scholarly journals Focal, Symptomatic Bone Marrow Lesions in Waldenström Macroglobulinaemia Characterised By Dense Infiltration with Lymphoplasmacytic Lymphoma: A Newly Defined Indication for Systemic Treatment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-4
Author(s):  
Suzanne Arulogun ◽  
Maaz Ali Abbasi ◽  
Sabine Pomplun ◽  
Aideen Therese O'Neill ◽  
Simon Wan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Systemic Treatment ◽  
Low Grade ◽  
High Grade ◽  
Lymphoplasmacytic Lymphoma ◽  
Ct Guided ◽  
Bone Marrow Lesions ◽  
High Grade Transformation ◽  
Skeletal Pain

BACKGROUND Waldenström Macroglobulinaemia (WM) is an indolent, IgM-producing lymphoplasmacytic lymphoma (LPL) that infiltrates bone marrow (BM) and other tissues. Only symptomatic patients (with IgM-related complications, cytopenias, constitutional symptoms, bulky extramedullary disease) require treatment. Symptomatic BM lesions are not a recognised manifestation of WM and, if present, may raise the possibility of high-grade transformation. AIMS To characterise the clinical, radiological and histological features of focal bone marrow lesions (FBML) identified in WM patients with unrelenting pain in bones and/or joints, and outline implications for treatment. METHODS This study retrospectively reviewed investigations performed at the time of FBMLpresentation, including MRI of the site of pain, total body FDG-PET/CT, review of histology from BM trephine biopsy of the posterior superior iliac spine (PSIS) and CT-guided core biopsy of the identified FBML, and routine blood panels. RESULTS The 6 patients identified (Table 1) presented with localised skeletal pain at different stages of their WM disease course: 1 at initial WM diagnosis, 1 after 10 years of observation, 3 in remission following R-chemotherapy, and 1 during active treatment with R-chemotherapy. Median age at diagnosis of WM was 57 years (41-64 years). Median time from diagnosis to presentation with FBML was 28 months (0-120 months). MRI demonstrated well-defined areas of abnormal signal within the medullae of symptomatic bones and no evidence of cortical or trabecular bone involvement (Fig. 1A), with T1 hypointensity, diffusion restriction and mild STIR hyperintensity in excess of background BM changes. The FBML showed a predilection for the lower limbs (knees, ankles and/or feet involvement in 3 patients, 50%) and periarticular spaces (5 patients, 83%). They were CT-occult and only mildly FDG-avid. In all cases, core biopsies of the FBML showed heavy BM infiltration with diffuse interstitial infiltrate of small, mature lymphocytes (Fig. 1B, 1C) expressing CD20, CD79a and IgM; CD138 staining highlighted scattered interstitial plasma cells (<10%). There was no evidence of infarct or high-grade transformation. When compared to contemporaneous PSIS biopsies (Fig. 1D, 1E), all FBML demonstrated significantly higher proportions of lymphoid infiltration into the haematopoietic space (80-100% vs 0-80%, p=0.03), confirming FBML represent heavier disease infiltrationthan the background BM disease burden. On blood panels, LDH, ALP and platelet count were normal and Hb was >100g/L in all but the 1 patient with active WM (who had Hb 79g/L and ALP 149IU/L). There was no corresponding rise in paraprotein at the time of FBML presentation. In all cases, the detection of FBML prompted initiation/escalation of systemic treatment despite no evidence of progression using conventional criteria; this resulted in resolution of pain and disappearance of the T1 hypointense lesions on MRI in all cases. CONCLUSION Painful, LPL-dense, infiltrative lesions confined to the BM of affected appendicular bones are an unreported manifestation in WM. They are clinicopathologically different from the osteolytic lesions seen in myeloma and the painless, diffuse BM infiltration seen in low-grade lymphomas and can induce unrelenting focal skeletal pain. Based on our findings, such cases should be evaluated for focal bone marrow lesions; MRI is the preferred modality as lesions are CT-occult. They do not necessarily represent high-grade transformation. This small yet comprehensive series suggests they constitute a hitherto undescribed novel indication for systemic therapy irrespective of the general disease status. Disclosures D'Sa: Janssen:Honoraria, Research Funding;BeiGene:Honoraria, Research Funding;Sanofi:Honoraria.

