Risk Of Central Nervous System Recurrence Research Articles

High-Grade B-Cell Lymphoma, Not Otherwise Specified: CNS Involvement and Outcomes in a Multi-Institutional Series

Little is known about the central nervous system (CNS) risk in high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS). Hence, we sought to describe the rates of baseline CNS involvement, risk of CNS recurrence after primary therapy, and management strategies in HGBL, NOS. In this multicenter retrospective study, we included 160 adults with newly diagnosed HGBL, NOS treated between 2016 and 2021 at 20 US institutions. Eleven patients (7%) had baseline CNS involvement at diagnosis (leptomeningeal=6, parenchymal=4, and both=1). Baseline CNS involvement was significantly associated only with MYC rearrangement (OR=3.5) and testicular (in men) or female pelvic (in women) involvement (OR=8.1). There was no significant difference in survival outcomes between HGBL, NOS patients with (median PFS=4 years) or without (median PFS=2.4 years) baseline CNS involvement (p=0.45). The cumulative incidence of CNS recurrence at 3 years was 11%. Patients with baseline CNS involvement were at the highest risk (48.5% versus 8% for those without baseline CNS involvement) and were excluded from the risk factors analysis for CNS recurrence. The risk for CNS recurrence was significantly associated with blood or bone marrow involvement, CD5 expression, non-GCB subtype, and DEL phenotype, however, high CNS-IPI was not. The prognosis of relapsed HGBL, NOS was poor, regardless of whether recurrence was systemic or limited to the CNS, and with currently available salvage strategies, including autologous transplantation and CAR T-cell modalities, almost all patients with CNS recurrence ultimately succumbed to their disease. These patients represent an unmet need and should be prioritized for experimental approaches.

Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE

In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n= 743) or trastuzumab (n= 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR)= 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR= 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

Patterns and Risk of CNS Recurrence after R-EPOCH Treatment for Double/Triple Hit Lymphoma

Patterns and Risk of CNS Recurrence after R-EPOCH Treatment for Double/Triple Hit Lymphoma

Molecular predictors of central nervous system (CNS) recurrence in diffuse large B-cell lymphoma (DLBCL).

e20082 Background: CNS recurrence is a devastating outcome after treatment of DLBCL. Clinical features poorly predict CNS recurrence risk or the need for prophylactic therapy. We examined whether specific mutational profiles in DLBCL may correlate with the risk of CNS recurrence. Methods: We evaluated DLBCL tumors from patients (pts) with either isolated CNS or systemic (without CNS) recurrence using a 592 gene next generation sequencing (NGS) assay (Illumina NextSeq platform, average coverage depth > 750x; Caris Life Sciences). 3 common molecular subtypes of DLBCL were identified using a simplified classification: (1) MCD subtype ( MYD88L265P or > 2 other mutations in CD79B, PIM1, ETV6, BTG1, TBL1XR1, or PRDM1) , (2) subtype characterized by TP53 mutations (± complex karyotype with multiple structural variants), and (3) GCB subtype characterized by ≥2 mutations in BCL2, CREBBP, EZH2, KMT2D, TNFRSF14, GNA13, MEF2B, or PTEN. We compared prevalence of these subtypes between our groups and unselected DLBCL datasets by Chapuy et al. ( Nat Med; n = 135) and Reddy et al. ( Cell, 2018; n = 1001). We additionally examined clinicopathologic data, including cell of origin, MYC, BCL2 and/or BCL6 rearrangements, and complex karyotype. Results: The study included 26 cases of DLBCL with CNS-only recurrence (n = 13) or systemic-only recurrence (n = 13). We observed no significant difference between these groups in any clinicopathologic characteristics, and no significant difference for mutations in any specific gene (using Fisher’s exact test adjusted for multiple testing). The MCD subtype was more frequent among pts with CNS recurrence (46%) versus systemic recurrence (31%), and was statistically significantly enriched in our CNS recurrence group compared with the unselected DLBCL datasets by Reddy (18%, P= 0.017) or Chapuy (19%, P= 0.030). In contrast, we observed no difference in CNS or systemic recurrence for the TP53 subtype (23% in both groups) or the GCB subtype (15% in both groups), and these proportions were not significantly different compared with the unselected DLBCL datasets ( P> 0.05). Conclusions: In-depth molecular classification of DLBCL using single nucleotide, structural chromosomal, and copy number variants is unfeasible in current clinical practice. Our data demonstrate that a clinically meaningful molecular signature predicting future CNS recurrence could be designed from standard NGS assays using a simplified classification. With further validation, this signature may prove useful for selecting pts for CNS-directed prophylaxis.

