Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions

Blood ◽  
2021 ◽  
Author(s):  
Victor Manuel Orellana-Noia ◽  
Daniel Reed ◽  
Ashley Alesia McCook ◽  
Jeremy Michael Sen ◽  
Christian M Barlow ◽  
...  
Keyword(s):  
High Risk ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Standard Of Care ◽  
High Dose ◽  
Cns Prophylaxis ◽  
Cns Relapse ◽  
Significant Difference ◽  
Relapse Rates

Prophylaxis is commonly used to prevent central nervous system (CNS) relapse in diffuse large B cell lymphoma, with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013-2019. Prophylaxis was administered intrathecally (IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7 %) had CNS relapse, after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4 vs 6.8%, p=0.4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected versus observed CNS relapse rates were nearly identical (5.8 vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated and reconsideration of prophylaxis strategies in DLBCL is of critical need.

Timing of high dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1,384 patients

Blood ◽  
2022 ◽  
Author(s):  
Matthew R. Wilson ◽  
Toby Andrew Eyre ◽  
Amy A Kirkwood ◽  
Nicole Wong Doo ◽  
Carole Soussain ◽  
...  
Keyword(s):  
High Risk ◽  
International Prognostic Index ◽  
Multivariable Analysis ◽  
B Cell Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Cns Prophylaxis ◽  
Dose Methotrexate ◽  
Cns Relapse ◽  
Increased Risk

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1,384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n=749) or at the end (n=635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT; 5.7% vs 5.8%, p=0.98, 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n=1,253). In patients with high CNS international prognostic index (n=600), 3-year CNS relapse rate was 9.1% with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX versus EOT, with 308/1573 (19.6%) i-HD-MTX treatments resulting in delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk versus i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

scholarly journals Timing of high-dose methotrexate CNS prophylaxis in DLBCL: an analysis of toxicity and impact on R-CHOP delivery

2020 ◽  
Vol 4 (15) ◽  
pp. 3586-3593
Author(s):  
Matthew R. Wilson ◽  
Toby A. Eyre ◽  
Nicolas Martinez-Calle ◽  
Matthew Ahearne ◽  
Katrina E. Parsons ◽  
...  
Keyword(s):  
International Prognostic Index ◽  
Multivariable Analysis ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
End Points ◽  
Cns Prophylaxis ◽  
Dose Methotrexate ◽  
Cns Relapse

Abstract High-dose methotrexate (HD-MTX) is increasingly used as prophylaxis for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of central nervous system (CNS) relapse. However, there is limited evidence to guide whether to intercalate HD-MTX (i-HD-MTX) between R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone given at 21-day intervals) or to give it at the end of treatment (EOT) with R-CHOP-21. We conducted a retrospective, multicenter analysis of 334 patients with DLBCL who received CNS prophylaxis with i-HD-MTX (n = 204) or EOT HD-MTX (n = 130). Primary end points were R-CHOP delay rates and HD-MTX toxicity. Secondary end points were CNS relapse rate, progression-free survival, and overall survival. The EOT group had more patients with a high CNS international prognostic index (58% vs 39%; P < .001) and more concurrent intrathecal prophylaxis (56% vs 34%; P < .001). Of the 409 cycles of i-HD-MTX given, 82 (20%) were associated with a delay of next R-CHOP (median, 7 days). Delays were significantly increased when i-HD-MTX was given after day 9 post–R-CHOP (26% vs 16%; P = .01). On multivariable analysis, i-HD-MTX was independently associated with increased R-CHOP delays. Increased mucositis, febrile neutropenia, and longer median inpatient stay were recorded with i-HD-MTX delivery. Three-year cumulative CNS relapse incidence was 5.9%, with no differences between groups. There was no difference in survival between groups. We report increased toxicity and R-CHOP delay with i-HD-MTX compared with EOT delivery but no difference in CNS relapse or survival. Decisions on HD-MTX timing should be individualized and, where i-HD-MTX is favored, we recommend scheduling before day 10 of R-CHOP cycles.

