Short Time between Progression after Immunochemotherapy and Initiation of Salvage Therapy (PTI) Is Associated with Inferior Long-Term Outcomes in Patients with Relapsed/Refractory DLBCL

Abstract Background An association has been identified between the diagnosis-to-treatment interval (DTI) and prognostic clinical factors and outcomes in patients with previously untreated diffuse large B-cell lymphoma (DLBCL) (Maurer et al, JCO 2018). This association can result in inadvertent selection bias in clinical trials to exclude patients with aggressive disease due to the inability to delay treatment long enough to fulfill enrollment criteria, compromising the validity of clinical trial study results to the general population. A similar concern exists in the relapsed/refractory (r/r) DLBCL setting regarding patient selection bias against patients with aggressive disease requiring immediate treatment following relapse or progression. Here we examine the time from progression after immunochemotherapy (IC) to the initiation of first salvage chemotherapy and its association with outcome. Patients and Methods: Newly diagnosed patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER), now a subcohort of the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study, and followed for progression/relapse, retreatment, and death. This analysis includes patients with their first r/r DLBCL following frontline IC who initiated aggressive salvage chemotherapy as identified and included in a previous publication (Farooq et al, BJH 2017). The progression-to-treatment interval (PTI) was defined as the time in days from date of progression from IC to initiation of salvage therapy. The date of progression was defined as either a) the date biopsy was obtained for patients who had a biopsy to confirm progressive disease or b) the date of the scan or clinical examination indicating progression in patients who did not have a biopsy performed. Event-free survival (EFS) was defined as time from initiation of first salvage therapy to progression or relapse, initiation of new anti-lymphoma therapy, or death due to any cause; overall survival (OS) was defined as time from initiation of salvage therapy until death due to any cause. Results: 162 patients with r/r DLBCL enrolled in the MER from 2002-2012 who initiated aggressive salvage chemotherapy with intent to transplant and had confirmed dates for both progression after IC and start of salvage therapy were evaluated. Median age at first progression for these patients was 64 years (range 36-76) and 104 (64%) were male. Median time from diagnosis to first progression on IC was 6.7 months (IQR: 4.6-12.7). Initial salvage therapy was R-ICE (80%), R-DHAP (8%), rituximab, oxaliplatin, cytosine arabinoside, and dexamethasone (ROAD) (6%), and other (7%). At a median follow-up of 49 months from initiation of salvage therapy (IQR: 33-74), 116 patients had died (72%). Median PTI was 6 days (IQR: 2-13). 110 patients (68%) had biopsy confirmation of disease prior to initiating salvage therapy; median PTI was 2 days (IQR: 1-7) for patients who had biopsy confirmation vs. 7 days (IQR: 3-16) in patients without biopsy confirmation, Wilcoxon p=<0.0001. There was no difference in OS from initial salvage therapy between patients who did not have biopsy confirmation (HR=1.09, 95% CI: 0.74-1.60, p=0.68) compared to patients with biopsy confirmation. Patients with short PTI (0-6 days) had significantly worse overall survival from initiation of salvage therapy (median OS = 7.6 months, HR=2.10 (95% CI: 1.43-3.08) compared to patients who initiated therapy 7 or more days from progression (median OS = 29.7 months), logrank p<0.0001. This association remained consistent (HR=2.20, 95% CI: 1.48-3.26, p<0.0001) after adjusting for age and biopsy confirmation of progression. Short PTI was also associated with inferior response rate to initial salvage therapy (51% vs. 65%, p=0.058), lower rate of proceeding to transplant after initial salvage therapy (33% vs. 55%, p=0.0063), lower rate of being event-free 24 months from initial salvage therapy (16% vs 33%, p=0.011) and lower rate of ever proceeding to transplant (44% vs. 59%, p=0.057). Conclusions: A short progression-to-treatment interval is strongly associated with inability to proceed to transplant and inferior overall survival in r/r DLBCL. These results have implications for the design and interpretation of clinical trials in the relapsed/refractory setting. Figure. Figure. Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Ansell:Trillium: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Takeda: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cerhan:Nanostring: Research Funding; Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board.

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Outcomes of Relapsed/Refractory B-Cell Lymphoma Is Improved by Salvage Chemotherapy Consisting of Two to Three Cycles of Dexamethasone (D), High Dose Ara-C (HA) and Carboplatin (DHAC) with or without Rituximab (R) Followed by Autologous Stem Cell Transplantation.

Blood ◽

10.1182/blood.v110.11.5130.5130 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5130-5130

Author(s):