Interim Positron Emission Tomography-Computed Tomography (PET-CT) Is Predictive of Post-Therapy Outcome in High Grade Transformation of Low Grade Lymphoproliferative Disorders

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5038-5038
Author(s):  
Louise Imlay-Gillespie ◽  
David Simon Kliman ◽  
Kelly Wong ◽  
Christopher Arthur ◽  
Luke Coyle ◽  
...  
Keyword(s):  
Research Funding ◽  
Metabolic Response ◽  
B Cell Lymphoma ◽  
Low Grade ◽  
High Grade ◽  
Interim Pet ◽  
Pet Ct ◽  
High Grade Transformation ◽  
Post Therapy ◽  
Initial Staging

Abstract Background PET-CT has become an essential tool in the management of Lymphoma. PET-CT is utilized in both the initial staging of lymphoma as well as assessing treatment-response. High grade transformation of a low grade lymphoproliferative disorder (LPD) is associated with a poor prognosis. Patients (pts) are usually treated with standard of care for Diffuse Large B-Cell Lymphoma (DLBCL) with R-CHOP but generally have poorer outcomes and can experience relapse of either low or high grade disease. To our knowledge, PET-CT has not been evaluated as a prognostic tool for the subgroup of transformed DLBCL. Methods A retrospective audit was performed of patients treated at Royal North Shore Hospital in Sydney, Australia between 2003-2012. Pts were included if they were treated with Rituximab for DLBCL during the study period and if this occurred on a background of low-grade LPD. Clinical data including LPD type, initial staging, treatment and outcomes were also collected. Treatments were stratified into standard R-CHOP-like versus more intensive regimens including Hyper-CVAD and dose-adjusted R-EPOCH. PET-CT reports were reviewed at staging, interim and post-therapy time points and outcomes stratified to complete metabolic response (CR), partial metabolic response (PR) and progressive disease (PD),based on the nuclear medicine physician's report. Results 64 pts were identified in the study period with median follow up 4.4 yrs (range, 50d-11yrs)Male:female ratio was 1:1. Median age was 65 yrs (range 30-89). LPD diagnosis included Follicular Lymphoma (FL) (75%), Chronic Lymphocytic Leukemia (CLL) (6%) and others (19%) that included Mucosa Associated Lymphoid Tissue and Marginal Zone Lymphomas. 39 pts (61%) had PET-CT reports available for review. 45 pts (70%) were treated with R-CHOP with the remainder having more intensive regimes. 26% of pts received consolidation radiotherapy. 13 pts (20%) underwent autologous and 6 (9%) proceeded to an had an allogeneic transplant. 3 yr OS and EFS was 89% and 73% respectively. Univariate analysis demonstrated both interim and post therapy PET-CT to be significant for both OS and EFS (p<0.01) with three groups identified; CR, PR and PD with 3 year OS for negative interim PET of 100%, 91% and 0% accordingly. CR on end of therapy CT was associated with improved OS (p<0.05) but not interim CT (p=0.967). On multivariate analysis interim PET-CT was the strongest independent predictor for EFS but not OS (p < 0.05). Discussion PET-CT is an invaluable tool in the management of LPD. This retrospective review demonstrates the utility of interim PET-CT in the prognostication of pts with transformed LPD. Larger prospective studies should be considered using PET-CT to more accurately stratify treatment for pts with transformed LPD. Figure 1. Figure 1. Disclosures Imlay-Gillespie: Novartis: Honoraria. Arthur:Amgen: Honoraria; Amgen: Honoraria; BMS: Honoraria. Mackinlay:Sanofi Aventis: Research Funding; Roche: Research Funding. Mulligan:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Sanofi Aventis: Research Funding; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

High Grade Transformation in Splenic Marginal Zone Lymphoma: A Description of a Series of 8 Cases.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4599-4599
Author(s):  
Moez R. Dungarwalla ◽  
Andrew Wotherspoon ◽  
Gareth Morgan ◽  
Daniel Catovsky ◽  
Claire E. Dearden ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Low Grade ◽  
Splenic Marginal Zone Lymphoma ◽  
High Grade ◽  
Large B Cell Lymphoma ◽  
High Grade Transformation ◽  
Large B Cell

