scholarly journals Secondary CNS Relapse in DLBCL in the Rituximab Era - an Analysis of Prospective Studies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1644-1644 ◽  
Author(s):  
Abhimanyu Ghose ◽  
Harold Kunal Elias ◽  
Gunjan Guha ◽  
Mahender Yellu ◽  
Ria Kundu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Prospective Studies ◽  
T Test ◽  
Population Characteristics ◽  
Cns Prophylaxis ◽  
Cns Relapse ◽  
Study Population ◽  
The Mean ◽  
One Way Anova

Abstract INTRODUCTION CNS relapse in DLBCL carries poor prognosis. Some studies have suggested decreased incidence with rituximab, but there are several others reporting otherwise. We analyzed prospective studies in literature to understand the role of rituximab and CNS prophylaxis in DLBCL, in comparison to CHOP based therapy. METHOD Extensive searches using PUBMED, EMBASE, CENTRAL and major hematology conferences were conducted for prospective studies. The keywords “CNS”, “diffuse large B-cell lymphoma”, “relapse”, “prophylaxis”, “rituximab”, “CHOP” were used. Inclusion: (i) prospective or randomized trials (ii) Entire study population or a significant majority of patients were newly diagnosed DLBCL, (iii) no evidence of CNS involvement at baseline, (iv) use of rituximab-chemotherapy or CHOP-based chemotherapy, (v) have data relevant to our study. Exclusion: (i) retrospective studies, review article or case reports, (ii) exclusively testicular, mediastinal or double hit lymphoma, (iii) HIV positive patients. Data is presented as mean ± standard error of mean. Significant differences (at P<0.05) between groups and couplets were determined by one-way ANOVA and by two-tailed unpaired t-test respectively. Significance of the Kaplan-Meier survival curves was determined using Log-rank (Mantel-Cox) and Gehan-Breslow-Wilcoxon tests. RESULTS The study population characteristics are shown in Table. The mean incidence of CNS relapse with rituximab-chemotherapy (R-CHOP/R-CHOEP) was found to be 5.52% (3.21%-7.73%), while that with CHOP-based chemotherapy alone was 4.43% (3.53% -5.33%). No significant difference was observed by two-tailed unpaired t test (P = 0.94). The median time from diagnosis to CNS relapse was 6.5-7 months. The mean incidence of leptomeningeal, parenchymal and both relapses in the rituximab-chemotherapy group were 38.62(±1.93)%, 57.32(±3.06)%, 5.36(±1.79)% compared to 16.17(±0.44)%, 66.17(±0.44)%, 22.06(±0.41)% with chemotherapy alone. One-way ANOVA also showed that use of rituximab resulted in statistically significant (P<0.0001) differences between the patterns of CNS relapse. About 74.1% of CNS relapses among patients receiving rituximab-chemotherapy were isolated CNS relapse, compared to 69.2% for those receiving CHOP chemotherapy. The mean incidence of CNS relapse with the use of any prophylactic CNS directed therapy was observed to be a significantly (P = 0.044) lower [2.97% (2.32%-3.62%)] compared to that without [6.12% (5.91%-6.335]. Median survival following CNS relapse of 365 days following rituximab based chemotherapy and 75 days after CHOP were significantly different (HR for CHOP use 4.867±0.77 at P<0.05). CONCLUSION Rituximab hasn't significantly decreased overall incidence, but causes less parenchymal CNS relapse. CNS prophylaxis has a definite role in high risk population. There is significantly better survival after CNS relapse in the rituximab era. Abstract 1644. TABLE STUDY Age (yr) Sex (M:F) No. Stage 3/4 IPI int-high/ high (>=3 IPI or >=2 aa IPI) Extranodal (>=2) high LDH Follow up (m) Criteria for CNS prophylaxis Patients receiving CNS prophylaxis (IT=intrathecal, S=systemic) Chemo Tilly 2003 61-69 ACVBP vs CHOP : M 182 vs 177 F 141 vs 135 635 (501 DLBCL) 267 vs 253 210 vs 207 (aa IPI) 155 VS 156 231 VS 241 68 None for CHOP VS ACVBP (IV methotrexate, etop + IT mtx) 323 (ACVBP) 323 ACVBP vs 312 CHOP Feugier 2004 69 M 92 (CHOP-R) vs 107 (CHOP) 202 vs 197 161 vs 157 121 vs 120 61 vs 51 131 vs 132 24 NA no prophylaxis 202 R-CHOP Vs 197 CHOP Bernstein 2009 97/ 225 for CHOP were >60 yrs NR 899 aggressive lymphoma 191/ 225 CHOP 95/ 225 CHOP 81/225 CHOP 146/ 225 CHOP 20 years none for CHOP 121 IT MTX or radiation (24 Gy) 225 CHOP vs ProMACE-CytaBOM vs mBACOD vs MACOP-B Boehme 2009 68 648 vs 569 1217 (944 DLBCL) 687 507 212 602 24 bone marrow, testes, sinuses, orbits, oral cavity, tongue, salivary glands. 475/1217 (IT-MTX) 608 RCHOP Vs 609 CHOP Kim 2012 59.5 NR 564 276 192 193 NR 10.5 ≥1 risk factor 59 IT RCHOP Kumar 2012 56 (prophylaxis) VS 58 (no prophylaxis) male: 74 vs 476 female: 43 vs 396 989 85 vs 454 55 vs 240 66 vs 220 57 vs 372 30 High risk site involvement : orbit, testis, peripheral blood, vertebra, bone marrow, nasal/paranasal sinuses 117/989 IT- 84/117 (AraC/MTX) S--33/117 (MTX) R-CHOP Holte 2013 54 97 vs 59 156 (145 DLBCL) 150 156 41 151 36 everyone 156/156 (S- Ara-c+ MTX) 1 dose of IT-MTX RCHOEP Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Early and Sustained Response to Azacytidine in High-Risk MDS Patients with Monosomy 7 Correlates with Increased Apoptosis and Not CDKN2B Demethylation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2530-2530 ◽  
Author(s):  
Kavita K. Raj ◽  
Alison M. John ◽  
Aloysius Ho ◽  
Nicholas Shaun B. Thomas ◽  
Ghulam J. Mufti
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Complete Remission ◽  
Promoter Methylation ◽  
Annexin V ◽  
T Test ◽  
Bone Marrow Mononuclear Cell ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
The Mean