LBA4 - Peripheral neuropathy (PN), thrombocytopenia (TCP) and central nervous system (CNS) recurrence: An update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab (H) in patients (pts) with residual invasive HER2-positive breast cancer (BC)

LBA4 - Peripheral neuropathy (PN), thrombocytopenia (TCP) and central nervous system (CNS) recurrence: An update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab (H) in patients (pts) with residual invasive HER2-positive breast cancer (BC)

LBA19 - Peripheral neuropathy (PN), thrombocytopenia (TCP) and central nervous system (CNS) recurrence: An update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab (H) in patients (pts) with residual invasive HER2-positive breast cancer (BC)

LBA19 - Peripheral neuropathy (PN), thrombocytopenia (TCP) and central nervous system (CNS) recurrence: An update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab (H) in patients (pts) with residual invasive HER2-positive breast cancer (BC)

PF302 CENTRAL NERVOUS SYSTEM RELAPSE IN DIFFUSE LARGE B CELL LYMPHOMA: RISK FACTORS AND ROLE OF INTRATHECAL PROPHYLAXIS

Background:Relapse of diffuse large B cell lymphoma (DLBCL) in the central nervous system (CNS) is a devastating event with dismal prognosis. Several risk factors for CNS recurrence have been reported including parameters of the International Prognostic Index (IPI) and involvement of particular extranodal sites by lymphoma. These have been combined into a risk stratification tool termed CNS‐IPI (Schmitz et al, JCO 2016). The method and efficacy of CNS prophylaxis remain controversial.Aims:We analyzed a large single institution cohort of patients with DLBCL treated in the rituximab era and who were candidates to receive intrathecal (i.t.) prophylaxis with methotrexate according to the guidelines of the Italian Society of Hematology (SIE) of 2006. We analyzed risk factors for CNS recurrence and the possible impact of i.t. prophylaxis on CNS recurrence.Methods:From our patient registry, we identified 684 patients with diffuse large B cell lymphoma diagnosed between 1/2006 and 12/2017. Ten patients (1.5%) with CNS involvement at diagnosis were excluded. Fifty‐six patients (8.3%) aged >80 years were not considered candidates for i.t. CNS prophylaxis. In the final analysis, we included 618 patients who were potential candidates for i.t. prophylaxis when risk factors, according to the SIE guidelines, were present. Prophylaxis consisted in 4 cycles of i.t. methotrexate during the first 4 cycles R‐CHOP and was administered to 177 patients (29%). We investigated the incidence of CNS relapse according to CNS‐IPI, involvement of particular extranodal sites and application of i.t. prophylaxis in a competing‐risk analysis with systemic relapses as competing event.Results:Progression‐free survival at 4 years in 618 patients with DLBCL was 72% (95% C.I., 67–75%). We observed 159 events of disease recurrence, of these 16 involved the CNS. CNS relapse involved the brain parenchyma in 10 patients and leptomeningeal infiltration occurred in 6 patients. CNS relapses were observed in 5/227 patients with a CNS‐IPI score 0–1, in 4/286 patients with a CNS‐IPi score 2–3 and in 7/149 patients with CNS‐IPI score ≥4. Considering systemic relapse as competing risk, a CNS‐IPI score ≥4 was only of borderline significance (p = 0.08). Analyzing for involvement of extranodal sites we found that involvement of testes, peripheral blood and kidney/adrenal glands (the latter sites combined with > 3‐fold elevation of LDH) were associated with high risk of CNS relapse (>20%). As these risk factors were independent, they could be combined into a risk model. Patients with at least one risk factor had a 15.6‐fold (95% C.I, 5.1–48.3) risk of CNS recurrence. This risk was not modified by administration of intrathecal prophylaxis.Summary/Conclusion:Involvement of extranodal sites as testes and peripheral blood that are not included in the CNS‐IPI, in addition to kidney/adrenal glands should be considered high‐risk factors for CNS recurrence. Prophylaxis with i.t. methotrexate appears not to be sufficient to contrast this risk.image

Extranodal Diffuse Large B Cell Lymphoma: Molecular Features, Prognosis, and Risk of Central Nervous System Recurrence.

