High-dose methotrexate is effective for prevention of isolated CNS relapse in diffuse large B cell lymphoma

The role of central nervous system (CNS) prophylaxis with high-dose methotrexate (HDMTX) in DLBCL is controversial. In this retrospective study, we evaluated the efficacy of prophylactic HDMTX on isolated CNS relapse, concomitant CNS and systemic relapse, systemic relapse, and survival outcomes in 226 patients with newly diagnosed DLBCL and high-risk CNS International Prognostic Index (CNS-IPI) score treated with RCHOP. The three-year risk of isolated CNS relapse was significantly lower in patients who received HDMTX, at 3.1% compared to 14.6% (P = 0.032) in those who did not. However, neither concomitant CNS-systemic relapse rates, systemic relapse rates, nor three-year PFS and OS were significantly different between treatment groups in multivariable analysis. Among propensity score-matched patients (N = 102), HDMTX was also associated with significantly lower isolated CNS relapse rates (HR 0.06, 95% CI 0.004–0.946, P = 0.046). HDMTX was well tolerated with manageable toxicities when given at a dose of 3 g/m² by day 3 of RCHOP chemotherapy. Using propensity score matching and multivariable regression to yield treatment groups with well-balanced covariates, we showed that prophylactic HDMTX improved isolated CNS relapse rates but did not decrease concomitant CNS-systemic relapse rates, systemic relapse rates, or improve survival outcomes.Subject terms: B-cell lymphoma, Preventive medicine     

The role of intrathecal chemotherapy prophylaxis in patients with diffuse large B-cell lymphoma.

BACKGROUND: Relapse in the central nervous system (CNS) following initial treatment of diffuse large B-cell lymphoma (DLBCL) is an uncommon but serious complication. This single centre retrospective study investigated the rate of CNS relapse in patients with DLBCL who received standardised intrathecal (IT) chemoprophylaxis. PATIENTS AND METHODS: A total of 259 patients were newly diagnosed and treated for DLBCL from October 1996 to May 2005 and retrospectively analysed for incidence of CNS relapse. Our institutional policy for patients at risk for CNS relapse was for IT chemoprophylaxis to be administered concurrently with systemic treatment. Defined at-risk patients were those with lymphoma involvement at the following sites: bone marrow, testis, nasal/paranasal sinuses, orbits, bone/vertebrae and peripheral blood. RESULTS: Of 259 patients with DLBCL, a total of 51 patients (19.7%) received IT chemoprophylaxis. Forty-four patients received single agent IT methotrexate (MTX) 12.5 mg (median 3 doses, range 1-7); 27 patients (53%) received 1-3 doses and 17 patients (33.3%) 4-7 doses of MTX. Seven patients (13.7%) received a combination of IT MTX plus cytarabine. Three patients (1.1%) subsequently developed CNS relapse. One of these patients had IT chemoprophylaxis, the other two did not meet the Royal Marsden Hospital (RMH) criteria for IT chemoprophylaxis. The median time from diagnosis of DLBCL to CNS relapse was 31.8 months (range 27.3-34.1 months). CONCLUSION: The CNS relapse rate in this cohort of patients with primary DLBCL was low at 1.1%. This retrospective analysis demonstrates in a homogeneous group of DLBCL patients that a relatively low-intensity IT chemoprophylaxis regimen given according to site-based risk can be associated with a low risk of CNS relapse.     

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

Although 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.Subject terms: B-cell lymphoma, Disease-free survival     

Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial

BackgroundCentral nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial.Patients and methodsThe R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged ≥18 years with bulky stage I–IV DLBCL (n = 1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated.Results177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX)n = 163, intravenous (IV) MTXn = 2, prophylaxis type unknownn = 11 and IT MTX and cytarabinen = 1). At a median follow-up of 6.5 years, 21 cases of CNS relapse (isolatedn = 11, with systemic relapsen = 10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI, >1 extranodal site of disease and presence of a ‘high-risk’ extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively.ConclusionDespite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence.ClinicalTrials.govISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34.     