Abstract Disease progression in MDS is associated with CDKN2B (encodes p15INK4b) promoter methylation and an inhibition of apoptosis. We therefore studied predominantly high-risk MDS patients treated with azacitidine in order to determine whether clinical responses correlated with changes in CDKN2B promoter methylation and bone marrow apoptosis. In all, 24 patients (19 male) with a median age of 66.7 years were treated with azacitidine (75mg/m2/day x 7 days, every 28 days). Patients were FAB RA (n=2), RAEB (n=7), RAEB-T (n=13) and AML (n=2) with 18/24 having an IPSS risk of Int-2 or High. Cytogenetic abnormalities were present in 17 patients (4 patients with monosomy 7; 1 with der(7) as the sole cytogenetic abnormality and 1 as part of a complex karyotype; 4 with trisomy 8; 1 with 11q abnormalities; 1 with 5q-, 1 with 20q, 1 with iso 17p; and the remaining -y or misc). A median of 5 courses of azacitidine was administered (range: 1–13). Complete remission was achieved in 6 patients: 2 with trisomy 8, 3 with monosomy 7, and 1 with der(7). Haematological Improvement (HI) in Platelets occurred in 6 patients, HI-E in 2 patients, and HI-N in 3 patients. Five patients had a reduction in blast percentage. Importantly, even in complete cytogenetic remission bone marrow dysplasia persisted. All patients with monosomy 7/der(7) are in complete remission (median follow up of 10 months) whereas those with trisomy 8 relapsed their response at 2 and 5 months. CDKN2B promoter methylation in patients pre-treatment and at hematological remission was studied by bisulfite genomic sequencing (region: −263 to +243). There was no difference in CDKN2B methylation in CD34+ or CD33+ cells of responders and non-responders (both had low level, heterogeneous methylation patterns). However, CDKN2B was unmethylated in lymphocytes of responders and methylated in non-responders. Demethylation was not evident following treatment. Baseline bone marrow mononuclear cell apoptosis of 16 patients (12 RAEB, 2 RAEB T, 2 AML) analysed by PI/Annexin V staining (6% mean, 4.06% median); was not significantly different from normal controls (2%: mean, 0.77%; median, n=3) (2 sample T-test 0.103). From 12 treated patients, 8 patients responding to azacitidine (6 CR; 2 blast reduction with HI-E major and HI-N major, regardless of cytogenetic subtype), the mean apoptosis at the time of remission (11.61% mean; 9% median) was significantly higher than the mean apoptosis of 1.82% (median, 1.095%) in 4 non- responders (2 sample t-test p = 0.006). Azacitidine treatment induced sustained responses in all patients with monosomy 7, in whom the CDKN2B promoter is unmethylated. We propose that increased bone marrow apoptosis disrupts the leukaemic clone and leads to disease regression to an earlier stage.