Abstract Splenic marginal zone lymphoma (SMZL) without or with villous lymphocytes (SLVL) is a low grade B cell non-Hodgkin’s lymphoma that comprises &lt;1% of lymphoid malignancies. SLVL is indistinguishable histologically from SMZL and it is believed that the 2 entities represent different phases of the same process in the spleen and the bone marrow. Characteristic features of SMZL are splenomegaly, moderate lymphocytosis, immunophenotype with a CLL score &lt; 2 and nodular/intrasinusoidal pattern of bone marrow infiltration. Despite its slow clinical course, and response to splenectomy, approximately 50% of deaths in patients with SMZL are caused by progressive disease. As in other low grade lymphoproliferative disorders, SMZL may undergo high grade transformation. We describe 8 cases of SMZL that showed clinical, morphological and histological features of progression to large B cell lymphoma. These 8 cases represent 19% of our series of 41 SMZL patients followed up between 1996 and 2006. Patients were aged between 44 and 76 years, and there were 4 men and 4 women. Progression to high grade B cell lymphoma occurred between 1 and 48 months from diagnosis. The cases can be divided into 2 distinct groups on the basis of the site of transformation. Those cases with high grade transformation in the bone marrow had a median overall survival of 10 months, although 1 patient did attain a complete remission with combination chemotherapy (R-CHOP) and is alive at 12 months. In contrast, there were 3 cases of transformation in peripheral lymph nodes with a median overall survival of 60 months. Large B cell lymphoma was also diagnosed in the spleen in the initial stages of the disease in 1 case. This patient achieved a complete remission with R-CHOP post splenectomy, and is still alive at 36 months follow up. In a previous report of transformation to large B cell lymphoma in SMZL (Camacho et al, Am J Surg Pathol 2001) a 13% incidence was reported. In our series of 8 cases the incidence of transformation is 19%. Hence it appears that while the incidence of large B cell transformation seems to be higher than in CLL (1–10%) it is lower than that reported in follicular lymphoma (25–60%). Two of the 4 cases of high grade transformation in the bone marrow had previously been treated with fludarabine in the year prior to their progression to large B cell lymphoma. In 1 of these cases Epstein Barr Virus encoded RNA was detected in the malignant cells at the time of transformation. This may suggest that EBV is involved in the pathology of SMZL transformation, and treatment with immunosuppressive agents such as the purine analogues, may increase this risk. In our series of 41 patients, 6 have received fludarabine therapy and the risk of high grade transformation in this small group is significantly higher at 33% (2/6).

Bone marrow involvement by non-Hodgkin's lymphoma: the clinical significance of morphologic discordance between the lymph node and bone marrow. Nebraska Lymphoma Study Group.

1990 ◽  
Vol 8 (7) ◽  
pp. 1163-1172 ◽  
Author(s):  
M G Conlan ◽  
M Bast ◽  
J O Armitage ◽  
D D Weisenburger
Keyword(s):  
Bone Marrow ◽  
Lymph Node ◽  
T Cell ◽  
Cell Lymphoma ◽  
Bone Marrow Involvement ◽  
Large Cell ◽  
Small Cell ◽  
Low Grade ◽  
High Grade ◽  
Lymphoid Aggregates

