The CNS Relapse in T-Cell Lymphoma Index Predicts CNS Relapse in Patients with T- and NK-Cell Lymphomas.

Little is known about risk factors for central nervous system (CNS) relapse in mature T- and NK-cell neoplasms (MTNKN). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKN, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. Using a complete case analysis (N=182), of whom 91 had CNS relapse, we applied a LASSO Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (N=566). CNS relapse was most frequently observed in patients with PTCL, NOS (25%). Median time to CNS relapse and median overall survival after CNS relapse was 8.0 months and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (N=158) and high-risk (N=188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (HR 5.24, 95%CI 1.50-18.26, P=0.018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at highest risk of developing CNS relapse.

Nationwide Assessment of Patient Trajectories in Mantle Cell Lymphoma: The Swedish MCLcomplete Project.

Mantle cell lymphoma (MCL) is a B-cell malignancy currently considered incurable. Although some patients obtain prolonged remission after first-line chemoimmunotherapy, many will need several treatment lines. Here, we present a nationwide assessment of treatment strategies, time to progression and survival in MCL. All patients diagnosed with MCL 2006-2018 were identified in the Swedish Lymphoma Register. Information on all lines of therapy was extracted from the medical records. Overall and progression-free survival (OS and PFS) were assessed through August 2021. In total, 1367 patients were included (median age, 71 years) and median follow-up was 6.8 years. Two hundred and one (15%) were managed initially with watch-and-wait, but 1235 (90%) eventually received treatment. The most frequently used first-line regimens were rituximab-bendamustine (BR) (n = 368; 30%) and Nordic MCL2 (n = 342; 28%). During follow-up, 630 patients (46%) experienced relapse/progression and 546 (40%) received second-line treatment. The most frequently used second-line regimen was BR (n = 185; 34%) but otherwise a wide variety of second-line treatments were used. Further, 382 and 228 patients experienced a second or third relapse/progression, respectively. Median PFS after first (PFS-1), second (PFS-2), third (PFS-3), and fourth (PFS-4) treatment lines was 29.4, 8.9, 4.3, and 2.7 months. Patients with early progression, defined as a PFS-1 <24 months, had an inferior median OS of 13 versus 37 months in patients with later relapse. For patients treated with frontline BR, however, time to relapse had no impact on later outcome. By use of nationwide population-based data, we provide important benchmarks for future studies of all treatment lines in MCL.

Idelalisib (PI3Kδ inhibitor) therapy for patients with relapsed/refractory chronic lymphocytic leukemia: A Swedish nation-wide real-world report on consecutively identified patients.

OBJECTIVES: We examined the efficacy and toxicity of the PI3Kδ inhibitor idelalisib in combination with rituximab salvage therapy in consecutively identified Swedish patients with chronic lymphocytic leukemia (CLL). METHODS AND RESULTS: Thirty-seven patients with relapsed/refractory disease were included. The median number of prior lines of therapy was 3 (range 1-11); the median age was 69 years (range 50-89); 22% had Cumulative Illness Rating Scale (CIRS) >6 and 51% had del(17p)/TP53 mutation. The overall response rate was 65% (all but one was partial response [PR]). The median duration of therapy was 9.8 months (range 0.9-44.8). The median progression-free survival was 16.4 months (95% CI: 10.4-26.3) and median overall survival had not been reached (75% remained alive at 24 months of follow-up). The most common reason for cessation of therapy was colitis (n = 8, of which seven patients experienced grade ≥3 colitis). The most common serious adverse event was grade ≥3 infection, which occurred in 24 patients (65%). CONCLUSIONS: Our real-world results suggest that idelalisib is an effective and relatively safe treatment for patients with advanced-stage CLL when no other therapies exist. Alternative dosing regimens and new PI3K inhibitors should be explored, particularly in patients who are double-refractory to inhibitors of BTK and Bcl-2.

Outcome of limited-stage peripheral T-Cell lymphoma after CHOP(-like) therapy: A population based study of 239 patients from the Nordic lymphoma epidemiology group.