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.

Lack of Influence of Rituximab and CNS Directed Prophylactic Therapy on CNS Relapse in High-Risk Diffuse Large B Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1711-1711
Author(s):  
Mahender Yellu ◽  
Ehsan Malek ◽  
Berry Thavalathil ◽  
Tahir Latif
Keyword(s):  
High Risk ◽  
Cell Lymphoma ◽  
Risk Group ◽  
B Cell Lymphoma ◽  
High Risk Group ◽  
Intrathecal Methotrexate ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma ◽  
Cns Relapse ◽  
Standard Risk

Abstract Background/method: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) although uncommon, can be devastating. Conflicting reports have been published regarding the reduction in incidence of CNS relapse in post-rituximabera.We retrospectively identified all the patients with DLBCL who has received rituximab-based chemotherapy at initial presentation in our institute between 2004 and 2014. Patients were divided into two groups, ‘high risk’ group and ‘standard risk’ group, based on following definition. High risk group will have at least one of the following risk factors 1) LDH ≥ 650 U/L 2) Age adjusted International Prognostic Index (IPI) of ≥ 4 3) Involvement of > 1 extra nodal site 4) Involvement of testis 5) Breast 6) Bones 7) Kidneys 8) Adrenal glands 9) Retroperitoneal lymph nodes 10) Para-meninges or 11) Bone marrow. Patients without any of these risk factors were deemed standard risk. Descriptive statistics were used to analyze the incidence of CNS relapse, patient and disease characteristics. Historically reported incidence rates were used for comparison. Results:One hundred and forty two consecutive patients with DLBCL were included in our study. One hundred and twenty two patients received rituximab-based therapy at the initial diagnosis. Forty-nine patients (40%) met the criteria for ‘high risk’ based on the above definition. Seventy-three patients (60%) qualified for standard risk group. Standard risk group received no CNS directed prophylaxis and none of these patients had CNS relapses. Thirty-one of 49 ‘high risk’ patients received CNS prophylaxis, mainly intrathecal methotrexate. Total 5 patients (4.09%) developed CNS relapse. CNS relapse in high-risk group was 10.2% (5/49). Median age at diagnosis in patients with CNS relapse was 53 years. Median time to relapse was 8.76 months. Median survival after the CNS relapse was 9.16 months. Four out of 5 patients received CNS prophylaxis with intrathecal methotrexate or systemic methotrexate or systemic cytarabine or a combination of them. Average number of doses of prophylaxis received by each patient was 3.2 (range 1-7). Only one patient who developed CNS relapse did not receive any CNS directed therapy as prophylaxis. Conclusion:No significant reduction in the incidence of CNS relapse was noted with upfront use of rituximab. Our study confirms that majority of the DLBCL patients do not need CNS directed therapy. For high risk DLBCL patients, we not only need to develop better predictive markers for CNS relapse but also need better CNS directed therapies to prevent this fatal complication of highly curable disease. Disclosures No relevant conflicts of interest to declare.