Bone marrow specimens from 317 patients with non-Hodgkin's lymphoma (NHL) obtained at initial staging were evaluated for the presence of lymphoma or benign lymphoid aggregates. Thirty-two percent (102 patients) had lymphoma in their bone marrow, and 9% had benign lymphoid aggregates. Bone marrow lymphoma was present in 39% of low-grade, 36% of intermediate-grade, and 18% of high-grade lymphomas. The bone marrow was involved in 25% of patients with diffuse large-cell or immunoblastic NHL (ie, diffuse histiocytic lymphoma of Rappaport). Bone marrow involvement did not affect survival of patients with low-grade NHL, but survival was significantly shorter (P = .03) for patients with intermediate- and high-grade NHL with bone marrow involvement. Bone marrow involvement was equally common in B-cell and T-cell NHL (31% v 32%). However, patients with T-cell NHL and bone marrow involvement had shorter survival than B-cell NHL with marrow involvement (P = .02) or T-cell NHL without marrow involvement (P = .05). A high incidence of morphologic discordance between lymph node and bone marrow was observed (ie, 40%), always with a more aggressive subtype in the lymph node than in the bone marrow. Presence of large-cell lymphoma in the bone marrow predicted for short survival. Survival for patients with small-cell lymphoma in their bone marrow did not differ significantly from patients with negative bone marrows. We conclude that bone marrow involvement in large-cell NHL, especially in those of T-cell origin, portends a poor prognosis. However, the subgroup of patients with an aggressive histologic subtype of NHL in a lymph node biopsy and small-cell NHL in the bone marrow do not have a poorer outlook than those without bone marrow involvement.

High-grade Transformation of Low-grade B-cell Lymphoma

2016 ◽  
Vol 40 (1) ◽  
pp. e1-e16 ◽  
Author(s):  
Rose Lou Marie C. Agbay ◽  
Sanam Loghavi ◽  
L. Jeffrey Medeiros ◽  
Joseph D. Khoury
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Low Grade ◽  
High Grade ◽  
High Grade Transformation

Morphologic and Phenotypic Features of Concurrent Clonal T-Cell Large Granular Lymphocytic Expansion and Myelodysplastic Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2803-2803
Author(s):  
Xiaohui Zhang ◽  
Lynn Moscinski ◽  
John M. Bennett ◽  
Reza Setoodeh ◽  
Deniz Peker ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
T Cell ◽  
Peripheral Blood ◽  
Low Grade ◽  
Gene Rearrangements ◽  
High Grade ◽  
Bone Marrow Cellularity ◽  
Hla Dr ◽  
Marrow Cellularity