Swaminathan Padmanabhan ◽

Anjana Elefante ◽

Prakash Varadarajan ◽

Minoo Battiwalla ◽

Arvinder Bir ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

B Cell ◽

Median Survival ◽

Salvage Therapy ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

High Dose ◽

Overall Response

Abstract Introduction: Relapsed/refractory B-cell lymphomas are challenging to treat but can be salvaged by High- dose chemotherapy and stem cell transplant (HDC-SCT). Various non-cross resistant salvage regimens have been developed to treat patients with relapsed/refractory B-cell lymphoma. In this report we present our institution’s experience with DHAC ± R in patients requiring salvage therapy prior to HDC-SCT. Methods: The DHAC regimen consists of Dexamethasone at 15mg/m2/dose po every 6 hrs x 10 doses, High-dose Ara-C at 3G/m2 (1.5G/m2 if >50 yrs old) iv over 3 hrs every 12 hrs for 4 doses and Carboplatin at 200mg/m2 iv every 24 hrs for 2 doses. When utilized, patients received rituximab at the standard dose of 375mg/m2, 48 hrs prior to each cycle of DHAC. Growth factor support and anti-microbial prophylaxis was implemented 24 hrs after completion of chemotherapy. The regimen was repeated every 21 days for 2-3 cycles prior to HDC-SCT. We treated 37patients with relapsed/refractory lymphomas; median age was 47 yrs (range 18 – 78); 25 male and 19 females. Histological subtypes included (DLBCL (n=16); follicular lymphoma (n=10); marginal zone lymphoma with blastoid features (n=1); small lymphocytic lymphoma (n=1) and Hodgkin’s lymphoma (n=8). The majority of the patients presented with Stage III (n=43%), Stage IV (n=39%) at the time of DHAC therapy. Seventeen patients were treated with R+DHAC, and 20 were treated with DHAC, either as second line or third line salvage therapy. 19 of 37 proceeded to HD-SCT. Results: The overall response rate (ORR, CR+PR) for all patients was 61% (16 CR and 7 PR). The remaining 14 patients had either stable disease (n=10) or progressed (n=4). Complete responders (43%) had a longer median survival of 107 (range 78 – 136) months compared to 66 months (range 49 – 83) for partial responders (19 percent) and non-responders who had a mean survival of 30.8 months (range 9–54),[P = 0.008]. Patients who proceeded to HD-SCT had an ORR of 79% [11CR and 4 PR] compared to only 44% in those who did not [5 CR and 3 PR]. The median survival in patients transplanted was longer than non-transplanted patients (92 vs 68 months). Conclusions: DHAC with or without rituximab appears to be an effective salvage treatment for patients with relapsed or refractory advanced-stage B-lymphoma undergoing HDC-SCT. An overall response of 61% which increases to 79% when followed by autologous SCT were demonstrated. Median survival was longer in patients experiencing CRs compared to partial or non-responders suggesting that the quality and quantity of the cytoreduction after salvage chemotherapy is an important predictor factor of post-SCT survival. Data looking at prognostic factors predicting response to DHAC±R treatment are being analyzed and will be reported at the ASH annual meeting. Figure 1. Overall survival on DHAC±R depends on response to chemotheraphy. Figure 1. Overall survival on DHAC±R depends on response to chemotheraphy.

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Importance of diagnosis-to-treatment interval in newly diagnosed patients with diffuse large B-cell lymphoma

Scientific Reports ◽

10.1038/s41598-021-82615-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Masahiro Yoshida ◽

Yosuke Nakaya ◽

Katsujun Shimizu ◽

Naoko Tatsumi ◽

Minako Tsutsumi ◽

...

Keyword(s):

Clinical Trials ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Strongly Correlated ◽

Newly Diagnosed ◽

Aggressive Disease ◽

Large B Cell Lymphoma ◽

Treatment Interval ◽

Large B Cell

AbstractTreatment of patients with malignancy sometimes be delayed due to various reasons. Several studies revealed that an influence of diagnosis-to-treatment interval (DTI) on outcomes differs depending on the type of malignancy. In this study, we evaluated the influence of DTI on clinical outcomes in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL). A total of 199 patients were identified with a median DTI of 22 days. At 2 years, patients with short DTI (0–22 days) showed significantly poorer OS (62.7% vs 86.4%) and PFS (55.1% vs 75.9%) compared to those with long DTI (over 22 days). Although short DTI was strongly correlated with several known adverse factors, it remained to be an independent prognostic factor by multivariate analysis. In conclusion, our study confirmed the importance of DTI in patients with DLBCL. Researchers should consider DTI as one of the important prognostic factors and plan clinical trials to be able to enroll patients with aggressive disease requiring urgent treatment.

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Relapses after Achieving EFS24 in Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era

Blood ◽

10.1182/blood-2018-99-113213 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 454-454 ◽

Cited By ~ 1

Author(s):

Yucai Wang ◽

Umar Farooq ◽

Brian K. Link ◽

Mehrdad Hefazi ◽

Cristine Allmer ◽

...

Keyword(s):