Long-term evaluation of a CNS prophylaxis trial--treatment comparisons and outcome after CNS relapse in childhood ALL: a report from the Childrens Cancer Study Group.

1987 ◽  
Vol 5 (10) ◽  
pp. 1646-1654 ◽  
Author(s):  
J A Ortega ◽  
M E Nesbit ◽  
H N Sather ◽  
L L Robison ◽  
G J D'Angio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Current Status ◽  
Intrathecal Methotrexate ◽  
Childhood All ◽  
Cns Disease ◽  
Cns Prophylaxis ◽  
Cns Relapse ◽  
Significant Difference

The current status of children with acute lymphoblastic leukemia (ALL) who had developed CNS disease while being treated on protocol CCG-101 was investigated. Seven hundred thirty-six eligible patients were entered into the study between June 1972 and July 1974. All children who were greater than 18 months of age were eligible for randomization to a CNS prophylaxis trial for which one regimen gave only a short course of intrathecal methotrexate (IT MTX) as prophylaxis. All other regimens included radiation therapy as prophylaxis. Current follow-up (median, greater than 10 years) shows no significant difference by standard life-table analysis for ultimate survival, although a substantial excess of CNS episodes occurred on the IT MTX regimen. Of the 675 patients who completed induction therapy and achieved remission in the study, 100 (14.8%) developed CNS disease as the first evidence of relapse. Fifty-five of these 100 had no subsequent CNS episodes. Only 17 of these 55 patients are surviving without further relapses since the CNS episode. The median time to isolated CNS relapse was 457 days. Time to the initial CNS relapse was found to be the most important factor for predicting outcome. Thirty-five of the 55 patients with isolated relapse subsequently relapsed in the bone marrow, and of these, 32 have died. Twenty patients of the 100 with CNS disease as the first evidence of relapse developed two episodes of CNS involvement and 17 of these 20 patients subsequently relapsed in the bone marrow; only one patient survived. Twenty-five patients of the 100 have shown a pattern of chronic CNS disease with multiple CNS relapses. The overall disease-free survival for the 100 patients who developed one or more relapse was only 16%. These data demonstrate that the occurrence of a CNS relapse is an indicator of poor subsequent outcome. Comparison of results of groups receiving different CNS prophylaxis required careful consideration of the entire pattern of relapses and mortality.

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.

Central Nervous System Relapse in Patients with Acute Promyelocytic Leukemia Treated with All-Trans Retinoic Acid and Reinforced Anthracycline Monochemotherapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 592-592 ◽  
Author(s):  
Pau Montesinos ◽  
Jose D. Gonzalez ◽  
Edo Vellenga ◽  
Chelo Rayon ◽  
Ricardo Parody ◽  
...  
Keyword(s):  
High Risk ◽  
High Dose ◽  
Cns Involvement ◽  
Cns Prophylaxis ◽  
Trans Retinoic Acid ◽  
Cns Relapse ◽  
All Trans Retinoic Acid ◽  
High Dose Cytarabine ◽  
Risk Patients ◽  
First Relapse

