Transformation Of Indolent Lymphoma Research Articles

Transformation of indolent lymphomas into diffuse large B-cell lymphoma

Transformation of indolent lymphomas into diffuse large B-cell lymphoma

Real-World Outcomes of CD19CAR T Cell Therapy in Adult Patients with Relapsed Refractory Transformed Indolent Lymphoma

Introduction Transformation of indolent lymphomas to diffuse large B-cell lymphoma (DLBCL) is associated with poor outcomes, particularly for patients (pts) with relapsed or refractory (r/r) disease. While chimeric antigen receptor (CAR) T cell therapy has revolutionized the management of r/r DLBCL and is approved for transformed indolent lymphoma (TIL), patients with TIL were largely underrepresented in the pivotal trials leading to the approval of CD19CAR T. In this study, we evaluate the safety and efficacy of standard of care (SOC) CD19CAR T in TIL relative to de novo DLBCL (dDLBCL). Methods We performed a multi-center retrospective study to evaluate safety and efficacy of SOC CD19CAR T in adults with r/r TIL and dDLBCL treated at 5 centers. Eligibility criteria included age ≥ 18 years old, diagnosis of DLBCL (de novo or transformed), r/r disease, and receipt of SOC CD19CAR T. Pts who received CAR T on clinical trials were excluded. We defined TIL as DLBCL transformed from follicular lymphoma (FL), marginal zone lymphoma (MZL), or Waldenstrom's macroglobulinemia (WM). Pts with Richter's syndrome were excluded. Safety endpoints: incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. Response was assessed using 2014 Lugano Criteria. Efficacy endpoints include best overall response rate (ORR) (proportion of patients achieving a complete or partial response), complete response (CR) rate, progression/relapse-free survival (PFS) and overall survival (OS). Results A total of 788 pts were included (212 (27%) TIL, 576 (73%) dDLBCL) with the CAR T infusion date ranging from 12/2017 to 03/2023. In the TIL cohort, 192 (91%) pts transformed from FL, 14 (7%) MZL, 5 (2%) WM, and 1 indolent lymphoma NOS. In TIL and dDLBCL cohorts, respectively, the median age at infusion was 64 (range 33-85)/64 (21-85) yrs, 37%/36% were female, pts received a median of 3 (range: 1-11)/ 3 (1-13) prior lines of therapy, and 11%/13% had ECOG ≥2 at time of lymphodepletion. In TIL cohort, 44 (21%) pts received prior stem cell transplantation (41 autologous, 3 allogeneic, and none both), while in dDLBCL cohort, 135 (23%) received prior SCT (122 autologous, 9 allogeneic, and 4 both). In TIL and dDLBCL cohorts, 76%/73% received axicabtagene ciloleucel, 17%/18% tisagenlecleucel, and 7%/10% lisocabtagene maraleucel, respectively. Similar toxicities were observed in both cohorts. Any grade CRS/grade ≥ 3 CRS were observed in 76% (95% CI: 70-82%)/ 5% (3-9%) of TIL pts and 81% (78-84%)/ 6% (4-8%) of dDLBCL pts, respectively. Any grade ICANS/grade ≥ 3 ICANS rate were observed in 37% (95%CI: 31-44%)/ 16% (11-21%) of TIL pts and 49% (45-53%)/ 23% (20-27%) of dDLBCL pts, respectively. In TIL and dDLBCL cohorts, respectively, 49%/59% of pts received tocilizumab for CRS and 41%/51% received steroids for CRS or ICANS. Efficacy outcomes were comparable. The best ORR/ CR rate were 78% (95%CI: 72-83%)/ 63% (56-70%) in the TIL cohort and 77% (73-80%)/ 55% (51-59%) in the dDLBCL cohort. Among responders, the median time from infusion to best response was 33 days (IQR: 29-69) and 34 days (IQR: 29-85), respectively. With a median overall follow-up of 13.4 (0.03-63.1) months (mons), the median PFS was 11.2 mons (95%CI: 6.3-20.8) in the TIL and 7.9 mons (95%CI: 6.1-12.2) in the dDLBCL cohort, with a 24-month PFS of 39.4% (95%CI: 32.2-46.5%) and 39.7% (95%CI: 35.5-44.0%) respectively (logrank p=0.45). Median OS was 41.7 mons (95%CI: 24.9-not reached) and 29.7 mons (95%CI: 22.1-not reached) with a 24-month OS of 57.8% (95%CI: 50.1-64.7%) and 53.2% (95%CI: 48.4-57.7%) in TIL and dDLBCL cohorts, respectively (logrank p=0.49). There was no statistically significant difference between the survival outcomes of the TIL and dDLBCL cohorts. 41% (86/212) and 42% (241/576) pts died in the TIL and dDLBCL cohorts respectively, with similar rates of CAR T cell related deaths (9.3% vs 7.1%). Conclusion This study represents the largest evaluation to date of outcomes of CD19CAR T in TIL. The results indicate that CD19CAR T is tolerable and active in pts with r/r TIL with safety and efficacy outcomes similar to that observed in pts with dDLBCL. Our findings suggest CD19CAR T cell therapy may be able to overcome the historically poor prognosis associated with r/r TIL.