Peripheral T-Cell Lymphomas (PTCLs) are rare, aggressive lymphomas with poor outcomes, but limited-stage disease is infrequent and not well-described. This study reports outcomes and prognostic factors in limited-stage nodal PTCLs in a binational population-based setting. Patients were identified from the Danish and Swedish lymphoma registries. Adults diagnosed with limited-stage nodal PTCL (stage I-II) and treated with CHOP(-like) therapy ±radiotherapy between 2000 and 2014 were included. Medical records were reviewed by local investigators. A total of 239 patients with a median age of 62 years were included; 67% received 6-8 cycles of CHOP(-like) therapy and 22% received 3-4 cycles, of which 59% also received radiotherapy. Autologous stem cell transplant consolidation was administered to 16% of all patients. Median follow-up was 127 months with 5-years overall survival (OS) of 58% (95% CI: 53-65) and progression-free survival (PFS) of 53% (95% CI: 47-59). In multivariable analysis, age ≥ 60 years and B-symptoms were unfavorable and ALK+ anaplastic large cell T-Cell lymphoma was favorable for survival outcomes. There was no difference in treatment-specific outcome (3-4 cycles vs. 6-8 cycles of CHOP(-like) ± radiotherapy). Low-risk patients (age < 60 without B-symptoms) had a 5-year OS of 77% (95% CI 67-89%). In the present study of limited-stage nodal PTCL, survival after curative intent chemotherapy +/- radiotherapy was inferior to that of limited-stage diffuse large B-cell lymphoma, but a subgroup of young patients without B-symptoms had very good outcomes. Treatment outcomes after 3-4 cycles versus 6-8 cycles of CHOP(-like) therapy were comparable.

Impact of comorbidity in older patients with peripheral T-cell lymphoma: an international retrospective analysis of 891 patients.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive neoplasms with poor outcomes, commonly affecting older patients with comorbidities. This study aims to describe outcomes of older patients with PTCL in a large international cohort. Patients aged ≥70 years with PTCL diagnosed from 1 January 2010 to 31 December 2015 in the Swedish Lymphoma Registry (SLR) and California Cancer Registry (CCR) were identified. Data on comorbidity were retrospectively collected according to the Charlson Comorbidity Index (CCI), and clinical outcomes were extracted. A total of 891 patients were included (SLR, n = 173; CCR, n = 718). Median age was 77 (SLR) and 78 (CCR) years. Included subtypes were as follows: angioimmunoblastic T-cell lymphoma, n = 226; anaplastic large-cell lymphoma, n = 122; enteropathy-associated T-cell lymphoma (EATL), n = 31; hepatosplenic TCL, n = 7; natural killer-/T-cell lymphoma, n = 62; PTCL not otherwise specified, n = 443. CCI data were available in 775 patients (87%), and CCI scores were divided into the groups CCI = 0 (39%), CCI = 1 (22%), and CCI > 1 (39%). Median age did not differ among the CCI groups (P = .72). Patients with a CCI > 1 had a worse median overall survival (4.4 months) compared with patients with CCI = 0 (11.9 months) and CCI = 1 (8.4 months; P < .001). Comorbidity and advancing age in as little as 5-year increments are important adverse factors in this group. Most patients died of lymphoma within a year from diagnosis, underscoring the importance of developing new treatments.

Burkitt Lymphoma International Prognostic Index.

PURPOSE: Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches. METHODS: We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019. RESULTS: In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively. CONCLUSION: The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.

Minimal relapse risk and early normalization of survival for patients with Burkitt lymphoma treated with intensive immunochemotherapy: an international study of 264 real-world patients.

Non-endemic Burkitt lymphoma (BL) is a rare germinal centre B-cell-derived malignancy with the genetic hallmark of MYC gene translocation and with rapid tumour growth as a distinct clinical feature. To investigate treatment outcomes, loss of lifetime and relapse risk in adult BL patients treated with intensive immunochemotherapy, retrospective clinic-based and population-based lymphoma registries from six countries were used to identify 264 real-world patients. The median age was 47 years and the majority had advanced-stage disease and elevated LDH. Treatment protocols were R-CODOX-M/IVAC (47%), R-hyper-CVAD (16%), DA-EPOCH-R (11%), R-BFM/GMALL (25%) and other (2%) leading to an overall response rate of 89%. The two-year overall survival and event-free survival were 84% and 80% respectively. For patients in complete remission/unconfirmed, the two-year relapse risk was 6% but diminished to 0·6% for patients reaching 12 months of post-remission event-free survival (pEFS12). The loss of lifetime for pEFS12 patients was 0·4 (95% CI: -0·7 to 2) months. In conclusion, real-world outcomes of adult BL are excellent following intensive immunochemotherapy. For pEFS12 patients, the relapse risk was low and life expectancy similar to that of a general population, which is important information for developing meaningful follow-up strategies with increased focus on survivorship and less focus on routine disease surveillance.