B Cell ◽

Cumulative Incidence ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

Newly Diagnosed ◽

Indolent Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Introduction: The addition of Rituximab to chemotherapy has significantly improved the outcome of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients treated with immunochemotherapy for DLBCL who achieve EFS24 (event-free for 2 years after diagnosis) have an overall survival equivalent to that of the age- and sex-matched general population. Relapses after achieving EFS24 have been considered to be unusual but have been understudied. We sought to define the rate, clinical characteristics, treatment pattern, and outcomes of such relapses. Methods: 1448 patients with newly diagnosed DLBCL from March 2002 to June 2015 were included. Patients were enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE, treated per physician choice (predominantly R-CHOP immunochemotherapy) and followed prospectively. An event was defined as progression or relapse, unplanned re-treatment after initial therapy, or death from any cause. Cumulative incidence of relapse and non-relapse mortality after achieving EFS24 were analyzed as competing events using Gray's test in the EZR software. Post-relapse survival was defined as time from relapse to death from any cause and analyzed using Kaplan-Meier method in SPSS (V22). Results: Among the 1448 patients, 1260 (87%) had DLBCL alone at diagnosis, and 188 (13%) had concurrent indolent lymphoma (follicular lymphoma 115, marginal zone lymphoma 18, chronic lymphocytic leukemia 14, lymphoplasmacytic lymphoma 4, unspecified 37) at diagnosis. After a median follow-up of 83.9 months, 896 patients achieved EFS24. For all 896 patients who achieved EFS24, the cumulative incidence of relapse (CIR) was 5.7%, 9.3% and 13.2%, respectively, at 2, 5 and 10 years after achieving EFS24. Patients with concurrent indolent lymphoma at diagnosis had a higher CIR compared to those with DLBCL alone at diagnosis (10.2 vs 4.8% at 2 years, 15.7 vs 8.0% at 5 years, 28.8 vs 9.7% at 10 years, P<0.001; Figure 1). There were a total of 84 patients who relapsed after achieving EFS24. The median age at initial diagnosis was 66 years (range 35-92), and 48 (57%) were male. At diagnosis, 11 (13%) had ECOG PS >1, 37 (50%) had LDH elevation, 62 (74%) were stage III-IV, 14 (17%) had more than 1 extranodal site, and 26 (31%) were poor risk by R-IPI score. There were 58 patients with DLBCL alone at diagnosis who relapsed after achieving EFS24, and 38 (75%) relapsed with DLBCL, 13 (25%) relapsed with indolent lymphoma (predominantly follicular lymphoma), and pathology was unknown in 7 patients. In contrast, there were 26 patients with concurrent indolent lymphoma at diagnosis who relapsed after achieving EFS24, and 9 (41%) relapsed with DLBCL, 13 (59%) relapsed with indolent lymphoma, and pathology was unknown in 4 patients. In the 47 patients who relapsed with DLBCL after achieving EFS24, 45% received intensive salvage chemotherapy, 19% received regular intensity chemotherapy, 9% received CNS directed chemotherapy, and 36% went on to receive autologous stem cell transplant (ASCT). In the 26 patients who relapsed with indolent lymphoma after achieving EFS24, 27% were initially observed, 54% received regular intensity chemotherapy, 4% received intensive salvage chemotherapy, and 19% received ASCT after subsequent progression. The median post-relapse survival (PRS) for all patients with a relapse after achieving EFS24 was 38.0 months (95% CI 27.5-48.5). The median PRS for patients who relapsed with DLBCL and indolent lymphoma after achieving EFS24 were 29.9 (19.9-39.9) and 89.9 (NR-NR) months, respectively (P=0.002; Figure 2). Conclusions: Relapses after achieving EFS24 in patients with DLBCL were uncommon in the rituximab era. Patient with DLBCL alone at diagnosis can relapse with either DLBCL or indolent lymphoma (3:1 ratio). Patients with concurrent DLBCL and indolent lymphoma at diagnosis had a significantly higher CIR, and relapses with DLBCL and indolent lymphoma were similar (2:3 ratio). Even with high intensity salvage chemotherapy and consolidative ASCT, patients who relapsed with DLBCL had a significantly worse survival compared to those who relapsed with indolent lymphoma. Late relapses with DLBCL remain clinically challenging, with a median survival of 2.5 years after relapse. Figure 1. Figure 1. Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Takeda: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Cerhan:Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding.

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The Effects of Rituximab Added to Front-Line or Salvage Chemotherapy in Diffuse Large B-Cell Lymphoma (DLBCL) Undergoing High-Dose Chemotherapy (HDC) and Autologous Stem Cell Transplant (ASCT).

Blood ◽

10.1182/blood.v112.11.1138.1138 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1138-1138 ◽

Cited By ~ 1

Author(s):

Umeer Ashraf ◽

Ritika Mahajan ◽

Theresa Hahn ◽

Shannon L Smiley ◽

Philip L. McCarthy ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Disease Control ◽

B Cell ◽

Salvage Therapy ◽

Salvage Chemotherapy ◽

Front Line ◽

Resistant Disease ◽

Line Therapy ◽

Line Setting

Abstract Despite the improved outcome in patients with DLBCL treated with rituximab (R) in combination with systemic chemotherapy (R + chemotherapy), a significant number of patients either relapse or fail to respond as a consequence of resistant disease. HDC and ASCT is the best therapeutic strategy to rescue relapsed/refractory DLBCL. It has been postulated that R+chemotherapy may lead to the selection of highly resistant lymphoma cells diminishing the clinical benefit of HDC and ASCT. Preliminary data from the CORAL study (Gisselbrecht et al Blood2007; 11:517a) suggest that overall response rates (ORR) and 2-year event free survival (EFS) are lower in R+chemotherapy relapsed/ refractory DLBCL when compared to DLBCL treated with chemotherapy alone. However the second randomization of this study to observation versus R-maintenance may affect the interpretation of the data. We retrospectively studied the difference in the outcomes of relapsed/refractory DLBCL patients following HDC and ASCT according to the front line therapy utilized (R+chemotherapy versus chemotherapy). Using the Roswell Park Cancer Institute (RPCI) Tumor Registry and the RPCI Blood and Marrow Transplant (BMT) Database we identified 130 patients with relapsed/refractory NHL who underwent for HDC + ASCT from 1991 to 2008. After excluding patients with a diagnosis other than B-cell DLBCL (patients with transformed NHL were excluded) and those patients receiving allo-BMT after progression from ASCT, the analysis included 63 refractory/ relapsed DLBCL. Demographic characteristics, clinical data, treatment history in the front line and salvage setting were collected. In addition response to salvage therapy and disease status at day +100 from ASCT was recorded for each subject. Progression free and overall survival were calculated from ASCT. Differences in clinical outcomes between patients receiving R as part of first line or salvage treatment and those treated with chemotherapy alone were evaluated by multivariate analysis, adjusting for significant univariate predictors of survival. The patient cohort included 34 males and 29 females with median age of 46 yrs (14.4 to 69.4). Two-thirds of the patients had advance disease and the majority had a Karnofsky performance status (KPS) of 80–100% at diagnosis. R+chemotherapy was given in the front line setting to 25 pts and while 38 received chemotherapy alone. In the salvage setting, 35 pts (55%) received R+chemotherapy. Most relapses (44 pts) occurred within 6 months of completion of front line therapy (17 pts with vs. 27 pts without R). The use of R in the front line setting was associated with significantly higher response rates (PR + CR) to salvage chemotherapy (P = 0.036) and better disease control on day +100 post-ASCT (P = 0.016) when compared to chemotherapy alone. In our cohort, there have been 32 deaths, 23 in chemotherapy treated DLBCL in contrast to 9 deaths in R+chemotherapy treated patients There was a significantly higher response rate post-ASCT for R+chemotherapy treated (as front-line or salvage) DLBCL versus chemotherapy alone (P = 0.007). A multivariate analysis demonstrated that achieving a CR pre-ASCT was the most important predictor of post-ASCT progression free and overall survival . In summary, our data suggest that the use of R + chemotherapy during frontline therapy and in the salvage setting yields better disease control and less incidence of chemo-resistant disease at the time of BMT. Applying the natural selection theory, the use of R+chemotherapy is expected to result in the development of resistant lymphomas. The length of time and the amount of R therapy that will render lymphoma cells resistant to chemo-immunotherapy remain to be determined. Standard doses of R (6 to 8 doses) do not appear to affect response to salvage therapy or autologous BMT outcomes. In our single institution analysis over the last 18 years, it appears that HDC + ASCT is an effective and viable option for patients with R +/− chemotherapy relapsed/refractory DLBCL.