CD5-positive diffuse large B-cell lymphoma: a retrospective study in 337 patients treated by chemotherapy with or without rituximab

BackgroundCD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) shows poor prognosis and frequent central nervous system (CNS) relapses under anthracycline-containing chemotherapy. The aim of this study was to determine the prognosis and CNS relapse incidence of CD5+ DLBCL in the rituximab era.Patients and methodsWe analyzed 337 patients with CD5+ DLBCL who received chemotherapy with (R-chemotherapy group; n = 184) or without (chemotherapy group; n = 153) rituximab.ResultsNo significant difference was found in clinical background comparisons between the two groups. In the R-chemotherapy group, 60% of the patients were older than 65 years at diagnosis. Both the complete response rate and overall survival (OS) were significantly better in the R-chemotherapy group (P = 0.0003 and P = 0.002, respectively). Multivariate analysis confirmed that chemotherapy without rituximab was associated with unfavorable OS. However, the probability of CNS relapse did not differ between the two groups (P = 0.89). The CNS relapse was strongly associated with short OS (P < 0.0001). In the R-chemotherapy group, 83% of patients who experienced CNS relapse had parenchymal disease.ConclusionsOur results indicate that rituximab improves the OS of patients with CD5+ DLBCL but does not decrease the CNS relapse rate. More effective treatments with CNS prophylaxis are needed for CD5+ DLBCL patients.     

Ki-67 is a strong predictor of central nervous system relapse in patients with mantle cell lymphoma (MCL)

High Ki-67 is strongly associated with the risk of CNS relapse in patients with mantle cell lymphoma. Two-year incidence of CNS relapse in patients with Ki-67 ≥ 30 exceeds 25%. The incidence was not decreased by rituximab, high-dose cytarabine, high-dose methotrexate or consolidative ASCT. Development of new prophylactic strategies for CNS involvement is mandatory in patients with high Ki-67.BackgroundCentral nervous system (CNS) relapse is an uncommon but challenging complication in patients with mantle cell lymphoma (MCL). Survival after CNS relapse is extremely poor. Identification of high-risk populations is therefore critical in determining patients who might be candidates for a prophylactic approach.Patients and methodsA total of 608 patients (median age, 67 years; range 22–92) with MCL newly diagnosed between 1994 and 2012 were evaluated. Pretreatment characteristics and treatment regimens were evaluated for their association with CNS relapse by competing risk regression analysis.ResultsNone of the patients received intrathecal prophylaxis. Overall, 33 patients (5.4%) experienced CNS relapse during a median follow-up of 42.7 months. Median time from diagnosis to CNS relapse was 20.3 months (range: 2.2–141.3 months). Three-year cumulative incidence of CNS relapse was 5.6% [95% confidence interval (95% CI) 3.7% to 8.0%]. Univariate analysis revealed several risk factors including blastoid variant, leukemic presentation, high-risk MCL International Prognostic Index and high Ki-67 (proliferation marker). Multivariate analyses revealed that Ki-67 ≥ 30 was the only significant risk factor for CNS relapse (hazard ratio: 6.0, 95% CI 1.9–19.4, P = 0.003). Two-year cumulative incidence of CNS relapse in patients with Ki-67 ≥ 30 was 25.4% (95% CI 13.5–39.1), while that in the patients with Ki-67 < 30 was 1.6% (95% CI 0.4–4.2). None of the treatment modalities, including rituximab, high-dose cytarabine, high-dose methotrexate or consolidative autologous stem-cell transplant, were associated with a lower incidence of CNS relapse. Survival after CNS relapse was poor, with median survival time of 8.3 months. There was no significant difference in the survival by the site of CNS involvement.     

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

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

New risk factors and new tendency for central nervous system relapse in patients with diffuse large B-cell lymphoma：a retrospective study