Abstract Background: Central nervous system (CNS) relapse can complicate the course of patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and chemotherapy, especially of those with high WBC at diagnosis (≥10 × 109/L). While ATRA and anthracyclines do not crosses the cerebrospinal fluid barrier, some trials for APL includes the use of intratechal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. Objectives: Analyze the incidence and characteristics of CNS involvement at first relapse, in patients with newly diagnosed APL treated with ATRA and reinforced anthracycline monochemotherapy, without CNS prophylaxis. Methods: From 1999 to 2005, 564 patients (median age 40 years, range 2-83) were included in the PETHEMA LPA99 trial. Induction therapy consisted of ATRA and idarubicin. Patients in CR received 3 monthly courses of risk-adapted consolidation therapy as follows: “low-risk” patients (WBC <10×109/l and platelets >40×109/l), idarubicin 5 mg/m2/d × 4 (course #1), mitoxantrone 10 mg/m2/d × 5 (course #2), and idarubicin 12 mg/m2/d × 1 (course #3); “intermediate-risk “ (WBC <10×109/l and platelet <40×109/l) and “high-risk” (WBC >10×109/l) patients received ATRA (45 mg/m2/d × 15) in combination with reinforced chemotherapy (Idarubicin 7 mg/m2/d in the course #1 and two days instead of one in the course #3). Maintenance therapy consisted of low-dose oral chemotherapy (mercaptopurine and methotrexate with ATRA). We measured the cumulative incidence (CI) of CNS involvement at first relapse during the course of APL patients who achieved the CR. Results: CR was achieved in 511 patients (91%). The median follow-up of the cohort was 57 months (range 20–94 months). Overall, 52 patients relapsed, of whom 5 presented a first relapse in CNS. In all cases, CNS relapses occurred without bone marrow or other extramedullary involvement. CNS relapses occurred after a median of 14 months (range 10–41 months) from the achievement of CR. At the initial diagnosis, APL were classified, according to the Sanz score, as low-, intermediate- and high-risk, in 0, 2, and 3 patients, respectively. The median WBC at diagnosis was 34.5 × 109/L (range 1.9–68.8 × 109/L), and 4 patients showed a Bcr3 PML-RARalpha isoform. Using a competitive-risk method, the overall 5 year CI of CNS relapse was 1.03%. The 5 year CI of CNS relapse in low-, intermediate- and high-risk patients was 0%, 0.77% and 2.71%, respectively (low- vs high-risk and intermediate vs high-risk; p=0.12 and p=0.11, respectively). The 5 year CI of CNS relapse in patients with Bcr3 and Bcr1 PML-RARalpha isoform was 0.45% and 2.44%, respectively (p=0.12). Conclusion: Despite the lack of intratechal prophylaxis or high-dose cytarabine in the therapeutic schedule of the LPA99 trial, the overall 5 year CI of CNS relapse was very low (1%). Our results does not hold up the systematic use of CNS prophylaxis in APL patients treated with ATRA and reinforced anthracycline monochemotherapy.

Risk-Tailored CNS Prophylaxis In 194 Patients With Diffuse Large B-CELL Lymphoma (DLBCL) Treated In The Rituximab ERA: Risk Definition By Clinical Variables and Ontogenic Stratification

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4365-4365
Author(s):  
Marta Bruno Ventre ◽  
Marco Foppoli ◽  
Giovanni Citterio ◽  
Giovanni Donadoni ◽  
Maurilio Ponzoni ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Risk Group ◽  
High Risk Group ◽  
Low Risk ◽  
Cns Involvement ◽  
First Line ◽  
Clinical Variables ◽  
Cns Prophylaxis ◽  
Cns Relapse