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Efficacy of a Brief, Cyclophosphamide-Intensive Regimen for Older Patients with Newly Diagnosed Burkitt's or Atypical Burkitt's Lymphoma/Leukemia.

Blood ◽

10.1182/blood.v114.22.2685.2685 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2685-2685

Author(s):

Yvette L. Kasamon ◽

Robert A. Brodsky ◽

Michael J. Borowitz ◽

Pamela A. Crilley ◽

Richard F. Ambinder ◽

...

Keyword(s):

Overall Survival ◽

Median Time ◽

Older Patients ◽

Research Funding ◽

Tumor Lysis Syndrome ◽

B Cell Lymphoma ◽

Burkitt’S Lymphoma ◽

Burkitt's Lymphoma ◽

High Dose ◽

Newly Diagnosed

Abstract Abstract 2685 Poster Board II-661 Background: Although standard therapies cure most adolescents and young adults with Burkitt's lymphoma/leukemia (BL), older patients (pts) have an inferior prognosis with an estimated 1-year survival of 50%. The inferior outcome is attributable to both insufficient efficacy and excess toxicity. Cyclophosphamide (Cy) has long been recognized to be arguably the most active agent in BL. Prior work at our institution showed that high-dose Cy, equivalent to transplantation doses, could be given without stem cell rescue with minimal toxicity even in older pts. Patients and Methods: A phase II trial for pts age ≥ 30, based on intensive Cy and incorporating rituximab but no anthracycline, was developed with a primary endpoint of 1-year overall survival. Entry requirements included newly diagnosed BL or atypical BL; any performance status (PS); HIV negative; and no significant cardiac dysfunction. Renal failure, even if necessitating dialysis, was permitted if it was acute. Treatment consisted of 3 cycles, with successive cycles beginning on day 15 or when ANC was ≥ 500/μL. Cycles 1 and 2 consisted of Cy 1500 mg/m2 IV day 1; vincristine 1.4 mg/m2 (2 mg cap) day 1; prednisone 100 mg days 1-5; rituximab 375 mg/m2 IV days 1 and 8; methotrexate 3 g/m2 IV day 8 with leucovorin rescue; cytarabine 100 mg intrathecally days 1, 4, and 11; and filgrastim. Cycle 3 consisted of rituximab 375 mg/m2 IV day 1; high-dose Cy (50 mg/kg IV days 2, 3, 4, and 5) with uroprotection; filgrastim; and rituximab 375 mg/m2 IV weekly for 4 weeks once ANC was ≥ 1000/μL. Eligibility for cycle 3 included ECOG PS < 4; no disease progression or uncontrolled meningeal disease; not on dialysis; and transaminases ' 5X upper limit of normal. Results: A prespecified interim analysis of the first 12 of a planned 20 evaluable pts is presented. Diagnosis was BL in 8 and atypical BL/unclassifiable high-grade lymphoma with features intermediate between BL and diffuse large B-cell lymphoma in 4. Median age was 56 (range 34 – 75), 8/12 (67%) had Ann Arbor stage III/IV disease, and all were high-risk by Magrath's criteria. PS ranged from 0 to 4. Two pts received hemodialysis on presentation. For all pts, actuarial event-free survival and overall survival (Figure) are 66% and 75%, respectively, at both 1 year and 2 years after treatment initiation. Three pts died during cycle 1: tumor lysis syndrome on day 1, neutropenic sepsis on day 8, multiorgan failure on day 46 after respiratory arrest on day 20. All of the other 9 pts completed protocol therapy: 8 (89%) achieved anatomic CR/CRu as well as a complete metabolic response by PET, and are event-free at a median of 29 months (range < 1 – 44 months) after therapy completion. The remaining pt had residual marrow disease followed by progression and is in remission 1 year after myeloablative allogeneic BMT. Adverse events in these 9 pts included 7 neutropenic fevers; 1 non-neutropenic bacteremia; and 1 self-limited episode of pericarditis with rapid atrial fibrillation. Grade 3 peripheral neuropathy was limited to 2 pts. The planned dose intensity was achievable: median time to cycle 2 was 15 days (14 – 21), and median time from start of cycle 1 to start of cycle 3 was 31 days (28 – 35). Median time to neutrophil recovery after the last dose of Cy was 16 days (10 – 21); median time to platelets ≥ 20,000/μL, without transfusion in the preceding week, was 22 days (0 – 30). Early stopping criteria for response or all-cause mortality have not been met. Conclusion: A very short regimen based on intensive Cy without anthracycline produces a high rate of durable CR's in older, poorer-risk pts with BL or atypical BL. Disclosures: Kasamon: Genentech: Research Funding. Swinnen:Genentech: Consultancy, Research Funding; Enzon: Consultancy; Abbot: Consultancy, Research Funding.

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Azacitidine (Vidaza®, Aza) and Donor Lymphocyte Infusions (DLI) In Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS) Relapsing After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Interim-Analysis From the AZARELA-Trial (NCT-00795548).