Background:In patients with diffuse large B?cell lymphoma (DLBCL), central nervous system (CNS) relapse is uncom?mon but is nearly always fatal. This study aimed to determine the risk factors for CNS relapse in DLBCL patients and to evaluate the effcacy of rituximab and intrathecal chemotherapy prophylaxis for CNS relapse reduction. Methods:A total of 511 patients with newly diagnosed DLBCL treated at the Sun Yat?sen University Cancer Center between January 2003 and December 2012 were included in the study. Among these patients, 376 received R?CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment, and 135 received CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment. Intrathe?cal chemotherapy prophylaxis (methotrexate plus cytarabine) was administered to those who were deemed at high risk for CNS relapse. In the entire cohort and in the R?CHOP set in particular, the Kaplan–Meier method coupled with the log?rank test was used for univariate analysis, and the Cox proportional hazards model was used for multivariate analysis. Differences were evaluated using a two?tailed test, andP<0.05 was considered signiifcant. Results:At a median follow?up of 46months, 25 (4.9%) patients experienced CNS relapse. There was a trend of reduced occurrence of CNS relapse in patients treated with rituximab; the 3?year cumulative CNS relapse rates were 7.1% in CHOP group and 2.7% in R?CHOP group (P=0.045). Intrathecal chemotherapy prophylaxis did not confer much beneift in terms of preventing CNS relapse. Bone involvement [hazard ratio (HR)=4.21, 95% conifdence interval (CI) 1.38–12.77], renal involvement (HR=3.85, 95% CI 1.05–14.19), alkaline phosphatase (ALP) >110U/L (HR=3.59, 95% CI 1.25–10.34), serum albumin (ALB) <35g/L (HR=3.63, 95% CI 1.25–10.51), treatment with rituxi?mab (HR=0.34, 95% CI 0.12–0.96), and a time to complete remission≤ 108days (HR=0.22, 95% CI 0.06–0.78) were independent predictive factors for CNS relapse in the entire cohort. Bone involvement (HR=4.44, 95% CI 1.08–18.35), bone marrow involvement (HR=11.70, 95% CI 2.24–60.99), and renal involvement (HR=10.83, 95% CI 2.27–51.65) were independent risk factors for CNS relapse in the R?CHOP set. Conclusions:In the present study, rituximab decreased the CNS relapse rate of DLBCL, whereas intrathecal chemo?therapy prophylaxis alone was not suffcient for preventing CNS relapse. Serum levels of ALB and ALP, and the time to complete remission were new independent predictive factors for CNS relapse in the patients with DLBCL. In the patients received R?CHOP regimen, a trend of increased CNS relapse was found to be associated with extranodal lesions.     

Non-Hodgkin lymphoma of the breast

BACKGROUND: Primary lymphoma of the breast has been reported to have a high local and central nervous system recurrence (CNS) rate, suggesting the need for consolidation radiotherapy and CNS prophylaxis. A retrospective study was done to evaluate the institutional experience in this patient population. METHODS: In all, 37 patients with lymphoma involving the breast at initial diagnosis and managed at Stanford University from 1981-2005 were included. Diagnostic tissue biopsies were obtained either from the breast mass or an involved lymph node. Treatment and response data, patterns of recurrence, and outcomes were reviewed. RESULTS: Diffuse large B cell lymphoma (DLBCL) was the most common histologic subtype seen in 18 of 37 (49%) patients. Follicular and marginal zone subtypes were seen in 38%. Most patients presented with an incidental breast mass in stage I(E) or II(E). Four (11%) patients presented with bilateral breast involvement, with only 1 patient presenting with CNS disease. DLBCL patients received doxorubicin-based chemotherapy, with 70% receiving involved field radiotherapy and a single patient receiving intrathecal therapy. No recurrences occurred in the involved breast and a single parenchymal CNS recurrence was recorded. Among the DLBCL patients, the 5-year progression-free survival (PFS) was 61%, with a median follow-up of 3.8 years (range, 5 months to 19 years) and the 5-year overall survival (OS) was estimated at 82%. Patients with indolent lymphoma had an estimated 5-year PFS of 76% and an OS of 92%. CONCLUSIONS: DLBCL of the breast was successfully treated with doxorubicin-based chemotherapy alone or with involved field radiotherapy in an estimated 61% of patients at 5 years. A single CNS recurrence was observed in our series of patients, most of whom presented with limited disease.     

Central nervous system involvement in adult acute leukemia

Central nervous system (CNS) involvement was present in 16 of 59 (27%) adults with leukemia, i.e. in 13 of 40 (33%) with AML, of 3 (33%) with AMoL, and 2 of 8 (25%) with ALL. CNS leukemia was found at the time of diagnosis in 2 patients, during induction therapy in 2 patients, early in remission in 2 patients, during remission in patients, and at relapse in 4 patients. Fifteen of the 16 patients responded to intrathecal methotrexate, cytosine arabinoside or cranial irradiation. Only patients developed CNS relapse. CNS leukemia had no effect on survival. In 3 of 5 patients without CNS prophylaxis, the onset of neurologic manifestations was observed within one year of remission, whereas it was delayed for more than one year in all patients who had received prophylactic intrathecal methotrexate.     