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

2020 ◽  
Author(s):  
Mohammad Ma'koseh ◽  
Mohammad Ma’koseh ◽  
Faris Tamimi ◽  
Alaa Abufara ◽  
Lana Abusalem ◽  
...  
Keyword(s):  
High Risk ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Intrathecal Chemotherapy ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma ◽  
Cns Relapse ◽  
Selection Of

Abstract Background The central nervous system international prognostic index [CNS-IPI]is being usedwidely for the identification of patients with diffuse large B cell lymphoma [DLBCL]with highrisk of CNS relapse. The aim of our study is to confirm the value of the CNS-IPI in predicting CNS relapse in our young study population and to evaluate the impact on selection of patients for CNS prophylaxis. Methods We retrospectively reviewed patients with pathological diagnosis of DLBCL who were treated with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] regimen from January 2004 till December 2016 with no evidence of CNS involvement on diagnosis. Different demographic, disease characteristics and treatment given including the use of intrathecal chemotherapy prophylaxis were collected. Correlation between CNS-IPI and CNS relapse was examined through chi square test. Median time to CNS relapse and median overall survival [OS] after CNS relapse were estimated using the Kaplan-Meier plots. Results 354 patients were included. Median age was 46 years. 52 [15%] patients were given intrathecal chemotherapy [ITC] prophylaxis, of whom CNS-IPI was high in 7[13%]. Overall, 5% of the patients [n = 17] developed CNS relapse.The median survival after CNS relapse was 7 months. The rate of CNS relapse in patients with low, intermediate and high risk CNS-IPI was 0.6%, 3% and 22% respectively [p = < 0.001].On multivariate analysis, involvement of bone marrow [p = 0.039]and renal or adrenal glands[p = 0.023]significantly correlated with CNS relapse. Considering theCNS-IPI and high risk anatomical sites [breast, uterus, testis and epidural space], 26% of our patients with DLBCLwould have needed prophylaxis. Conclusion Although CNS-IPI helps in better selection of DLBCL patients for CNS prophylaxis, it will significantly and possibly unnecessarily increase the number of patients exposed to prophylaxis. More investigational biomarkers and methods are necessary to better refining high risk patients.

Safety of same day HD-MTX with induction therapy for DLBCL with concurrent CNS disease or as prophylaxis for high risk of CNS relapse.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19545-e19545
Author(s):  
Brett Barlow ◽  
Haris Hatic ◽  
Charles Douglas Bodine ◽  
Amitkumar Mehta ◽  
Gaurav Goyal ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Chemotherapy ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Treatment Delays ◽  
Cns Disease ◽  
Cns Relapse ◽  
End Of Treatment

e19545 Background: High-dose methotrexate (HD-MTX) at a dose between 2.5 to 5 gm/m2 is commonly administered in conjunction with standard induction chemotherapy to patients with Diffuse Large B Cell Lymphoma (DLBCL) at high risk of central nervous system (CNS) relapse, as defined by the Lymphoma International Prognostic Index (CNS-IPI). Optimal timing of HD-MTX in relation to induction chemotherapy is unknown. A recent study suggested that HD-MTX intercalated with R-CHOP cycles was associated with increased toxicity and treatment delays without improvement in survival or CNS relapse compared with end of treatment MTX (Wilson et al 2020). This retrospective study evaluates the toxicities and treatment delays associated with HD-MTX administered on day 1 of cycles of chemo-immunotherapy. Methods: This single center retrospective cohort study included 45 patients (pts) with DLBCL with concurrent CNS disease or at high risk of CNS relapse who received HD MTX on day 1 of chemo-immunotherapy at our center. Data was abstracted from chart review and included variables describing clinical and treatment characteristics, time to MTX clearance, toxicities experienced and treatment delays. Results: 31 pts received HD-MTX on the day of R-CHOP chemotherapy, 6 pts received HD-MTX on the day of R-EPOCH (Rituximab, Etoposide, Doxorubicin, Vincristine, Cyclophosphamide, and Prednisone), and 8 pts received HD-MTX with R-MiniCHOP (dose reduced R-CHOP). Same day HD MTX with chemo-immunotherapy was associated with acute kidney injury (AKI; 17-25%), treatment delays >7 days (13-17%), and grade 2 mucositis (11-50%). The burden of toxicities was numerically higher in patients treated with R-EPOCH vs. R-CHOP (Table). Clinical outcomes are summarized in table below. Conclusions: In our heterogeneous population of pts, we describe that the incidence of toxicities and treatment delays experienced with same day HD-MTX are higher with R-EPOCH than with R-CHOP. Comparative studies with intercalated or end of treatment MTX will determine if the incidence of treatment delays, toxicities and de-escalations are higher with same day HD-MTX administration. [Table: see text]

scholarly journals Patients with high-risk DLBCL benefit from dose-dense immunochemotherapy combined with early systemic CNS prophylaxis