Abstract Background CNS dissemination is an uncommon but lethal event in non-Hodgkin lymphomas. Early detection of CNS disease and a timely and effective CNS prophylaxis are the main strategies to reduce related mortality. However, both the criteria for recognition of lymphoma patients (pts) with increased risk of CNS involvement and the most effective prophylaxis modality remain important, unmet clinical needs. Some international guidelines recommend intrathecal chemotherapy by lumbar injection as exclusive prophylaxis; however, this strategy results in erratic, short-lived drug bioavailability and does not prevent brain parenchymal relapses. Herein, we report a retrospective analysis of the value of clinical variables and immunohistochemical ontogenic stratification in predicting CNS dissemination and of risk-tailored CNS prophylaxis in a mono-institutional series of 194 pts with DLBCL treated in the rituximab era. Methods Consecutive HIV- adults with DLBCL without CNS involvement at diagnosis treated with first-line rituximab-CHOP or similar ± radiotherapy were considered. Primary CNS, mediastinal and cutaneous leg-type lymphomas were excluded. ‘High risk’ of CNS relapse was defined by the involvement of the testis, spine, skull, orbit, nasopharynx, kidney, and/or breast or by IPI ≥2 (including two among extranodal sites ≥2, advanced stage and high serum LDH). DLBCLs were ontogenically subclassified in ‘germinal-centre B-cell-like’ (GCB) and ‘non-germinal-centre B-cell-like’ (non-GC) by immunohistochemistry following the Hans algorithm. Results 194 patients were analyzed (median age 65, range 18-89; M:F ratio 1.1). Risk of CNS relapse was low in 90 pts and high in 104. Low-risk pt did not receive CNS prophylaxis, while 40/104 (38%) high-risk pts received 3-4 courses of methotrexate 3 g/m2 ± intrathecal (IT) liposomal cytarabine (n=30), cytarabine 16 g/m2 in 4 days (n=2) or IT chemotherapy (n=8). In the high-risk group, IPI ≥2 was more common among pts who did not receive prophylaxis (89% vs. 68%; p=0.006), while “high-risk” extranodal lymphomas were more common among pts who did (88% vs. 33%; p= 0.0001). One hundred and forty-one cases were assessable for Hans algorithm: 74 (52%) were GCB and 67 (48%) were non-GCB DLBCL. GCB DLBCLs were significantly associated with low CNS risk (55% vs. 31%; p= 0.004), and normal LDH levels (57% vs. 36%; p= 0.02); ontogenic stratification was not associated with high-risk extranodal sites, IPI ≥2, bone marrow infiltration, stage and systemic symptoms. After first-line treatment, 160 pts achieved a CR (82%; 95%CI= 77-87%), 34 pts had PD. At a median follow-up of 60 months (13-156), a single low-risk pt and 9 high-risk pts (1% vs. 9%; p= 0.016) experienced CNS relapse (exclusive site in all cases; brain in 5 pts, meninges in 5), with a median TTP of 12 months (7-55). CNS relapses occurred in 3 pts with IPI ≥2, in 1 pt with extranodal disease (testis) and in 5 pts with both features (kidney 3; testis, orbit). Ontogenic stratification was not associated with CNS recurrence, which was 5% for GCB and 6% for non-GCB; these figures were confirmed when analysis was limited to high-risk pts managed without prophylaxis. In the high-risk group, CNS relapses occurred in 7/64 (11%) pts who did not receive prophylaxis, in 2/8 (25%) pts who received only IT chemotherapy, whereas no CNS relapses were detected in the 32 pts treated with intravenous (IV) prophylaxis. CNS relapse rate was 13% for pts treated with “inadequate” prophylaxis (none or IT only) and 0% (p= 0.03) for pts managed with IV prophylaxis. Eight pts with CNS relapses died of lymphoma after 7-37 months (median 12), which represented 28% of all lymphoma-related deaths (n=29) in the high-risk group. Pts treated with IV prophylaxis had a significantly better OS than the other high-risk pts (5-yr: 94 ± 7% vs. 49 ± 6%; p= 0.001). Conclusions Stratification by specific extranodal sites and IPI is superior to ontogenic stratification to recognize CNS risk groups in DLBCL. However, the low sensitivity of predictive clinical variables suggests that molecular studies focused on the predictive and pathogenic role of molecules involved in CNS tropism will contribute to a more accurate definition of lymphoma candidates for CNS-directed strategies. In this context, IV high-dose methotrexate-based prophylaxis may significantly reduce CNS failures in high-risk pts. Disclosures: No relevant conflicts of interest to declare.