Risk factors for high-dose methotrexate associated acute kidney injury in patients with hematological malignancies

High dose methotrexate (HDMTX)-induced acute kidney injury (AKI) is a well-known adverse event in hemato-oncology patients. Our purpose was to define factors and setup cut-offs that may help better identify patients at-risk for developing AKI following HDMTX. All consecutive patients who received MTX dose ≥1 g were retrospectively reviewed. We compared patients with or without renal toxicity. We used a logistic regression model to define baseline variables associated with AKI. Overall survival (OS) was estimated by the Kaplan-Meier method employing log-rank test. Between 2012 and 2017, 160 patients were included with a total of 265 courses. Indications included: primary central nervous system (CNS) lymphoma, CNS prophylaxis in other lymphoma types, acute lymphatic leukemia and others. Median age at diagnosis was 58 years (range, 18-84), 54% were males, median MTX dose was 1941 mg/m² (range, 743-5442) and AKI developed in 9% of drug administrations (n = 24). In univariate analysis: age > 40, LDH > 380 units/L, eGFR < 112 mL/min, albumin <3.6 mg/dL at baseline and Charlson comorbidity index (CCI) were associated with AKI. In multivariable analysis, only LDH > 380 units/L (OR = 4.1, 95% confidence interval [CI] 1.04-20.9, P = .04) and albumin levels <3.6 g/dL (OR = 4.17, 95% CI 1.04-6.5, P = .04) remained significant. In patients with AKI, median drug elimination was longer (8 days vs 5 days). In 80% of cases, the creatinine levels returned to normal within 1 month. Yet, the median survival of patients who developed AKI was 37 months, compared to 145 months in patients without AKI (Log rank = 0.015). In conclusion, LDH > 380 units/L and albumin <3.6 g/dL were the strongest factors associated with AKI in patients receiving HDMTX. Although the rise in creatinine levels was almost uniformly reversible, AKI was associated with increased mortality rates.     

Hematopoietic stem cell transplantation in mantle cell lymphoma.

BACKGROUND: Patients with mantle cell lymphoma (MCL) have in general, lower response rates and overall survival (OS) than those with other B-cell non-Hodgkin's lymphomas. The role of hematopoietic stem cell transplantation (HSCT) in MCL is unclear. Hence we decided to study the clinical course of patients who received autologous and allogeneic HSCT for MCL. METHODS: Ninety-seven patients, (80 patients-autologous; 17 patients-allogeneic) who received a HSCT for mantle cell lymphoma were included in the study. RESULTS: The complete response rates at day 100 between the two groups were similar (73% vs. 62%). Day-100 mortality was higher in the allogeneic HSCT group (19% vs. 0%) (P < 0.01). The estimated 5-year relapse rates, 5-year event-free survival (EFS) and 5-year OS among the allogeneic HSCT patients were 21%, 44% and 49%, respectively, similar to 56%, 39% and 47% in the autologous group. Ten patients received HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone + high-dose methotrexate and cytarabine) +/- rituximab prior to transplant. There have been no relapses or deaths amongst these patients at a median follow-up of 16 months. CONCLUSIONS: Patients treated with allogeneic HSCT had a lower relapse rate, but similar EFS and OS to autologous HSCT. Treatment of MCL with HyperCVAD +/- rituximab followed by HSCT seems promising.     

CNS involvement in small noncleaved-cell lymphoma: is CNS disease per se a poor prognostic sign?

Of 120 patients with small noncleaved-cell lymphoma who were entered sequentially on four National Cancer Institute (NCI) protocols, 29 (24%) had CNS involvement at some time in their clinical course. Seventeen had initial CNS involvement, and 12 developed CNS involvement at the time of first relapse. All 29 patients had extensive disease at presentation. The median serum lactate dehydrogenase (LDH) levels at presentation were 1,150 IU/L for patients with initial CNS involvement and 1,083 IU/L for patients with CNS involvement at relapse. CNS disease was significantly associated with serum LDH levels (P less than .0001), bone marrow involvement (P less than .0001), and jaw involvement (P = .018), but not involvement of the abdomen. There were nine long-term survivors among the 29 patients (31%). CNS disease did not appear to confer a worse prognosis on these patients than on patients without CNS involvement who had similar degrees of serum LDH elevation or who had bone marrow involvement, suggesting that extensive disease rather than CNS involvement was responsible for the poor prognosis. Event-free survival for patients with serum LDH levels above 500 IU/L was not different whether CNS disease was present or not (P = .29), nor was event-free survival different for patients with stage IV disease, whether CNS disease was present or not (P = .92). Although some patients had CNS radiation, there was no evidence that this was of therapeutic benefit. Intrathecal (IT) chemoprophylaxis effectively prevented spread to the CNS in patients without initial CNS involvement. Five of 18 patients (28%) who received no IT prophylaxis had CNS relapse (four isolated to the CNS), but only seven of the 85 patients (8%) who received IT prophylaxis had CNS relapse (two isolated to the CNS). The differences in overall and isolated CNS relapse rates were statistically significant (P = .034 and P = .008, respectively).     