Blood ◽

10.1182/blood.v116.21.1294.1294 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1294-1294

Author(s):

Thomas Schroeder ◽

Akos Gabor Czibere ◽

Nicolaus Kröger ◽

Uwe Platzbecker ◽

Gesine Bug ◽

...

Keyword(s):

Overall Survival ◽

Missing Data ◽

Salvage Therapy ◽

Interim Analysis ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Significant Activity ◽

Hematopoietic Stem ◽

Allogeneic Hsct

Abstract Abstract 1294 Background: Patients with AML or MDS who relapse after allogeneic HSCT have a poor prognosis and therapeutic options are limited. The DNA hypomethylating agent Aza has significant activity in patients (pts) with AML and MDS and retrospective analyses have recently shown encouraging results with the use of Aza +/− DLI in patients with AML and MDS, who relapsed after allogeneic HSCT (Czibere et al., 2010; Luebbert et al., 2010). In line with these clinical observations preclinical data suggest that Aza enhances a Graft-versus-Leukemia (GvL) effect while mitigating Graft-versus-Host Disease (GvHD). Design/Methods: To evaluate the activity and safety of Aza in combination with DLI as first salvage therapy in pts with AML or MDS relapsing after HSCT, we conducted a prospective, multicenter, single-arm phase-II trial. Pts were allowed to receive up to 8 cycles Aza (100 mg/m2/d d1-5, every 28 days) and 3 DLI with increasing dosages (1-5×106 – 1–5×108 cells/kg) after every 2nd Aza treatment cycle. Additional DLI were permitted. Results: Between January 2009 and May 2010, 30 pts from 6 German transplant centres were included into this trial. So far, 25 pts (15 female/10 male) were evaluable and are presented in this analysis: Of these, 23 (92%) suffered from AML (15 de novo/8 secondary following MDS), 1(4%) from a MDS (RAEB-1) and 1 (4%) from a myelodysplastic/myeloproliferative syndrome (MDS/MPS, CMML-1). Median age was 54 years (range 29–71). Conditioning was myeloablative in 24 pts (96%) and non-myeloablative in 1 patient (4%). Eight pts (35%) received a graft from a matched sibling donor, while 15 (65%) were transplanted with a matched unrelated donor (2 pts missing data). Peripheral blood stem cells (PBSC) were used in 24 pts (96%; 1 pt missing data). At the time of transplant 6 pts (24%) had primary induction failure, another 6 (24%) suffered from first or secondary relapse, 10 pts (40%) were in first or second complete remission (CR), while 3 pts (12%) were untreated. With regard to their molecular and genetic characteristics at diagnosis, 21 pts belonged to an adverse (9 pts) or intermediate (12 pts) group, whereas 2 pts were diagnosed with a favourable genetic phenotype (2 pts not performed). Prior to relapse 9 (36%) and 3 (12%) pts had episodes of acute GvHD and/or chronic GvHD, respectively. Relapse occurred in all pts after a median of 160 days (range 19–1199) following HSCT (median BM blasts: 34%, range 5–100%, median chimerism: 63% range-1-100%). At the time of relapse, karyotype was evaluable in 13 of 25 pts (52%). Of these 13 pts, 4 pts had a normal karyotype, while 9 had chromosomal aberrations including 6 pts with a complex karyotype. Patients received a median of 3 courses Aza (range 1–8) and 18 of 25 pts (72%) received DLI (median: 1, range: 1–4, median CD3 dose 5×106/kg/DLI, range: 1–207×106). Following treatment, overall response rate was 64% with 5 pts (20%) achieving a CR or CRi, 3 (12%) a partial remission (PR) and 8 (32%) a stable disease (SD). Median response duration was 266 days. Acute GvHD occurred in 6 pts (24%) (2 skin/6 liver/ 2 gut) after a median of 65 days (range 19–179) following the first DLI, while chronic GvHD was observed in 3 pts (12 %, all limited). Hematotoxicity (grade III-IV) was observed in 64% of all evaluated patients. Common adverse events were gastrointestinal side effects as well as infections. After a median follow-up of 100 days (range 25–485) 15 of 25 pts (60%) are currently alive. Median overall survival of all pts is 184 days (range 87–281). All pts, who achieved a CR/CRi, remained in ongoing remission for a median time of 229 days. Achieving a CR (CR: not reached vs. no CR: 117 days, p .008) or any type of response (CR/CRi, PR or SD) to the combination of Aza and DLI (any response: not reached vs. no response: 79 days, p .0001) were associated with a significantly longer overall survival. Conclusion: The combination of Aza and DLI as salvage treatment for patients with AML or MDS who relapse after allogeneic HSCT seems to be safe and shows significant anti-leukemic activity. Response, including CR rates, so far match those from retrospective analyses. Data presented in this interim-analysis suggest that salvage therapy with Aza and DLI is of substantial therapeutic benefit in these challenging patients. Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bug:Celgene: Honoraria. Luft:Celgene: Research Funding. Fenk:Celgene: Research Funding. Kobbe:Celgene: Research Funding.

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Diffuse Large B-Cell Lymphoma (DLBCL) Patients Failing Second-Line R-DHAP Or R-ICE Chemotherapy Included In The Coral Study

Blood ◽

10.1182/blood.v122.21.764.764 ◽

2013 ◽

Vol 122 (21) ◽

pp. 764-764 ◽

Cited By ~ 4

Author(s):

Eric Van Den Neste ◽

Christian Gisselbrecht ◽

Norbert Schmitz ◽

Nicolas Mounier ◽

Devinder S Gill ◽

...