Rapid Complete Response to Single-Agent Bcl-2 Inhibitor Venetoclax in a Heart-Transplanted Patient with Triple Refractory Immunoglobulin Light-Chain Amyloidosis.

Immunoglobulin light-chain amyloidosis (AL) is a disease with limited treatment options due to the frailty of patients caused by organ damage. Since the clonal plasma cells often contain the cytogenetic aberration t(11;14), the Bcl-2 inhibitor venetoclax is suggested to have a role in the treatment of AL. Here, we report of a heart-transplanted patient, refractory to multiple therapies, reaching a rapid complete response with single-agent venetoclax.

Impact of comorbidity on survival in peripheral T-cell lymphomas: A Swedish Lymphoma Registry study.

Comorbidity impacts survival in B-cell lymphoma patients, but the influence in peripheral T-cell lymphomas (PTCLs) has been little studied. To investigate the impact of comorbidity on outcome in PTCL, we identified adult patients with newly diagnosed PTCL from 2000 to 2009 in the Swedish Lymphoma Registry. Data on comorbidity at diagnosis were retrospectively collected according to the Charlson Comorbidity Index (CCI). Comorbid conditions were present in 263 out of 694 (38%) patients. A CCI score of ≥2 was associated with inferior overall survival (OS) (hazard ratio [HR] 1.63, P < .001) and progression-free survival (HR 1.54, P < .001) in multivariate analysis. In patients undergoing front-line autologous stem cell transplantation (auto SCT), CCI >0 was associated with inferior OS (HR 2.40, P = .013). Chemotherapy regimens were classified as curative or low-intensity treatments. Among patients aged ≥75 years (n = 214), low-intensity and curative treatment groups had similar OS (HR 0.8, P = .6), also when adjusted for CCI. In summary, our results demonstrate CCI to be independently associated with survival in PTCLs. Even limited comorbidity impacted survival after front-line auto SCT, which needs to be considered in treatment decisions. Intensive anthracycline-based chemotherapy in elderly PTCL patients might be of limited benefit.

International Assessment of Event-Free Survival at 24 Months and Subsequent Survival in Peripheral T-Cell Lymphoma.

Purpose Peripheral T-cell lymphomas (PTCLs) have aggressive clinical behavior. We have previously shown that event-free survival (EFS) at 24 months (EFS24) is a clinically useful end point in diffuse large B-cell lymphoma. Here, we assess EFS24 and subsequent overall survival (OS) in large, multinational PTCL cohorts. Patients and Methods Patients with systemic PTCL newly diagnosed from 2000 to 2012 and treated with curative intent were included from the United States and Sweden (initial cohorts) and from Canada (replication cohort). EFS was defined as time from date of diagnosis to progression after primary treatment, retreatment, or death. Subsequent OS was measured after achieving EFS24 or from the time of progression if it occurred within 24 months. OS rates were compared with the age-, sex-, and country-matched general population. Results Seven hundred seventy-five patients were included in the study (the median age at diagnosis was 64 years; 63% were men). Results were similar in the initial and replication cohorts, and a combined analysis was undertaken. Sixty-four percent of patients progressed within the first 24 months and had a median OS of only 4.9 months (5-year OS, 11%). In contrast, median OS after achieving EFS24 was not reached (5-year OS, 78%), although relapses within 5 years of achieving EFS24 occurred in 23% of patients. Superior outcomes after achieving EFS24 were observed in younger patients (≤ 60 years of age: 5-year OS, 91%). Conclusion EFS24 stratifies subsequent outcome in PTCL. Patients with PTCL with primary refractory disease or early relapse have extremely poor survival. However, more than one third of patients with PTCL remain in remission 2 years after diagnosis with encouraging subsequent OS, especially in younger patients. These marked differences in outcome suggest that EFS24 has utility for patient counseling, study design, and risk stratification in PTCL.