Abstract Abstract 2803 Myelodysplastic syndrome (MDS) and T-cell large granular (T-LGL) leukemia are both bone marrow failure disorders. It has been reported in a small number of cases that clonal T-LGL proliferation or leukemia can coincidentally occur with MDS. Also, clonal CD8+/CD57+ effector T cells expansion was detected in as many as 50% of MDS bone marrows [Epling-Burnette, 2007]. How clonal LGL cells that reside in the bone marrow interfere with hematopoiesis remains unclear, particularly in the setting of MDS. We analyzed the clinicopathological features of concomitant MDS and T-LGL, and evaluated bone marrow status for lineage or pan-hypoplasia in these patients. Design: Clinical and pathologic data from patients with a diagnosis of MDS and flow cytometry performed on the peripheral blood between 1/2005 and 12/2009 were reviewed. The concurrent bone marrow biopsies from each patient at the time of flow cytometric analysis were reviewed by two hematopathologists. Bone marrow cellularity, lineage hypoplasia (M:E >5: 1 or <1:2) were documented. Peripheral lymphocyte count and CD3+/CD57+ and CD8+/CD57+ populations by flow cytometry were calculated and T cell gene receptor (TCR) rearrangements were correlated. Results: We performed LGL flow cytometry panel on 76 MDS patients (high grade MDS, n=23; low grade, n=54), as well as TCR gene rearrangements, and identified clonal T-LGL cells in peripheral blood of 37 patients (48.7%), including 15 high grade MDS (40.5%, RAEB-I and RAEB-II), and 22 low grade MDS (59.4%), including RCMD(13), RA(1), RS(1), RCMD-RA(1), RCMD-RS (2), 5q- MDS(1), and MDS unclassifiable(3). The immunophenotype of the T-LGL cells was typically CD3+/CD57+/CD7 dim+/CD5 dim+/CD8+ with variable CD11b,CD11c, CD16, CD56 and HLA-DR. A frequent variant in these MDS patients was CD11b-,CD11c -, CD16+/−, CD56+/−, HLA-DR- and CD62L+.The TCRβ or/and TCRγ gene rearrangements were positive in 35 of the 38 cases (92.1%). The peripheral blood lymphocyte counts were 300–3820 cells/μL (1199±799 cells/μL); the CD3+/CD8+/CD57+ T-LGL cell counts were 30–624 cells/μL (229±154 cells/μL). In comparison, the remaining 39 patients with non-clonal T-LGL included 11 high grade MDS cases, and 28 low grade MDS cases. The peripheral blood lymphocyte counts were 308–2210 cells/μL (1030±461 cells/μL). CD3+/CD57+ cells were 1–425 cells/μL (105±98 cells/μL). There was no identifiable phenotypic features suggestive of clonal T-LGL cells such as dim CD5 and/or dim CD7 with aforementioned aberrant expressions on T-cells, although 7 of the 39 cases had TCRβ or/and TCRγ gene rearrangements. Thirty healthy donors were included for controls with absolute lymphocyte counts of 2136±661 cells/μL and baseline CD3+/CD57+ cells of 162±109 cells/μL. All showed no clonal LGL phenotype and negative TCR gene rearrangements. Since the presence of T-LGL cells may impair bone marrow hematopoiesis, we examined if there are bone marrow status differences between these two groups. All the bone marrows were obtained at diagnosis or not on chemotherapy. The bone marrow cellularity of the MDS patients with clonal T-LGL ranged from <3% to almost 100%, averaging 56%, with 8 cases with dramatic hypocellularity (<3%-20%), while the bone marrow cellularity of the MDS patients without clonal T-LGL ranged from 20% to 90%, averaging 62%, with only 2 cases with mild hypocellularity (20% in 73- and 65-year-old). In addition, among MDS patients with clonal T-LGL cells, 14 of 37 (37.8%; 5 high grade, and 9 low grade) bone marrows had certain lineage hypoplasia, including 3 cases of trilineal hypoplasia, 9 cases of erythroid hypoplasia, and 2 cases of myeloid hypoplasia. In contrast, among 39 MDS patients without T-LGL, there were only 1 bone marrow with trilineal hypoplasia and 3 others with erythroid hypoplasia (10.2%). The difference between the two groups was statistically significant (p=0.004, chi square test). In conclusion, our studies indicate that clonal T-LGL cells expansion is a fairly common finding in high grade as well as low grade MDS. The clonal T-LGL cells have more than one variant immunophenotypes and are typically positive for TCR gene rearrangements. Additionally, we observed that the clonal LGL cells present in MDS bone marrows could be associated with lineage hypoplasia, which, in this respect, might impact clinical treatment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Evolution of the Tumor Microenvironment throughout Progression and Transformation of EZH2 Mutant Follicular Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 446-446
Author(s):  
Yusuke Isshiki ◽  
Dylan McNally ◽  
Ari M. Melnick ◽  
Wendy Béguelin
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cells ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
Cell Line ◽  
Immune Cells ◽  
Research Funding ◽  
Low Grade ◽  
Lymphoma Cells