Hematopoietic stem cell transplantation for diffuse large B‐cell lymphoma having 8q24/MYC rearrangement in Japan

The prognosis of diffuse large B‐cell lymphoma (DLBCL) having MYC rearrangement (MYC‐R), including double hit lymphoma (DHL), is poor by standard immunochemotherapy. To evaluate the significance of hematopoietic stem cell transplantation (SCT) for DLBCL with MYC‐R, we retrospectively analyzed Japanese SCT registry data. In total, 54 patients with DLBCL with MYC‐R were identified from 4336 registered adult DLBCL patients. Detailed clinical and cytogenetic information was obtained for 48 patients. The median age at diagnosis of the 48 patients was 54.5 (range 21–67) years. Twenty‐six (54%) patients had MYC‐R only (single hit), and 22 (46%) had MYC‐R and BCL2, and/or BCL6 rearrangement (double/triple hit). In 12 patients who received auto‐SCT during the first complete response (CR), both the 2‐year overall survival (OS) and progression‐free survival (PFS) rates were 75.0% (95% confidence interval [CI], 40.8%–91.2%). In 20 patients who received auto‐SCT after relapsed or refractory state, the 2‐year OS and PFS rates were 68.2% (95% CI, 41.9%–84.5%) and 59.6% (95% CI, 35.1%–77.4%), respectively. In 17 patients who received allo‐SCT, only 4 patients underwent SCT in CR. The 2‐year OS and PFS rates were 29.4% (95% CI, 10.7%–51.1%) and 17.6% (95% CI, 4.3%–38.3%), respectively. The rate of non‐relapse mortality at 1 year was 41.2% (95% CI, 17.1%–64.0%) in this group. The outcomes of single hit and double or triple hit were not different. These findings suggest that auto‐SCT may be effective for MYC‐R DLBCL, including DHL patients of chemosensitive relapsed or refractory state. Since most patients received allo‐SCT not in CR, the outcome of allo‐SCT was unsatisfactory due to high non‐relapse mortality and early relapse. To clarify the role of allo‐SCT for MYC‐R DLBCL, further accumulation of patients is necessary.     

Incidence of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) including CNS relapse in a population-based cohort of 4243 patients in Sweden

We performed a national population-based study of all patients diagnosed with diffuse large B-cell lymphoma (DLBCL) in Sweden in 2007–2014 to assess treatment intent and risk of relapsed/refractory disease, including central nervous system (CNS) relapse, in the presence of competing risks. Overall, 84% of patients started treatment with curative intent (anthracycline-based) (n = 3550, median age 69 years), whereas 14% did not (n = 594, median age 84 years) (for 2% the intent was uncertain). Patients treated with curative intent had a 5-year OS of 65.3% (95% CI: 63.7–66.9). The median OS among non-curatively treated patients was 2.9 months. The 5-year cumulative incidence of relapsed/refractory disease in curative patients was 23.1% (95% CI: 21.7–24.6, n = 847). The 2-year cumulative incidence of CNS relapse was 3.0% (95% CI: 2.5–3.6, n = 118) overall, and 8.0% (95% CI: 6.0–10.6, n = 48) among patients with high CNS-IPI (4–6), when considering other relapse locations and death as competing events. The incidence of relapsed/refractory DLBCL overall and in the CNS was lower than in previous reports, still one in seven patients was not considered fit enough to start standard immunochemotherapy at diagnosis. These results are important for quantification of groups of DLBCL patients with poor prognosis requiring completely different types of interventions.Subject terms: Epidemiology, Cancer epidemiology, B-cell lymphoma     