Keyword(s):

Research Funding ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

New Drugs ◽

High Dose ◽

Second Line ◽

Line Therapy ◽

Significant Difference ◽

Third Line Therapy ◽

Third Line

Abstract Introduction and Methods Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT) is the standard of care for relapsing/refractory DLBCL. In the CORAL study, there was no difference between two randomized second line regimens (R-DHAP or R-ICE) and only half of the patients (pts) eventually underwent per protocol ASCT (Gisselbrecht et al, JCO 2010 & 2012). Because outcome data are limited in DLBCL pts failing second-line strategy, 145 pts included in the CORAL study who failed R-DHAP or R-ICE and could not proceed to scheduled ASCT were herein reviewed. Results Median age was 56y (range 20-67, 31% > 60y), M/F ratio 91/54, IPI 0-1 in 30%, 2-3 in 56%, and 4-5 in 14%. Third-line therapy consisted of ICE-type (19%), DHAP-type (19%), gemcitabine-containing (16%), CHOP-like (8%), dexaBEAM (8%), and miscellaneous (31%) regimens with or without rituximab according to centre policy. Overall response rate to third-line chemotherapy was 43%, with 21% complete response (CR), 8% CR unconfirmed (CRu), and 14% PR. CR/CRu and PR rates among pts treated with ICE-type, DHAP-type, gemcitabine-containing, or CHOP-like regimens were 23 and 23%, 35 and 8%, 9 and 4%, 25 and 25%, respectively. Among the 145 patients, 64 (44%) could eventually be transplanted (ASCT 56, allogeneic SCT 8). Median overall survival (OS), calculated from time of second failure until death, was 5.9 months (95% CI 4.6-7.5; min: 0.0-max: 68.8 months; median follow-up: 32.8 months) and was not influenced by the type of third-line regimen (p=.49). OS was statistically different (p<.0001) according to IPI at CORAL failure: IPI 0-2: 11.1 months (1-y OS 42.9%), IPI > 2: 3.7 months (1-y OS 7.7%, HR 3.021). OS in pts achieving CR/CRu, PR, or no response after third-line regimen was 63.6 m (1-y OS 72.1%, p<.0001), 12.8 m (1-y OS 53.5%, p=.04), and 4.4 months (1-y OS 9.2%), respectively. Median OS of pts who could eventually be transplanted was 11.1 months (1-y OS 41.6%), as compared to a median OS of 5.0 months in those who were not transplanted (1-y OS 19.2%) with a HR of 2.182 (1.41-3.38, p<.0001, Figure 1). Median OS of pts transplanted in CR after third-line regimen was not reached as compared to those in PR (11.8 months) or those with no response (4.4 months, p<.0001). There was no statistically-significant difference in median OS between ASCT and alloSCT, taking into account the low numbers. In multivariate Cox analysis, IPI at relapse (HR 2.409) and transplantation (HR 0.381) independently predicted for OS. Conclusions Outcome of DLBCL pts failing second-line R-DHAP or R-ICE is overall poor. However, response to third-line therapy occurs, and 44% of the pts can be further transplanted. Long-term disease control can be observed, especially in pts achieving CR after third-line. This approach (salvage chemotherapy aiming at achieving response followed by transplantation) should then be encouraged in these patients, although there is obviously an urgent need for new drugs improving salvage efficacy. Disclosures: Gisselbrecht: Roche: Consultancy, Research Funding; Baxter: Research Funding; Chugai Pharma: Research Funding. Trneny:Roche: Honoraria, Research Funding. Radford:Roche: Consultancy. Shpilberg:Roche: Consultancy, Honoraria, Research Funding. Dührsen:Roche Pharma: Honoraria, Research Funding. Moskowitz:Genentech: Consultancy, Research Funding. Glass:Roche: Honoraria, Research Funding.

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Stem Cell Dose and Time To Engraftment Does Not Predict Outcome After Autologous Stem Cell Transplantation For Relapsed Aggressive NHL

Blood ◽

10.1182/blood.v122.21.5542.5542 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5542-5542 ◽

Cited By ~ 1

Author(s):