Diffuse large B cell lymphoma (DLBCL) arises from extranodal organs in about 30% of cases. Its prognosis and risk of recurrence in the central nervous system (CNS) vary according to the primary site of origin. Recent studies begin to clarify these differences using molecular classification. Testicular, breast, and uterine DLBCL (as well as possibly primary cutaneous DLBCL, leg-type) share a high prevalence of the non-germinal center B cell (non-GCB) phenotype and the MYD88/CD79B-mutated (MCD) genotype. These biologic features, which resemble primary CNS lymphoma, may underlie their stage-independent propensity for CNS involvement. Management of these lymphomas should involve CNS prophylaxis, preferably using systemic high-dose methotrexate to prevent intraparenchymal recurrence. Involvement of the kidneys, adrenal glands, ovary, bone marrow, lung, or pleura usually indicates disseminated disease, conferring worse prognosis. Involvement of these sites is often associated with high CNS-International Prognostic Index (IPI), concurrent MYC and BCL2 or BCL6 rearrangements, or intravascular lymphoma-risk factors warranting CNS prophylaxis. In contrast, craniofacial, thyroid, localized bone, or gastric lymphomas have a variable prevalence of the non-GCB phenotype and lack MYD88 mutations. Their outcomes with standard immunochemotherapy are excellent, and the risk of CNS recurrence is low. We recommend individualized consideration of CNS prophylaxis based on the CNS-IPI score and anatomical proximity in cases of epidural, orbital, or skull involvement. Rituximab-containing immunochemotherapy is a standard approach for all extranodal DLBCLs. Surgery is no longer required for any primary site, but routine consolidative radiation therapy is recommended for testicular lymphoma. Radiation therapy also appears to be associated with better progression-free survival in primary bone DLBCL. Future studies should better distinguish primary from secondary sites of extranodal involvement, and investigate the association of newly identified genotypes with the risk of CNS or systemic recurrence.

Central nervous system involvement in intravascular large B‐cell lymphoma: A retrospective analysis of 109 patients

Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity with a high incidence of central nervous system (CNS) involvement at diagnosis. To evaluate CNS involvement, particularly recurrence including progression on therapy and relapse of IVLBCL, we retrospectively analyzed 109 patients with IVLBCL receiving chemotherapies with or without rituximab. In 82 patients (75%) without CNS involvement at initial diagnosis, risk of CNS recurrence at 3 years was 25% with a median follow-up in survivors of 39 months (range, 2-158 months). In 27 patients (25%) with CNS involvement at initial diagnosis, risk of CNS recurrence at 1 year was 25% with a median follow-up in survivors of 18 months (range, 10-77 months). Duration from diagnosis to CNS recurrence tended to be short in patients with CNS involvement at diagnosis. No significant difference in risk of CNS recurrence was found between patients receiving chemotherapies with or without rituximab. On multivariate analysis skin involvement at initial diagnosis was identified as a predictive factor for CNS recurrence in patients without CNS involvement at diagnosis (hazard ratio, 5.27; 95% confidence interval, 1.59-17.4; P = 0.007). Survival rate after CNS recurrence at 2 years was 12% in patients without CNS involvement at diagnosis. Central nervous system recurrence is a serious complication in IVLBCL patients and optimal strategies for CNS involvement should be established to obtain further improvements to clinical outcomes in the rituximab era.

Evaluation of Central Nervous System Recurrence of Intravascular Large B-Cell Lymphoma Treated with Rituximab-Containing Chemotherapy

Central nervous system (CNS) recurrence is a serious and usually fatal complication in the clinical course of aggressive lymphoma. Although our recent report suggested that the improvement of clinical outcomes in intravascular large B-cell lymphoma (IVLBCL) by the application of rituximab, the clinical impact of CNS recurrence in IVLBCL is unknown. To evaluate risks and risk factors associated with development of CNS recurrence in IVLBCL, we retrospectively analyzed 106 patients with IVLBCL receiving chemotherapies with or without rituximab, using our recent cohort (Shimada et al. J Clin Oncol. 2008). Clinical outcomes for our cohort were updated as of December 2007. For this analysis, we excluded 21 of 106 patients (20%) with CNS involvement at diagnosis, which was diagnosed by imaging modalities including computed tomography (CT) and/or magnetic resonance imaging (MRI), and/or cerebrospinal fluid (CSF) analysis. In all, 46 patients (54%) and 39 patients (46%) received chemotherapies without rituximab (chemotherapy) and with rituximab (R-chemotherapy), respectively. With a median follow-up for surviving patients of 39 months (range, 2–158 months), 11 of 46 patients (24%) in the chemotherapy group and 7 of 39 patients (18%) in the R-chemotherapy group developed CNS recurrence after beginning chemotherapy. Median duration between diagnosis and CNS recurrence in the both groups was 9 months (range, 1–44 months). Three patients in the each group displayed CNS progression on the initial series of chemotherapies. Risk of CNS recurrence at 3 years reached 29% in the chemotherapy group and 21% in the R-chemotherapy group, respectively (log-rank test, P = 0.41) (shown as figure). In univariate analysis, use of rituximab combined with initial chemotherapies was not identified as favorable predictive factors. In 12 patients who received autologous stem cell transplantation before CNS recurrence, 1 patient developed CNS relapse by the end of the study. Median survival after CNS recurrence was 6 months (range, 1–58 months), and survival rate at 2 years after CNS recurrence was 14%. This study indicates that CNS recurrence remains a critical problem in the rituximab era. Further studies are required to establish the optimal treatment strategy for CNS prophylaxis in IVLBCL. [Display omitted]