Leukemic High Grade B Cell Lymphoma is Associated With MYC Translocation,Double Hit/Triple Hit Status,Transformation, and CNS Disease Risk: The Mayo Clinic Experience

Introduction: Leukemic involvement in high grade B cell lymphoma (L-HGBL) is rare and has been sparsely described in the literature. We report our experience in a large single institution multicenter academic setting. Materials and Methods: Medical records of patients with HGBL who received care at Mayo Clinic between 2003 and 2020 were reviewed. L-HGBL was confirmed by peripheral blood smear and flow cytometry with corroboration from tissue and bone marrow biopsy findings. Results: Twenty patients met inclusion criteria. All patients had significant bone marrow involvement by HGBL. Leukemic involvement presented in 11 of 20 (55%) in the de novo and 9 of 20 (45%) in the relapsed setting. Seven of 20 patients had DLBCL, NOS, 6 of 20 had transformation (t-DLBCL), 3 of 20 had transformed double/triple hit lymphoma (t-DHL/THL), 2 of 20 had double hit lymphoma (DHL), and 2 of 20 had HGBL with intermediate features between DLBCL and Burkitt lymphoma. Nine of 15 patients had MYC translocation. Based on Hans criteria, 11 of 20 had germinal center B-cell (GCB) cell of origin (COO) and 9/20 had non-GCB COO. Five of 11 de novo patients experienced CNS relapse/progression. All de novo patients received anthracycline-based chemoimmunotherapy. Eighteen of 20 patients died of progressive disease. Median overall survival was significantly better in the de novo compared to relapsed group (8.9 months vs. 2.8 months, P = .01). COO, MYC status, DHL/THL status, HGBL subtype, or treatment group did not demonstrate a significant effect on overall survival. Conclusion: L-HGBL carries a poor prognosis and is associated with MYC translocation, DHL/THL status, transformation, and high CNS risk. Novel therapeutic approaches are needed for L-HGBL.     

Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high‐risk patients with diffuse large B‐cell lymphoma

BACKGROUND:

The outcome of patients with systemic diffuse large B‐cell lymphoma (DLBCL) had improved over the past decade with the addition of monoclonal antibody therapy. Unfortunately, approximately 5% of these patients still developed a secondary central nervous system (CNS) recurrence followed invariably by rapid death. This rate is substantially increased in patients with certain high‐risk features. Although prophylaxis against CNS recurrence with either intrathecal or intravenous methotrexate is commonly used for such patients, to the authors' knowledge, there is no standard of care. Retrospectively evaluated was the role of high‐dose systemic methotrexate combined with standard cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab (R‐CHOP) chemotherapy to decrease CNS recurrence in high‐risk patients.

METHODS:

A total of 65 patients with DLBCL and CNS risk factors were identified at the study institution between 2000 and 2008 who received intravenous methotrexate as CNS prophylaxis concurrent with standard systemic therapy with curative intent. CNS recurrence rate, progression‐free survival, and overall survival were calculated.

RESULTS:

Patients received a median of 3 cycles of methotrexate at a dose of 3.5 gm/m² with leucovorin rescue. The complete response rate was 86%, with 6% partial responses. At a median follow‐up of 33 months, there were only 2 CNS recurrences (3%) in this high‐risk population. The 3‐year progression‐free and overall survival rates were 76% and 78%, respectively. Complications associated with methotrexate therapy included transient renal dysfunction in 7 patients and a delay in systemic chemotherapy in 8 patients.

CONCLUSIONS:

Intravenous methotrexate can be safely administered concurrently with R‐CHOP and is associated with a low risk of CNS recurrence in high‐risk patients. Cancer 2010. © 2010 American Cancer Society.     