Abstract The genetic hallmarks of follicular lymphomas include BCL2 translocations and somatic mutations of epigenetic modifier genes such as EZH2. Histologically, FLs typically feature a rich microenvironment, most notably featuring extensive follicular dendritic cell (FDC) networks with dendrites making extensive contact with lymphoma cells. In recent work we showed that the main effect of EZH2 gain-of-function mutations in GC B-cells is to enable them to become less dependent of T-cell help and strengthen their immune synapse formation with FDCs, which induces aberrant proliferation and survival of GC centrocytes and hence formation of a unique lymphoma-permissive immune niche. However, it is still unknown how interactions between EZH2 mutant GC B-cells and other immune cells change throughout the progression of the disease. To evaluate the evolution of the tumor microenvironment (TME) throughout EZH2 mutant lymphoma progression, we developed a genetically engineered mouse model designed for conditional expression of gain-of-function Ezh2 mutant and BCL2 in GC B-cells, Rosa26 LSL.BCL2.IRES.GFP;Ezh2 Y641F;Cγ1Cre (hereafter BCL2/Ezh2 Y641F), in which Cγ1-driven Cre excision of a STOP cassette in the Rosa26 locus leads to overexpression of BCL2 and GFP, and expression of the endogenous Ezh2 mutant Y641F. This mouse model develops low-grade follicular-like lymphoma, characterized by expanded follicles composed largely of centrocyte neoplastic GC B-cells and extensive FDC meshwork, along with presence of CD4 +, TFH and regulatory T cells (FOXP3 +), as depicted by multiparametric in situ imaging and multiparametric flow cytometry. At cytological level, cells are predominantly small with condensed chromatin, irregular nuclei, scant cytoplasm, and inconspicuous nucleoli, without sheets of large cells. Over time, these low grade FLs progress to advanced grade, characterized by disruption of follicle structures, expansion of centroblast-like large tumor cells and reduced CD4 + T cell infiltration and FDC meshwork. Furthermore, we have developed a murine transformed FL cell line by sequential passages of an original BCL2/Ezh2 Y641F low-grade FL into immunodeficient Rag1KO mice. We have transduced this BCL2/Ezh2 Y641F cell line with luciferase, and it successfully engrafted and homed to lymphoid organs when injected i.v. into immunocompetent C57BL6 mice. The cell line consists of high proliferative GC B-cells with multiple and irregular nuclei, open chromatin and prominent nucleoli that resemble DLBCL. The microenvironment of tumors developed in C57BL6 mice is characterized by disruption of follicle structures, severe reduction or absence of FDC meshwork, decreased CD4 +, CD8 + and Tregs, downregulation of MHC-I and MHC-II. Therefore, our mouse model also recapitulates progression and transformation stages. Since MYC translocations are frequent events that occur during histological transformation of FL, we modeled this more aggressive EZB MYC subtype of DLBCL. For that, we further crossed our BCL2/Ezh2 Y641F mice to Rosa26 LSL.MYC.IRES.hCD2. We generated cohorts of transplanted mice by injecting bone marrow cells from BCL2, BCL2/Ezh2 Y641F, BCL2/MYC, and BCL2/Ezh2 Y641F/MYC mice into lethally irradiated C57BL6 recipients. Recipient mice (n=5 per group) were immunized with SRBC to induce formation of GCs and sacrificed 5.5 months post bone marrow transplant. All genotypes showed expansion of FAS +CD38 -BCL2 GFP+ GC B-cells in spleen and lymph nodes; however, the proportion of GC B-cells in Ezh2 Y641F was significantly increased compared with Ezh2 WT, in both presence and absence of MYC. In contrast, FAS -CD38 +BCL2 GFP+ and CD138 +BCL2 GFP+ cells were significantly increased in MYC + mice and decreased in Ezh2 Y641F, suggesting that Ezh2 mutation is required to maintain the GC phenotype. The acquisition of Ezh2 Y641F in BCL2/MYC mice induced a reduction of CD4 + and CD8 + in the TME, and decreased TFH without changes in TFR proportions in GCs. Strikingly, FDC meshwork was significantly shrank in MYC + cases, and partially restored by acquisition of Ezh2 Y641F, indicating that MYC overexpression may contribute to acquire FDC independency for the survival of lymphoma cells. Our results indicate that progression of FL critically affects the TME and acquisition of additional mutations such as MYC alters the interactions between lymphoma cells and tumor supportive immune cells in TME. Disclosures Melnick: Epizyme: Consultancy; Janssen: Research Funding; KDAC Therapeutics: Current holder of individual stocks in a privately-held company; Celgene Corporation: Consultancy; Constellation Pharmaceuticals: Consultancy; Astra Zeneca: Consultancy; Daiichi Sankyo: Consultancy; Exo Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi US Services: Research Funding.

Results of a phase 2 trial of ribociclib and letrozole in patients with either relapsed estrogen receptor (ER)-positive ovarian cancers or relapsed ER-positive endometrial cancers.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5510-5510 ◽  
Author(s):  
Gerardo Colon-Otero ◽  
S. John Weroha ◽  
Valentina Zanfagnin ◽  
Nathan R. Foster ◽  
Erik Asmus ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Estrogen Receptor ◽  
Low Grade ◽  
Favorable Result ◽  
High Grade ◽  
Phase 2 ◽  
Ct Guided ◽  
Er Positive ◽  
Endometrial Cancers ◽  
Tumor Biopsies

