E-C. is funded by ISCIII/MINECO (PT17/0009/0019) which is co-funded by FEDER. M.C. holds a contract from Ministerio de Ciencia, Innovación y Universidades (RYC-2012-2018)