Methotrexate re-challenge for recurrent primary central nervous system lymphoma

The prognosis of primary CNS lymphoma (PCNSL) recurring after methotrexate is poor (objective response rates [ORR] = 26–53 %; 1-year overall survival [OS] = 35–57 %). Salvage PCNSL chemotherapies have been based on the use of different agents to avoid cross-resistance; however, methotrexate is the most active agent in PCNSL, and methotrexate re-challenge may be an effective strategy for recurrent disease. We report our experience with methotrexate re-challenge in PCNSL. We reviewed 39 patients with histologically confirmed PCNSL who responded to methotrexate at initial diagnosis, experienced disease relapse and received methotrexate re-challenge. At the time of re-challenge, median age was 66 and median Karnofsky performance score (KPS) was 70. Median time from initial diagnosis was 26 m. Twenty-six patients were at first relapse and 13 at second or later relapse. At re-challenge, methotrexate was given in combination with other agents to 33 patients and as a single agent to six. The objective response rate was 85 %, with a complete response in 29 (75 %) patients, partial response in four (10 %) and disease progression in six (15 %). At median follow-up of 26 m, the median progression-free survival was 16 m; 1-year OS was 79 % (95 % CI 63–89) and median OS was 41 m. KPS was a prognostic factor for progression free survival (p = 0.04). In this population selected by previous methotrexate response, methotrexate re-challenge was a safe and effective strategy, indicating chemosensitivity was retained. Efficacy compared favorably to other salvage treatments suggesting methotrexate re-challenge should be considered in recurrent PCNSL patients who previously responded to methotrexate.     

Histology impacts the outcome of peripheral T-cell lymphomas after high dose chemotherapy and stem cell transplant

The role of high dose chemotherapy (HDC) and stem cell transplant (SCT) in peripheral T-cell lymphoma (PTCL) was studied in 28 patients, from 1988 to 2002. The aim was to determine if subsets recognized by the REAL/WHO classification have different prognoses. Outcome was compared to 86 patients with diffuse large B-cell lymphoma (DLBCL) transplanted during 1986-2000. The 3-year overall survival (OS) and event free survival (EFS) were 69% and 50%. Patients with anaplastic large cell lymphoma (ALCL) had a better 3-year OS compared to those with non-ALCL histology (86% vs. 47%, P=0.0122). Anaplastic lymphoma kinase (ALK)- positive ALCL patients had a superior EFS compared to ALK-negative ALCL (100% vs. 0; P=0.0228). Patients with cutaneous ALCL (ALK-negative) relapsed, but had an indolent course after SCT. Low International Prognostic Index score at relapse predicted for a better 3-year OS (85% vs. 34%, P=0.0238). When compared to DLBCL, patients with ALCL had a superior OS (86% vs. 36%, P=0.0034) and patients with non-ALCL had a comparable OS. ALCL histology confers better survival compared to non-ALCL and DLBCL histologies. ALK-positive ALCL is associated with the best EFS after relapse with HDC and SCT. The timing of SCT for non-ALCL histology remains to be determined.     

Outcomes of HTLV-1 Carriers with Diffuse Large B-Cell Lymphoma: A Single-Center Retrospective Matched Cohort Study

BackgroundThe human T-cell lymphotropic virus type 1 (HTLV-1) is associated with aggressive diseases, such as adult T-cell leukemia/lymphoma (ATLL). However, less is known on the impact of HTLV-1 infection in non-ATLL hematologic malignancies. We aimed to investigate if HTLV-1 carriers with diffuse large B-cell lymphoma (DLBCL) have worse survival outcomes than non-HTLV-1 carriers.Materials and MethodsWe performed a single-center retrospective cohort study by matching HTLV-1 carriers to non-carriers based on age, sex, Ann Arbor stage, and year of diagnosis. Our outcomes of interest were overall survival (OS) and progression-free survival (PFS). The Kaplan-Meier method was used to estimate OS and PFS between carriers and non-carriers. We fitted multivariate Cox regression models to assess the mortality and recurrence/disease progression risk of HTLV-1 infection.ResultsA total of 188 patients, 66 with HTLV-1 infection and 122 without HTLV-1, were included in the study. HTLV-1 carriers had higher extranodal involvement than non-carriers (47% vs. 27%, P = .010). With a median follow-up of 78 months (95% CI: 41-90 months), HTLV-1 carriers had a similar 5 year OS (41% vs. 42%, P = .940) and PFS (34% vs. 32%, P = .691) compared to non-carriers. In the multivariate Cox analysis, HTLV-1 infection was not associated with worse OS (aHR: 0.98, 95% CI: 0.64-1.50) or PFS (aHR: 0.90, 95% CI: 0.60-1.34).ConclusionHTLV-1 carriers with DLBCL did not have worse survival outcomes compared to non-carriers. Our results suggest that clinicians should follow standard guidelines for DLBCL management on HTLV-1 seropositive patients.