5510 Background: Single agent aromatase inhibitor (AI) therapy is associated with limited clinical activity in ovarian cancer (OC) and endometrial cancers (EC). AI therapy was associated with a progression free survival (PFS) at 12 weeks of only 20% in relapsed OC (Bowman et al, 2002) and a median PFS of 1 month in relapsed EC (Rose et al, 2000). In Estrogen Receptor (ER) positive metastatic breast cancer, clinical studies had shown a significant prolongation of PFS with the addition of the cyclin kinase 4/6 inhibitor ribociclib to AI (Hortobagyi et al, 2016). Here, we report the results of a phase 2 clinical trial of the combination of ribociclib and letrozole in patients with relapsed ER positive OC or EC. Objectives: Primary endpoint was the proportion of patients with relapsed ER positive OC or EC alive and progression-free after 12 weeks of therapy (PFS12) with the combination of ribociclib given at a dose of 400 mg orally daily and letrozole 2.5 mg orally daily. A PFS of 45% was considered a favorable result based on the data referenced above from Bowman et al. Methods: Eligibility criteria included patients with relapsed ER positive OC or EC, with measurable disease, not previously treated with ribociclib or AIs. Xenografts were created from CT guided tumor biopsies at baseline to assess feasibility. Results: A total of 40 patients were enrolled (20 with OC and 20 with EC) ) with a median age of 61 years (range: 30-82) and 64.5 (range: 52-75) in the OC and EC groups respectively. Among the OC patients, 17 had high grade serous carcinomas and 3 had low grade serous carcinomas. 11 EC patients had endometrioid cancers (3 with grade 1 tumors) and 9 had high grade serous tumors. Ten out of 20 OC patients and 11/20 EC patients were alive and progression-free at 12 weeks (PFS12 of 50 and 55%, respectively). The most common grade 3 or higher adverse events (occurring in at least 5 pts) were leukopenia (18%), lymphopenia (18%), neutropenia (13%), and fatigue (13%). 34 tumor biopsies were suitable for injection into mice and 44% engrafted. ER expression persisted through multiple passages in mice. Two of three EC PDX models exhibited improved PFS with letrozole/ribociclib compared to letrozole alone. Conclusions: The combination of ribociclib and letrozole is associated with a promising 50% and 55% PFS12 in patients with ER positive relapsed OC or EC respectively. Creation of xenograft tumor models from CT guided biopsies of OC and EC tumors was feasible. Clinical trial information: NCT02657928.

Temozolomide-induced hypermutation is associated with high-grade transformation, distant recurrence, and reduced survival after transformation in initially low-grade IDH-mutant diffuse gliomas.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2506-2506
Author(s):  
Nancy Ann Oberheim Bush ◽  
Yao Yu ◽  
Javier Villanueva-Meyer ◽  
Matthew Grimmer ◽  
Stephanie Hilz ◽  
...  
Keyword(s):  
Somatic Hypermutation ◽  
Molecular Subtype ◽  
Distant Recurrence ◽  
Clinical Implications ◽  
Low Grade ◽  
High Grade ◽  
Who Grade ◽  
Low Grade Gliomas ◽  
Diffuse Gliomas ◽  
High Grade Transformation

2506 Background: Temozolomide, a commonly used alkylating agent to treat gliomas, can induce somatic hypermutation. The prevalence and clinical implications of this phenomenon are not well characterized. Methods: We used targeted and whole exome sequencing from a cohort of 82 patients with recurrent IDH-mutant low grade gliomas undergoing re-operation to evaluate the prevalence as well as the clinical implications of hypermutation. Results: Hypermutation was identified at transformation in 57% of recurrent gliomas exposed to Temozolomide, 94% of which were transformed to higher WHO grades. All patients who developed hypermutation were exposed to Temozolomide. Hypermutation was associated with transformation to higher WHO grade (OR 12.0 95% CI 2.5 – 115.5, p = 0.002) and shorter survival after transformation (HR 2.1, 95% CI 1.1-4.0, p = 0.018) compared with non-hypermutated transformed tumors, controlling for grade, molecular subtype, age, and prior radiotherapy. Patients with transformation to glioblastoma had poor survival regardless of hypermutation (p = 0.78). Hypermutated tumors were associated with development of discontiguous disease at a significantly higher frequency (p = 0.003), including four cases with spinal dissemination. Conclusions: TMZ-induced hypermutation is associated with high grade transformation, unique patterns of dissemination and shortened survival after transformation. Next generation sequencing should be considered in this patient population. These data have important implications for the management of newly diagnosed and recurrent IDH-mutant low grade gliomas.