2020 ◽  
Vol 4 (9) ◽  
pp. 1906-1915 ◽  
Author(s):  
Sirpa Leppä ◽  
Judit Jørgensen ◽  
Anne Tierens ◽  
Leo Meriranta ◽  
Ingunn Østlie ◽  
...  
Keyword(s):  
High Risk ◽  
International Prognostic Index ◽  
Survival Rates ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Free Survival ◽  
Cns Prophylaxis ◽  
Phase 2 Trial ◽  
Dose Dense

Abstract Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P = .002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates. This trial was registered at www.clinicaltrials.gov as #NCT01325194.

scholarly journals S5-KL-1 CURRENT TREATMENT FOR DLBCL AND PROPHYLAXIS AND TREATMENT FOR SECONDARY CNS LYMPHOMA

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii4-ii4
Author(s):  
Koji Izutsu
Keyword(s):  
High Risk ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
Large B Cell Lymphoma ◽  
Cns Relapse ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma, comprising 30% of all lymphoma cases. More than 60% of patients can be cured with current standard treatment, R-CHOP. On the other hand, prognosis of patients with relapsed or refractory DLBCL is disappointing with less than 10% being cured with salvage chemotherapy followed by high-dose chemotherapy with autologous stem cell transplantation. Prognosis of patients with central nervous system (CNS) relapse is especially poor because of a limited treatment option. Thus, evaluating risks of CNS relapse at diagnosis and administering prophylaxis including intrathecal methotrexate (MTX) or systemic high-dose MTX concurrently with R-CHOP or as consolidation therapy in high-risk patients are often-used approach. Clinically, higher risk according to the International Prognostic Index and extranodal involvement in organs such as kidney, adrenal gland, breast, testis, or bone marrow are considered to be high-risk for CNS relapse. Recently, CNS-International Prognostic Index has been proposed to integrate aforementioned risk factors. Moreover, patients with intravascular large B-cell lymphoma, CD5+ DLBCL, double hit lymphoma are reported as high-risk for CNS relapse. Further, the MYD88 L265P mutation, a common mutation in primary CNS DLBCL (PCNSL) is also common in DLBCL of testis or breast, which are the sites associated with CNS relapse. Strategies for CNS prophylaxis have not established yet, and it is still unclear whether intrathecal MTX or high-dose MTX can prevent CNS relapse. Moreover, treatment for secondary CNS relapse have not been established. In particular, for those with both CNS and extra-CNS lesions, effective treatment options are very limited. The role of novel agents such as BTK inhibitors, lenalidomide, and immune check point inhibitors, whose efficacy have been shown for PCNSL, should be investigated further in the management of secondary CNS lymphoma.

Cell of origin, germinal center versus nongerminal center, determined by immunohistochemistry on tissue microarray, does not correlate with outcome in patients with relapsed and refractory DLBCL

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3383-3385 ◽  
Author(s):  
Craig H. Moskowitz ◽  
Andrew D. Zelenetz ◽  
Tarun Kewalramani ◽  
Paul Hamlin ◽  
Simone Lessac-Chenen ◽  
...  
Keyword(s):  
De Novo ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Second Line ◽  
Cell Of Origin ◽  
Free Survival ◽  
Significant Difference ◽  
The Common

AbstractA number of prognostic factors affect outcome in patients with relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL), including refractory disease and the second-line age-adjusted international prognostic index. In de novo DLBCL, the cell of orgin, as determined by expression microarray analysis or immunohistochemistry (IHC), predicts event-free survival (EFS). We evaluated the cell of origin, as well as other pathologic markers of outcome, on the repeat biopsy specimen of 88 transplantation-eligible patients undergoing ifosfamide, carboplatin, etoposide (ICE) second-line chemotherapy (SLT) followed by high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) to see if were they prognostic in the salvage setting. Pretreatment clinical factors were well balanced between the cohorts. There was no significant difference in response to SLT, HDT, event-free or overall survival based on the cell of origin or any of the common pathologic markers examined. The cell of origin as determined by IHC does not predict outcome in transplantation-eligible patients with relapsed or primary refractory DLBCL.

scholarly journals Integration of cell of origin into the clinical CNS International Prognostic Index improves CNS relapse prediction in DLBCL