The addition of etoposide to CHOP is associated with improved outcome in ALK+ adult anaplastic large cell lymphoma: A Nordic Lymphoma Group study.

Anaplastic large cell lymphomas (ALCLs) are rare CD30+ peripheral T-cell lymphomas (PTCLs) classified according to the expression of the anaplastic lymphoma kinase (ALK+) protein or not (ALK-). We have analysed the outcome and risk factors for survival in a population-based bi-national cohort of patients with systemic ALK+ ALCL. A total of 122 adult (≥18 years) patients diagnosed with ALK+ ALCL between 2000 and 2010 were identified from the Danish and Swedish lymphoma registries, representing 0·4% of all lymphomas. The median age of the cohort was 40 years (range 18-85). The 5-year overall survival and progression-free survival (PFS) was 78% and 64%, respectively. Age was strongly associated with outcome, and only bone marrow (BM) involvement was independently associated with poorer PFS in multivariate analysis (Hazard Ratio [HR] = 8·57, P < 0·001). Age stratification of the patients demonstrated an association between treatment with CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisolone) and improved overall survival for patients aged 41-65 years, even when adjusted for risk factors (HR = 0·38, P = 0·047). Our results suggest that the addition of etoposide to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) in the treatment for ALK+ ALCL seems reasonable in this age group.

Outcome of peripheral T-cell lymphoma in first complete remission: a Danish-Swedish population-based study.

In the present study, we investigate the outcome of 109 Danish and 123 Swedish patients with nodal PTCL in first complete remission (CR), and examine the impact of imaging-based follow-up (FU) strategies. The patients were selected by the following criteria: (a) newly diagnosed nodal PTCL from 2007 to 2012, (b) age ≥18 years, and (c) CR after CHOP or CHOEP therapy. FU guidelines in Sweden included symptom assessment, clinical examinations and blood tests at 3-4-month intervals for 2 years. FU strategies in Denmark was similar but included routine imaging, usually every 6 months for 2 years. Patients had fully comparable characteristics. Overall survival (OS) estimates for patients in CR were similar for all patients (p = .6) and in PTCL subtypes. In multivariate analysis, country of follow-up had no impact on OS. However, despite continuous CR for ≥2 years, the OS of PTCL remained inferior to a matched general population.

Central nervous system relapse in peripheral T-cell lymphomas: a Swedish Lymphoma Registry study.

Central nervous system (CNS) relapse in non-Hodgkin lymphoma (NHL) carries a very poor prognosis. Risk factors and outcome have been studied in aggressive B-cell lymphomas, but very little is known about the risk in peripheral T-cell lymphoma (PTCL). We aimed at analyzing risk factors for CNS involvement at first relapse or progression, as well as the outcome of these patients, in a large population-based cohort of patients with PTCL. Twenty-eight out of 625 patients (4.5%) developed CNS disease over time. In multivariable analysis, disease characteristics at diagnosis independently associated with an increased risk for later CNS involvement were involvement of more than 1 extranodal site (hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.07-6.29; P = .035) and skin (HR, 3.51; 95% CI, 1.26-9.74; P = .016) and gastrointestinal involvement (HR, 3.06; 95% CI, 1.30-7.18; P = .010). The outcome of relapsed/refractory patients was very poor, and CNS involvement was not associated with a significantly worse outcome compared with relapsed/refractory patients without CNS involvement in multivariable analysis (HR, 1.6; 95% CI, 0.96-2.6; P = .074). The results from the present study indicate that CNS relapse in PTCL occurs at a frequency similar to what is seen in aggressive B-cell lymphomas, but the poor outcomes in relapse are largely driven by systemic rather than CNS disease.

Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry.

