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.

Effectiveness of intravenous high-dose methotrexate for prevention of relapse in patients with DLBCL.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19562-e19562
Author(s):  
Hind Alotaibi ◽  
Ibraheem Motabi ◽  
Ahmad Butt ◽  
Nawal AlShehry ◽  
Mohammed Marei ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell Lymphoma ◽  
Treatment Evaluation ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Data Set ◽  
Dose Methotrexate ◽  
Cns Relapse ◽  
End Of Treatment

e19562 Background: Central nervous system (CNS) relapse develops in 2-10% of patients with diffuse large B cell lymphoma (DLBCL) and has an adverse prognosis. Tools like IPI and CNS-IPI scores identify patients at high risk of systemic or CNS relapse based on the presence of established risk factors ( Schmitz et al. JCO 2016). International guidelines propose prophylactic intravenous high-dose methotrexate (HD-MTX) for patients at high risk of CNS relapse; however, limited data is backing this approach. Methods: We conducted a retrospective review of newly diagnosed DLBCL patients aged 18-75 years treated with curative intent at large academic medical centers in Riyadh, Saudi Arabia, between 2015-2018. Patients who were planned for CNS HD-MTX after cycles 2, 4, and 6 of R-CHOP and received at least one HD-MTX cycle were included. Results: We identified 35 DLBCL patients who received at least one R-CHOP cycle with one cycle of HD-MTX. The median IPI and CNS-IPI score were 3, (range = 0-4) and 3, (range = 0-5), respectively. The median number of R-CHOP cycles received was 6 (range 3-6) and HD-MTX 3 (range 1-6). The overall response rate was 91%, with 3 (9%) primary refractory patients per interim evaluation on cycle 3 of R-CHOP. Achieving complete remission after six cycles of RCHOP was noted in 80%, with four additional patients showed residual disease at the end of treatment evaluation. The entire cohort's overall survival was not reached, and five years estimated survival is 75%. With a median follow-up duration of 37.3 months, none of the patients relapsed after achieving CR at the end of treatment evaluation. The risk of systemic or CNS relapse in our cohort was 0%. In restricting the analysis to CNS-IPI of ≥ 4, a total of 13 patients with a median follow-up of 42 months were included; four patients did not achieve CR by the end of treatment, while nine patients continue to be in CR without any evidence of relapsed disease. Conclusions: High-dose methotrexate with high-intensity chemoimmunotherapy (R-CHOP) seems to be associated with an improvement in the expected rate of CNS relapse. Our data set is small, and a more extensive study evaluating HD-MTX's effectiveness in high-risk DLBCL is warranted.[Table: see text]

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.

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.

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

2021 ◽  
Vol 11 (8) ◽  
Author(s):  
Shin Yeu Ong ◽  
Sanjay de Mel ◽  
Nicholas Francis Grigoropoulos ◽  
Yunxin Chen ◽  
Yan Chin Tan ◽  
...  
Keyword(s):  
Propensity Score ◽  
B Cell Lymphoma ◽  
Survival Outcomes ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Treatment Groups ◽  
Dose Methotrexate ◽  
Cns Relapse ◽  
Systemic Relapse ◽  
Relapse Rates

AbstractThe 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.

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