Blood ◽  
2019 ◽  
Vol 133 (9) ◽  
pp. 919-926 ◽  
Author(s):  
Magdalena Klanova ◽  
Laurie H. Sehn ◽  
Isabelle Bence-Bruckler ◽  
Federica Cavallo ◽  
Jie Jin ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Cell Of Origin ◽  
Cns Relapse ◽  
Relapse Prediction ◽  
Expression Status ◽  
Dual Expression

Abstract Central nervous system (CNS) relapse carries a poor prognosis in diffuse large B-cell lymphoma (DLBCL). Integrating biomarkers into the CNS–International Prognostic Index (CNS-IPI) risk model may improve identification of patients at high risk for developing secondary CNS disease. CNS relapse was analyzed in 1418 DLBCL patients treated with obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy in the phase 3 GOYA study. Cell of origin (COO) was assessed using gene-expression profiling. BCL2 and MYC protein expression was analyzed by immunohistochemistry. The impact of CNS-IPI, COO, and BCL2/MYC dual-expression status on CNS relapse was assessed using a multivariate Cox regression model (data available in n = 1418, n = 933, and n = 688, respectively). High CNS-IPI score (hazard ratio [HR], 4.0; 95% confidence interval [CI], 1.3-12.3; P = .02) and activated B-cell‒like (ABC) (HR, 5.2; 95% CI, 2.1-12.9; P = .0004) or unclassified COO subtypes (HR, 4.2; 95% CI, 1.5-11.7; P = .006) were independently associated with CNS relapse. BCL2/MYC dual-expression status did not impact CNS relapse risk. Three risk subgroups were identified based on the presence of high CNS-IPI score and/or ABC/unclassified COO (CNS-IPI-C model): low risk (no risk factors, n = 450 [48.2%]), intermediate risk (1 factor, n = 408 [43.7%]), and high risk (both factors, n = 75 [8.0%]). Two-year CNS relapse rates were 0.5%, 4.4%, and 15.2% in the respective risk subgroups. Combining high CNS-IPI and ABC/unclassified COO improved CNS relapse prediction and identified a patient subgroup at high risk for developing CNS relapse. The study was registered at www.clinicaltrials.gov as #NCT01287741.

Diffuse Large B-Cell Lymphoma (DLBCL) with Central Nervous System (CNS) Relapse: Prognosis and Risk Factors by Retrospective Analysis from Single Center Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3436-3436
Author(s):  
Yutaka Shimazu ◽  
Takeshi Maeda ◽  
Kenji Notohara ◽  
Takeshi Ito ◽  
Satoko Morita ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cox Regression ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Intrathecal Methotrexate ◽  
Risk Category ◽  
High Dose ◽  
Cox Regression Analysis ◽  
Cns Relapse

Abstract Background: The introduction of rituximab into the therapy of DLBCL has improved the prognosis dramatically. However, relapse in CNS is still the issue. We studied the prognosis and risk factors of CNS recurrence in DLBCL. Method: Between Jan. 1996 and Apr. 2007, 441 patients were diagnosed to have DLBCL in our institute, of whom 31 patients were excluded due to CNS involvement at the time of initial diagnosis. We have analyzed 410 cases, in which 37 cases had relapsed in CNS. Before Sep. 2003, 168 patients were treated with the regimen based on CHOP, and after Sep. 2003, 242 patients were treated with the regimen based on CHOP plus rituximab. Once relapsing in CNS, the patients were treated with systemic chemotherapy plus high-dose methotrexate or radiation with intrathecal methotrexate. The risk category by the international prognostic index of these 411 cases was assessed as low: 36%, low-intermediate: 15%, high-intermediate: 23%, and high: 26%. Results: The median age was 71 years old (range: 17–92). Median follow-up period was 507 days, and the median period free from relapsing in CNS was 331 days. The mean survival period of the cases with CNS relapse, of the cases relapsed outside the CNS, and of the non-relapsed cases was 1328 days, 2290 days, and 2817days, respectively. The overall survival rate of cases with CNS relapse was significantly lower than that of the cases relapsed outside the CNS, or than that of the non-relapsed cases (p=0.0233, p=0.0003, respectively). Multivariate Cox regression analysis identified the increased lactate dehydrogenase (p=0.014), the involvement of more than one extranodal site (p=0.006), and not using rituximab before CNS relapse (p=0.040) as an independent predictor of CNS recurrence. Conclusion: CNS relapse has extremely poor prognosis than relapse outside the CNS in DLBCL. Rituximab may be effective in preventing CNS relapse. Since rituximab poorly penetrates into CNS, this may partly due to the reduction of all recurrence by rituximab. According to the risk assessment in CNS relapse, an effective CNS prophylaxis strategy should be determined.