Phase I Trial of Combination Therapy with 90y Ibritumomab Tiuxetan and Gemcitabine in Patients with Non-Hodgkin's Lymphoma, Final Report.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2753-2753
Author(s):  
Hossein Borghaei ◽  
Russell J. Schilder ◽  
Samuel Litwin ◽  
Michael Millenson ◽  
Adam D Cohen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
B Cell ◽  
Research Funding ◽  
Phase I Trial ◽  
Hodgkin's Lymphoma ◽  
Low Grade ◽  
Ibritumomab Tiuxetan ◽  
Non Hodgkin's Lymphoma ◽  
Grade 3

Abstract Abstract 2753 Y90-ibritumomab tiuxetan radioimmuotherapy (Y90-RIT) is an effective therapy against CD20+ lymphomas approved for use in patients (pts) with relapsed/refractory low grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL), as well as consolidation of first remission low grade NHL. Gemcitabine (Gem) also is active against NHL and is a potent radiation sensitizer. We conducted a phase I trial to assess the safety of concomitant administration of Y90-RIT and G in patients with NHL. Eligible pts had any histologic subtype of recurrent CD20+ NHL (not candidates for potentially curative options) and met standard Y90-RIT criteria: platelets 150,000/ul; < 25% bone marrow involvement by lymphoma; prior radiation to <25% of bone marrow and no prior bone marrow or stem cell transplant. Initially, nine pts in three cohorts were treated with 250 mg/m2 of Gem IV on days 1 and 8 of the Y90-RIT treatment program (rituximab + 111In-ibritumomab day 1 and rituximab + Y90 ibritumomab day 8), with Y90-RIT at 0.2, 0.3 or 0.4 mCi/kg respectively. We confirmed that a standard Y90-RIT dose of 0.4 mg/kg can be safely administered with Gem at 250 mg/m2. In subsequent cohorts, escalating doses of Gem were used according to a Bayesian based system. Response evaluation was by CT scan criteria (IWG JCO 1999). Between 2004–2012, twenty pts were treated (10 follicular (FL), 3 marginal zone (MZL), 7 diffuse large B-cell (DLBCL) lymphomas). Median age is 71.5 (range 55–82). The median number of prior treatments is 3 (range 1–6). Gem doses ranged from 250 mg/m2 to the maximum planned dose of 800 mg/m2 on days 1 and 8. One DLT occurred (thrombocytopenia) and MTD was not reached. Treatment-related toxicities consisted of grades 3 (N=11) and 4 (N = 2) neutropenia, grade 3 (N=11) leukopenia, grades 3 (N=14) and 4 (N=8) thrombocytopenia. One grade 3 infection occurred, unrelated to study drugs. All pts recovered counts to ≤ grade 1 by week 12. The only grade 3 non-hematologic toxicity was elevated bilirubin in 1 and increased GGT in 2 pts. Best responses seen include: 3 CR/CRu, 7 PR, 4 SD, 4 PD and 2 patients still in follow up. Median PFS for all patients is 192 days. Median PFS for all non-DLBCL histologies (10 FL and 3 MALT) is 202 days and for DLBCL is 77 days. Conclusion: Standard dose Y90-RIT combined with gemcitabine days 1 and 8 is safe and well-tolerated at doses up to 800 mg/m2 in pts with relapsed/refractory NHL. Further investigation with the established doses in non-DLBCL histologies is warranted. Disclosures: Borghaei: Biogen-IDEC: Research Funding. Off Label Use: 90Y Ibritumomab Tiuxetan in relapsed DLBCL. Schilder:Biogen-IDEC: Research Funding. Smith:Biogen-IDEC: Research Funding.

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