Secondary lymphomas of the central nervous system: risk, prophylaxis and treatment

The recurrence of non-Hodgkin lymphoma (NHL) in the central nervous system (CNS) is rapidly fatal in most cases. Highly aggressive lymphomas, such as lymphoblastic and Burkitt lymphomas, carry a high risk of CNS relapse. CNS relapse in intermediately aggressive subtypes, such as diffuse large B-cell lymphoma, is uncommon, but not rare. The risk of CNS relapse in indolent lymphomas is low. Prognostic markers of CNS relapse include elevated serum lactate dehydrogenase levels, the presence of B symptoms, and extranodal involvement at more than one site. Most centers give prophylactic CNS chemotherapy to patients considered at high risk of CNS recurrence. However, definitions of risk factors vary, and there is a lack of consensus regarding prophylaxis indications. More research is needed to define which patients might benefit from CNS prophylaxis at initial treatment and to find the optimal regimen for prophylaxis. A variety of treatments have been used to treat CNS relapse, but current regimens have had little success in extending survival after CNS relapse. Although long-term survival has been reported in a minority of patients with isolated CNS recurrence after treatment with methotrexate, more effective regimens are needed if survival times after relapse are to be prolonged.

Central nervous system recurrence in adult patients with acute lymphoblastic leukemia

Recurrence of acute lymphoblastic leukemia (ALL) in the central nervous system (CNS) confers a poor prognosis, although to the authors' knowledge, only a few studies have analyzed this issue in adults. For the current study, the authors analyzed the frequency, predictive factors, and prognosis of CNS involvement and recurrence in adult patients with ALL who did not receive cranial irradiation for CNS prophylaxis. Four hundred sixty-seven adult patients (age > or = 15 years) with ALL were treated on 4 protocols: ALL-89 (standard-risk and high-risk ALL; n = 108 patients), ALL-93 (high-risk ALL; n = 222 patients), ALL-96 (standard-risk ALL; n = 84 patients), and ALL3-97 (Burkitt leukemia; n = 53 patients). CNS prophylaxis consisted of intrathecal methotrexate, cytarabine, and hydrocortisone together with high-dose systemic methotrexate and cytarabine. The mean age (+/- standard deviation) was 33 years (+/- 16 years), and 272 patients were males. ALL subtypes included an early pre-B phenotype (15%), a common phenotype (45%), a pre-B phenotype (5%), a mature B phenotype (11%), and a T phenotype (24%). CNS involvement at diagnosis was observed in 18 patients (3.9%). Of 159 recurrences, 22 occurred (5.8%) in the CNS (14 isolated and 8 combined). A lactate dehydrogenase level > 1000 U/L was the only factor associated with the risk of CNS recurrence. A complete remission was attained in 7 of 22 patients (32%). The median overall survival after recurrence was 0.7 years for patients with isolated CNS recurrence, 0.13 years for patients with combined recurrence, and 0.41 years for patients with bone marrow recurrence (P = .11). The only 2 survivors underwent stem cell transplantation. The frequency of CNS recurrence in adult patients with ALL who do not receive radiotherapy for CNS prophylaxis was similar to the frequency observed in protocols that included cranial irradiation. A lactate dehydrogenase value >1000 U/L was the only factor found to be associated with CNS recurrence. The prognosis for patients who develop CNS recurrence is poor, identical to that for patients who develop bone marrow recurrence.

Actuarial risk of isolated cns involvement in Ewing's sarcoma following prophylactic cranial irradiation and intrathecal methotrexate

Records of 154 patients with Ewing's sarcoma treated at the National Cancer Institute were reviewed to assess the incidence and risk of developing isolated central nervous system (CNS) Ewing's sarcoma. Sixty-two of the 154 patients had received CNS irradiation and intrathecal (i.t.) methotrexate as part of their initial therapy to prevent the occurrence of isolated CNS Ewing's sarcoma. The risk of developing isolated CNS Ewing's sarcoma was greatest within the first two years after diagnosis and was approximately 10%. The overall risk of CNS recurrence in the group of patients receiving CNS treatment was similar to the group receiving no therapy directed to the CNS. The occurrence of isolated CNS involvement was not prevented by the use of CNS irradiation and i.t. methotrexate. Because of a lack of efficacy to the CNS irradiation regimen, current treatment regimens do not include therapy directed to the CNS.