Shane A Gangatharan ◽

John Kuruvilla ◽

Vishal Kukreti ◽

Armand Keating ◽

Manjula Maganti ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

Entire Cohort ◽

Cell Dose ◽

Cd34 Cells

Abstract Introduction Autologous stem cell transplantation (ASCT) is the standard of care for relapsed aggressive lymphomas. Time to neutrophil and platelet engraftment is strongly correlated with CD34+ cell number infused but data are conflicting as to whether patients who receive greater numbers of CD34+ stem cells have improved outcomes. We sought to determine whether short term engraftment predicts progression-free survival (PFS) independent of other disease-specific prognostic factors. Methods From the Princess Margaret Cancer Centre transplant database, we identified patients undergoing ASCT for relapsed aggressive lymphoma between 2007-2011. Data were extracted on prognostic features at relapse/progression, stem cell collection, engraftment, and time to progression and death. All patients received platinum-based salvage chemotherapy and those with chemosensitivity were mobilised with cyclophosphamide, etoposide and filgrastim (minimum threshold 2x106 CD34 cells/kg) and proceeded to ASCT. Patients who failed initial mobilisation were remobilised using plerixafor. High-dose therapy consisted of etoposide 60mg/kg Day -4 and melphalan 180mg/m2 Day -3 with stem cells infused on Day 0. Filgrastim 300µg daily was started from Day +7 until neutrophil recovery to >1.0 x106/uL. Platelet engraftment was defined as an unsupported platelet count >20 x 109/L. Results 97 patients with DLBCL (n=66), transformed (n=24) and T-cell lymphoma (n=7) were reviewed. Median age was 54 (range 20-67), 61% were male and median IPI score on relapse was 2. Fifty one percent relapsed within 12 months of last therapy, and of the patients with B-cell lymphoma, 81% received rituximab prior to salvage chemotherapy. Median stem cell dose was 5.7x106 CD34+ cells/kg (range 1.69-17.82) with a median number of apheresis sessions to achieve this of 2 (range 1-4). Median time to neutrophils >0.5x106/uL was 11 days (range 9-14) and platelets >20x106/uL was 14 days (range 10-23). The Spearman correlation test confirmed a higher stem cell dose was significantly associated with shorter time to neutrophil (p=0.0014) and platelet engraftment (p=0.0003). From date of ASCT, median follow-up was 3.1 years in progression-free patients. For the entire cohort, PFS was 50% and overall survival (OS) was 74% at 3 years. On univariable analysis, patients with B-cell lymphoma with IPI score of 0-2 had a 3-year PFS of 59%, v 28% for those with IPI of 3-4 (p=0.03) (n=90). Patients with early relapse within 12 months of last therapy had inferior 3-year PFS, 42% v 59% for those with initial PFS > 1 year (p=0.08). Patients with B-cell lymphoma who received rituximab with primary chemotherapy had worse 3-year PFS: 47% v 69% (p=0.11). There were no associations of PFS with lymphoma subtype, dose of stem cells infused, number of apheresis sessions and neutrophil or platelet engraftment. Similarly, on univariable analysis of OS for the entire cohort, only secondary IPI (0-2 v 3-4) was significant, with 3-year OS 82% v 48%, respectively (p=0.01). Multivariable Cox regression analysis of outcomes for patients with B-cell lymphoma in a model including IPI score, time to relapse, prior rituximab, CD34+ cell dose and neutrophil and platelet engraftment times confirmed IPI was the only significant variable predicting PFS (HR 1.99, p=0.03) and OS (HR 3.2, p=0.006). Conclusions In this cohort of patients with aggressive lymphomas, CD34+ cell dose was correlated with time to neutrophil and platelet engraftment but was not predictive of PFS or OS. Secondary IPI score, relapse within 12 months, and for B-cell lymphomas previous use of rituximab were predictive of outcomes post ASCT. Disclosures: Kuruvilla: Roche: Honoraria. Kukreti:Millennium Pharmaceuticals: Research Funding; Onyx: Research Funding. Keating:Roche: Honoraria. Crump:Roche: Honoraria; Jansen-Ortho: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Novartis: Research Funding; Seattle Genetics: Honoraria.

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Poor Outcomes Among Patients Failing Dose-Adjusted EPOCH in Aggressive Lymphoma: A Collaborative, Retrospective Study

Blood ◽

10.1182/blood.v126.23.1518.1518 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1518-1518 ◽

Cited By ~ 1

Author(s):

Jackie Vandermeer ◽

Allison M Winter ◽

Ajay K. Gopal ◽

Ryan D. Cassaday ◽

Brian T. Hill ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Salvage Therapy ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

First Line ◽

Advisory Committees ◽

First Line Therapy

Abstract Introduction Among patients with aggressive B-NHL who fail RCHOP, about half respond to standard salvage regimens and may proceed to curative-intent, transplant-based therapy. However, whether pts failing more intensive regimens such as dose-adjusted, infusional EPOCH benefit from standard salvage regimens is unclear. We hypothesized that such patients comprise a higher-risk cohort, facing inferior response rates and outcomes using standard salvage regimens. We undertook a collaborative study to assess response rates and survival among pts failing EPOCH for aggressive B-NHL, to inform patient management and design of clinical trials in this setting. Methods Pharmacy records and institutional databases were queried, identifying pts receiving EPOCH over the last 10 years at the University of Washington/SCCA and the Cleveland Clinic Foundation, for combined analysis. Under IRB approval, patient characteristics, histology, outcome with EPOCH, time to EPOCH failure, response to salvage, and overall survival were analyzed. Diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, B-cell-lymphoma unclassifiable, HIV-associated B cell lymphoma, and transformed B cell non-Hodgkin lymphoma were included. Pts receiving <2 cycles EPOCH, or who had inadequate follow-up (<3 months), were excluded. Failure of EPOCH was defined as failure to respond or progression during therapy, need for initiation of salvage therapy, or death during therapy of any cause. Adverse events or treatment change due to toxicity were not included in the definition of failure. JMP 11 was used to generate kaplan-meier survival estimates. Results 124 pts with aggressive B-NHL receiving EPOCH were identified. 54 had not relapsed, and among 70 remaining da-EPOCH failures, 37 met the above inclusion criteria. Median age was 55. 27% were female, and 23 received EPOCH as first-line therapy. All but 3 received rituximab with EPOCH. Histologies were primarily DLBCL in 22/37 (60%) and BCL-U in 12/37 (32%) carrying a MYC translocation; most of these harbored additional translocations in BCL2 and/or BCL6 (10/12). However, data regarding MYC rearrangement was not available for all pts. 2 had HIV-associated B-NHL and 3 had PMBCL. With 18 months follow up, the median time to EPOCH failure was 5 months. Only 3 EPOCH failures occurred late (>12 months). Median OS from the date of EPOCH failure was 10 months (Figure 1). Those receiving EPOCH as first-line therapy (23) had a median OS of 14 months from EPOCH failure, as opposed to 4 months for those receiving EPOCH as salvage therapy (log-rank p=.01). Salvage chemotherapy regimens after EPOCH were diverse, and generally ineffective; 6/28 (21%) regimens produced a response (Table 1). Among patients failing EPOCH within a year, platinum-containing salvage (RICE/RDHAP) was effective in only 2/13 patients (15%). 9 patients did not receive any salvage, most of whom died or proceeded to palliative measures and/or hospice care. Conclusions A relatively low overall response rate (21%) was observed in this retrospective analysis of patients failing EPOCH. Analogous to early RCHOP failure in the CORAL study, those failing EPOCH within a year may face inferior outcomes with platinum-based salvage therapy. While combined from two institutions, our data represent a modest sample size and require confirmation. If verified, examination of mechanisms of resistance to EPOCH, and selecting EPOCH failures for clinical trials of novel targeted therapies and transplant-based approaches, may prove critical. Table 1. Salvage Therapy for REPOCH failures Regimen: response/total number treated Notes Response to any salvage: 6/28 (21%) Some patients received more than 1 chemo salvage; responses were tabulated per regimen. RICE: 4/12 2/3 alive post transplant(1 auto 1 allo; 1 declined transplant and survived; 1 died) RDHAP: 1/6 Gemcitabine-based: 0/5 HyperCVAD (Part A and/or B): 1/5 Survivor had CNS only relapse, received regimen B and transplant 9- received no systemic treatmen; most died or proceeded to palliative measures and/or hospice Figure 1. Figure 1. Disclosures Gopal: Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Emergent/Abbott: Research Funding; Sanofi-Aventis: Honoraria; Seattle Genetics: Consultancy, Honoraria; BioMarin: Research Funding; Piramal: Research Funding; Janssen: Consultancy; Millenium: Honoraria, Research Funding; BMS: Research Funding; Merck: Research Funding. Hill:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Till:Roche/Genentech: Research Funding; Pfizer: Research Funding.