scholarly journals Prophylaxis with Intrathecal Chemotherapy and High Dose Methotrexate in Patients with Diffuse Large B Cell Lymphoma at High Risk for Central Nervous System Relapse: A Single Centre Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5420-5420
Author(s):  
Dario Marino ◽  
Silvia Finotto ◽  
Caterina Boso ◽  
Federica Vianello ◽  
Benedetta Chiusole ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
High Risk ◽  
Complete Remission ◽  
B Cell Lymphoma ◽  
High Dose ◽  
First Line ◽  
Cns Disease ◽  
Cns Prophylaxis ◽  
Cns Relapse

Abstract Central nervous system involvement (CNS) is a serious and mostly fatal complication of aggressive lymphoma. The incidence of CNS disease in diffuse large B-cell lymphoma (DLBCL) is low (about 5%) and there are not randomised prospective trial which specifically address a decision-making process for CNS prophylaxis. Potentially two methods exist for identifying patients requiring CNS directed treatment. Surveillance lumbar puncture and brain magnetic resonance (MRI) at the time of diagnosis could identify the presence of lymphoma; another method is the identification of patients whose characteristics are indicative of a high risk of CNS disease. Several site-specific risks are described in literature such as testicular, breast, paranasal sinuses, epidural spaces, and intravascular involvement with an incidence of CNS relapse ranging from 15% to 50%. Recently a modified IPI score (CNS IPI) was described to predict risk of CNS relapse. The efficacy of different forms of CNS prophylaxis has never formally been demonstrated. In the RICOVER 60 trial, patients treated with R-CHOP-14 instead of CHOP-14 presented a lower incidence of CNS relapse while intrathecal methotrexate (MTX) has not showed a role in preventing CNS disease for patients treated with combined immunochemotherapy. Recently, combination of intrathecal MTX and high dose MTX infusion after R-CHOP treatment was considered an effective strategy of prevention of CNS relapse. In order to evaluate the efficacy and feasibility of intrathecal MTX administration and high dose MTX after first line chemotherapy, we retrospectively reviewed 27 patients (11 males and 16 females, mean age 61 yrs, range 27-79) with newly diagnosed DLBCL at high risk for CNS relapse, treated from January 2009 to April 2018 at Veneto Institute of Oncology IOV-IRCCS. In our cohort 21 (78%) patients were at advanced stage (III-IV Ann Arbor stage) and 15 (56%) belonged to intermediate-high or high risk IPI categories, two patients presented with orbital localization. Almost all patients received R-CHOP as first line treatments, two patients with paravertebral localization received HyperCVAD as front line approach. For 20 patients CNS-IPI was intermediate or high. In the other cases with low CNS-IPI, disease localization was considered at high risk of CNS relapse (breast, paravertebral, orbit, paranasal sinus). In all patients we performed brain MRI and diagnostic lumbar puncture at diagnosis (all negative at flow cytometry analysis). All 14 patients >65 yrs were evaluated with comprehensive geriatric assessment (CGA) and 8 (57%) were considered fit. Nineteen (19) patients (70%) received at least 3 lumbar punctures with MTX and 24 (89%) two courses of high dose intravenous MTX during first line therapy. At the end of planned first line treatment, 24 (89%) patients obtained a complete remission at PET scan evaluation and 3 patients (11%) presented progressive disease, 2 with CNS involvement and another with peritoneal disease; this last patient had a Double Hit lymphoma with BCL6 and c-MYC rearrangements. Another patient in complete remission after R-CHOP chemotherapy, experienced CNS relapse three year after obtaining complete remission. Among the two patients treated with Hyper CVAD regimen, one is still in complete remission 5 years after the end of treatment; another developed early CNS relapse. All the 3 patient who experienced CNS involvement after R-CHOP, didn't receive prophylaxis because were evaluated frail at CGA. So, at a median follow up of 26.2 months (3.5-100 months) all patients who received the planned treatment at full dose including CNS prophylaxis did not experience central nervous system relapse. In conclusion, CNS prophylaxis including intrathecal MTX administration and high dose MTX infusion after first line chemotherapy is feasible and effective. Larger prospective trials are needed to evaluate the most effective prophylactic therapy and the correct timing of intravenous MTX infusion. Disclosures No relevant conflicts of interest to declare.

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