Risk Factors for CNS Relapse Among Patients with DLBCL Treated with EPOCH-R

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1500-1500 ◽  
Author(s):  
Mary Kathryn Malecek ◽  
Shaina Rozell ◽  
Benjamin A. Chu ◽  
Trifilio Steve ◽  
Natalie Galanina ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Research Funding ◽  
Bone Marrow Involvement ◽  
B Cell Lymphoma ◽  
Cns Prophylaxis ◽  
Upper Limit ◽  
Cns Relapse ◽  
Increased Risk ◽  
Ecog Ps

Abstract Background: Central nervous system (CNS) relapse in pts with aggressive non-Hodgkin lymphoma (NHL) is a generally fatal complication, with median overall survival (OS) of less than six months (Abramson et al., 2010). Several studies have identified features associated with increased risk of CNS relapse, such as extranodal (EN) sites of disease, elevated lactate dehydrogenase (LDH), presence of B symptoms, and bone marrow involvement (Bernstein et al., 2009; van Besien et al., 1998). Moreover, multivariate analyses have suggested that LDH greater than 3x upper limit of normal (ULN) is strongly associated with increased risk of death or progression among patients with aggressive NHL (Zhou et al., 2014). Despite little evidence on its true efficacy, prophylaxis (ppx) intrathecal (IT) chemotherapy, most frequently with methotrexate (MTX), is often used to among pts thought to be at high risk for CNS relapse. Data on efficacy or need for CNS prophylaxis in patients receiving infusional therapy with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (R-EPOCH) is not available. As R-EPOCH, is being increasingly used in pts with lymphoma, we sought to evaluate the role of IT chemotherapy when used with this regimen. Methods: We conducted a retrospective chart review analysis of patients with diffuse large B-cell lymphoma (DLBCL) who received R-EPOCH as frontline therapy, between 2005 and 2014. Use of IT ppx was at the discretion of the treating physician. We excluded patients under the age of 18, those receiving fewer than two cycles of R-EPOCH, those with CNS involvement at time of diagnosis, and those who received high-dose intravenous CNS ppx. Two-tailed Fisher's exact test was used to determine whether any of the following baseline features was associated with risk of CNS relapse: age>60, ECOG PS>1, LDH>normal and/or >3x ULN, presence of B symptoms, two or more EN sites, anatomic location of EN sites, international prognostic index (IPI) score > 1, bone marrow involvement, and HIV infection. In order to determine whether IT ppx was associated with any improvement in CNS and/or systemic control of disease, we compared, using Kaplan-Meier survival curves with log-rank analyses, the patterns of overall survival (OS), progression-free survival (PFS), and freedom from CNS progression (FFCP, in which death is not counted as an event) between patients receiving IT ppx and those not receiving it. Results: We identified 117 patients for analysis. Median age was 53 (range 19-80). 26% had ECOG PS>1; 76% had LDH above upper limit of normal (ULN). 38% had two or more EN sites of disease, and 68% had stage III-IV disease. 62 patients received IT ppx, and 55 did not. Of those receiving IT ppx, 95% received MTX, with the remainder receiving cytarabine. Those receiving IT ppx were more likely to have >1 EN site of disease, and IPI score >1 (Table 1). A total of seven had observed CNS relapse, occurring at a median of 6 months from time of NHL diagnosis (range 2-24 months). At a median follow up of 18 months, the 24-month PFS and OS were 80% and 83%, respectively. Median PFS and OS were not reached. The only factors associated with increased risk of CNS relapse were genitourinary EN disease and LDH >3x ULN (Table 2). There were no significant differences in OS, PFS, or FFCP among patients who did and did not receive CNS prophylaxis (Figure 1, panels A-C). Conclusions: The risk of CNS progression among DLBCL patients receiving R-EPOCH was similar to previous reports with R-CHOP, at 6%. GU location of EN disease and LDH >3xULN were associated with increased risk of CNS relapse. IT ppx was not associated with improved outcomes. Despite the common use of IT PPX in pts treated with R-EPOCH, our data suggest that this practice might not impact CNS progression and/or relapse, though randomized studies would be needed to answer this. Such studies are warranted in order to better determine what factors are associated with CNS progression, and whom, if anyone, may benefit from IT ppx. Figure 2. Figure 2. Disclosures Nabhan: Celgene Corporation: Honoraria, Research Funding. Petrich:Seattle Genetics: Consultancy, Honoraria, Research Funding.

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