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Outcomes of Patients with Chronic Lymphocytic Leukemia (CLL) after Idelalisib Therapy Discontinuation

Blood ◽

10.1182/blood.v126.23.4155.4155 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4155-4155 ◽

Cited By ~ 7

Author(s):

Jacqueline C. Barrientos ◽

Manmeen Kaur ◽

Alexis Mark ◽

Jaewon Chung ◽

Nancy Driscoll ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Salvage Therapy ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Therapy Discontinuation ◽

Progression Of Disease ◽

Grade 3 ◽

Extension Trial ◽

Parent Trial

Abstract Objective Idelalisib is a first-in-class oral PI3Kd inhibitor approved for use in combination with rituximab in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL). We describe the characteristics, causes of discontinuation, and outcomes in patients who discontinued treatment after idelalisib therapy. Methods 38 R/R CLL patients participated in 5 idelalisib combination trials at the North Shore-LIJ Cancer Institute and were included in this analysis. The patients were enrolled from 2011 until 2014, and data were locked in March 1st, 2015. Patients were evaluated for time to therapy discontinuation and reasons for discontinuation. The majority of the patients had been heavily pretreated and 39% of the patients had a high risk prognostic marker including deletion of 11q or 17p. 21 R/R CLL patients participated in the Phase Ib trial of idelalisib in combination with several agents including Rituximab (R), Bendamustine (B) ± R, Fludarabine, Chlorambucil ± R, and Ofatumumab. The trial was designed for 48 weeks and patients were allowed to continue on an extension trial with idelalisib if still deriving benefit. Patients on the parent trial were on therapy a median of 335 days. 42% (11/21) continued in the extension trial at the end of the parent trial. Causes of discontinuation from initial 48-week trial included: grade 4 transaminitis (1) on day 64 with failed rechallenge at lower doses; Richter's transformation (1) on day 161; grade 3/4 diarrhea/colitis (4) on days 52, 231, 255, and 365; refractory/progressive CLL (2) on days 8 and 170; aplastic anemia (1) on day 172; and septic shock in a patient with uncontrolled autoimmune hemolytic anemia (1) on day 271. Of the patients on the extension trial, the median time on drug was 412 days with 27% (3/11) discontinuing due to grade 3/4 diarrhea/colitis; 36% (4/11) due to progression, 9% (1/11) due to pneumonia and subsequent progression 2 months later. Of the 3 patients that remain on study, their median time on therapy is 1072 days without evidence of toxicities. Of the 17 patients that participated in placebo-controlled phase III studies, 11 participated in R +/- idelalisib (study 116) and 6 on BR+/-idelalisib (study 115). Study 116 was unblinded during the trial: 35% (4/11) received idelalisib + R upfront. Of these, only 2 patients (50%) were able to continue on extension study as the other 2 patients developed pneumonitis and were taken off study early. One patient is continues on study at day 1011 whereas the second patient developed progressive multifocal leukoencephalopathy on day 714 and died days after being taken off drug. 86% (6/7) of the remaining patients initially randomized to placebo crossed over to idelalisib at the time of confirmed progression. Of these, 14% (1/6) developed both colitis and later pneumonitis, 14% (1/6) withdrew consent, and 14% (1/6) had progression of disease. For blinded study 115 (BR+/-idelalisib), 6 patients participated: 33% (2/6) developed grade 3/4 diarrhea/colitis, 16% (1/6) developed pneumonitis, and 16% (1/6) has progressed. In our experience, none of the patients with severe diarrhea/colitis were able to maintain lower doses for a prolonged period of time without recurrent colitis or the development of pneumonitis. Since the start of these trials, 31% (12/38) of the patients have died: the overall survival after discontinuation for these patients varies widely from 0 to 303 days with a median overall survival of 64 days after discontinuation. Most patients with relapsed/refractory CLL who discontinued idelalisib early were difficult to treat and had poor outcomes. Over the course of the trials, the Bruton's tyrosine kinase inhibitor ibrutinib was approved and used as salvage therapy in 10 patients with confirmed progression; except for 1 patient, all patients successfully achieved a prolonged response with ibrutinib suggesting salvage therapy with a targeted agent may be a reasonable therapeutic approach for patients after idelalisib failure. Interestingly, the rate of Richter's transformation was extremely rare in this study (2%). Conclusions This single-institution experience with idelalisib identifies baseline factors associated with therapy discontinuation, mainly grade 3/4 diarrhea/colitis and progression of disease as a reason for discontinuation from therapy. Our data suggest the use of ibrutinib may be a reasonable choice in patients after idelalisib failure. Disclosures Barrientos: ASH-AMFDP: Research Funding; Gilead: Research Funding; NIH/NCATS: Research Funding. Off Label Use: idelalisib is approved in combination with rituximab only. I will discuss our experience of idelalisib in combination with other agents.

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