Peripheral T-cell lymphomas (PTCLs) are rare lymphomas with mostly poor outcome with current treatment. The addition of etoposide to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and upfront consolidation with autologous stem cell transplantation (auto-SCT) have shown promising results but have never been tested in randomized trials. As a complement to retrospective analyses of clinical trials, we aimed at analyzing prognostic factors and outcome in an unselected, population-based cohort. Through the Swedish Lymphoma Registry, we identified 755 PTCL patients diagnosed during a 10-year period. In addition to International Prognostic Index factors, male gender was associated with an adverse overall survival (OS) (hazard ratio [HR], 1.28; P = .011) and progression-free survival (PFS) (HR, 1.26; P = .014). In an intention-to-treat analysis in 252 nodal PTCL and enteropathy-associated T-cell lymphoma patients (excluding anaplastic lymphoma kinase-positive anaplastic large cell lymphoma), upfront auto-SCT was associated with a superior OS (HR, 0.58; P = .004) and PFS (HR, 0.56; P = .002) compared with patients treated without auto-SCT. The addition of etoposide to CHOP resulted in superior PFS in patients ≤60 years (HR, 0.49; P = .008). This study is the largest population-based PTCL cohort reported so far and provides important information on outcome in PTCL outside the setting of clinical trials.

Treatment outcome in T-cell lymphoblastic lymphoma in adults - a population-based study from the Swedish Lymphoma Registry.

BACKGROUND: T-cell lymphoblastic lymphoma (T-LBL) is a rare neoplasm of precursor lymphoblast origin, for which there is no standard treatment for adults. Results of current treatment strategies in selected populations do exist but are largely unreported for unselected series. Here, we aimed to investigate treatment outcome in a population-based cohort. MATERIAL AND METHODS: Patients were identified through the Swedish Lymphoma Registry and data was retrospectively collected for all adult (≥ 18 years) Swedish T-LBL patients diagnosed during 2000-2009. RESULTS: A total of 39 patients with median age 40 years (range 18-78) were identified with females being significantly older than males (median age 66 vs. 37, p = 0.027). The five-year overall survival for all patients was 42%. Female gender was associated with shorter survival also when adjusted for treatment strategy and age [hazard ratio (HR) 4.29; p = 0.002]. Thirty patients received intensive chemotherapy, otherwise used for treatment of acute lymphoblastic leukemia (ALL), which resulted in an overall response rate of 97% and a five-year progression-free survival (PFS) of 49%. In this group only CNS involvement at diagnosis predicted shorter PFS (HR 13.3; p = 0.03). Among patients treated with hyper-CVAD the addition of mediastinal irradiation resulted in prolonged time to progression compared to patients receiving only chemotherapy (p = 0.047). The major reason for treatment failure was relapse and in this series 18-fluoro-deoxyglucose positron emission tomography (PET) did not predict this risk. CONCLUSION: This population-based study indicates that all fit T-LBL patients should be considered for intensive treatment. Our results also suggest a beneficial effect of mediastinal irradiation in combination with hyper-CVAD treatment. Relapsing patients have a dismal outcome irrespective of salvage treatment.

Laminin alpha1 globular domains 4-5 induce fetal development but are not vital for embryonic basement membrane assembly.

During early mouse embryogenesis, each laminin (Lm) chain of the first described Lm, a heterotrimer of alpha1, beta1, and gamma1 chains (Lm-1), is essential for basement membrane (BM) assembly, which is required for pregastrulation development. Individual domains may have other functions, not necessarily structural. The cell binding C terminus of Lm alpha1 chain contains five Lm globular (LG) domains. In vitro, alpha1LG1-3 domains bind integrins, and alpha1LG4 binds dystroglycan, heparin, and sulfatides. A prevailing hypothesis is that alpha1LG4 is crucial as a structural domain for BM assembly, whereas integrin-binding sites conduct signaling. The in vivo role of alpha1LG4-5 (also called E3) has not been studied. Mice lacking alpha1LG4-5 were therefore made. Null embryos implanted, but presumptive epiblast cells failed to polarize and did not survive past day 6.5. BM components including truncated Lm alpha1 were detected in Reichert's membrane. Surprisingly, embryonic BM assembly between visceral endoderm and stem cells was normal in null embryos and in embryoid bodies of alpha1LG4-5-null embryonic stem cells. Yet, stem cells could not develop into polarized epiblast cells. Thus, alpha1LG4-5 provides vital signals for the conversion of stem cells to polarized epithelium.