Testicular mass: a rare presentation of Richter's syndrome

BackgroundRichter’s syndrome is the transformation of indolent lymphoma into an aggressive form, most commonly diffuse large B cell lymphoma. Most patients are known to have chronic lymphocytic leukemia. Richter’s syndrome arises in the lymph nodes or bone marrow and rarely presents with extra nodal involvement.Case presentationOur patient presented with Richter’s syndrome at an extremely uncommon site, i.e., testis. This is the fourth case reported in literature. Moreover, our case represents the longest follow-up reported so far with recurrence-free survival of more than 2 years now.ConclusionTesticular mass in a patient with a history of chronic lymphocytic leukemia should raise the clinical suspicion of Richter’s syndrome and accordingly the patient should be thoroughly investigated and treated. Treatment needs multidisciplinary team approach: urologist, pathologist and hematologist.

Survival from time of transformation in patients with transformed lymphoma at time of diagnosis.

e20054 Background: Histologic transformation (HT) to aggressive lymphoma can occur in indolent lymphoma and is considered to convey poor prognosis. Most data come from follicular lymphoma (FL). We conducted a retrospective analysis to compare outcomes of transformed marginal zone lymphoma and lymphoplasmacytic lymphoma (tMZL/LPL) with those of transformed FL (tFL). Methods: We collected data from patients diagnosed with HT between 2000 and 2018. Transformed CLL was excluded. Survival estimates were done with the Kaplan Meier method; comparisons were done with log-rank test. The effect of covariates on OS was evaluated with Cox proportional hazards method. Results: We identified 87 pts (58 tFL, 29 tMZL/LPL). There were no differences in baseline characteristics, except for COO subtype by Hans criteria and circulating IgM. There were no differences in OS or EFS based on the underlying lymphoma subtype (OS: tFL = 60.1m vs. tMZL/LPL = 64.8m, p = 0.53; EFS: tFL = 25.2m vs. tMZL/LPL = 27.6m). Univariate and multivariate analyses identified age at HT (HR for age > 60 = 3.5, 95% CI: 1.7-7.6), poor performance status (HR for ECOG ≥3 = 23, 95% CI: 7.3-70) and having a previous diagnosis of indolent lymphoma (HR for previous diagnosis = 3.7, 95% CI: 1.87-7.4) as adverse risk factors for OS after HT. Pts with previous diagnosis of indolent lymphoma with subsequent HT had inferior OS than pts presenting first with HT (median OS 25m vs. not reached, p < 0.0001); EFS (median EFS for treated pts = 11m vs. 49m). Conclusions: Underlying lymphoma does not affect OS after HT and long term survival can be achieved in pts who receive treatment. tMZL/LPL is more frequently of non-GCB origin has monoclonal IgM. Pts who present with HT as their first lymphoma-related event have better OS. These findings will lead to further exploration of the genetic changes that occur at the time of transformation of indolent lymphomas. [Table: see text]

PB1810 CLINICAL CHARACTERISTICS AND OUTCOMES OF DIFFUSE LARGE B‐CELL LYMPHOMA (DLBCL) LACKING THE IMMUNOGLOBULIN LIGHT CHAIN RESTRICTION (ILCR) BY FLOW CYTOMETRY

Background:The immunoglobulin light chain restriction (iLCR) detected by flow cytometric analysis is useful to prove the monoclonality of B‐cell lymphoma. However, we occasionally encounter cases of B‐cell lymphoma without iLCR. The lack of immunoglobulin expression on B‐cell lymphomas arises from abnormalities of gene transcription or translocation of fully assembled proteins on the cell surface. Few reports have evaluated patients of diffuse large B‐cell lymphoma (DLBCL) without iLCR, but the clinical characteristics and outcomes of DLBCL lacking iLCR has not been firmly elucidated.Aims:In the present study, we evaluated the clinical features and prognosis of DLBCL without iLCR.Methods:We conducted a retrospective analysis using a database of our hospital. From April 1, 2007 to March 31, 2017, patients who were performed flow cytometric analysis and diagnosed with DLBCL were eligible. The definition of iLCR was determined when κ‐positive cells were more than 3 times that of λ‐positive cells (κ‐DLBCL) or λ‐positive cells were more than 2 times that of κ‐positive cells (λ‐DLBCL) in dual‐color diagrams. We excluded cases with HIV infection, central nervous system involvement, intravascular lymphoma, primary mediastinal large B‐cell lymphoma, transformation of indolent lymphoma and cases in which flow cytometric analysis did not reflect the lymphoma cells. The endpoints of this study were overall survival (OS) and progression free survival (PFS) of iLCR‐positive/negative DLBCL and κ/λ‐DLBCL. The OS was defined as the time from diagnosis to the last follow‐up or death from any cause. The PFS was defined as the time from diagnosis to disease progression, relapse or death due to any cause.Results:70 patients were identified; 14 cases with iLCR‐negative (20%) and 56 cases with iLCR‐positive (80%), with a median age of 73 years (range 40–86), 80% > 60 years, 44% male, 74% Stage III/IV, 63% IPI high–int/high, 41% were treated with CHOP‐based, 44% THP‐COP‐based (THP‐COP: pirarubicin, cyclophosphamide and vincristine on day 1 and predonisolone on days 1–5) regimen and 91% were combined with rituximab. Median observation time was 605 days (range 2–3223). There were no differences in clinical characteristics with regard to sex, age, serum lactate dehydrogenase (LDH), performance status (PS), stage, number of extranodal lesions, International Prognositic Index (IPI), B‐symptoms and bulky lesion between the two groups. Cell surface markers also showed no difference between iLCR‐positive and iLCR‐negative DLBCL; CD5 (21.4% vs 14.2%; p = 0.72), CD10 (44.6% vs 21.4%; p = 0.138), CD19 (92.8% vs 96.4%; p = 0.494), CD20 (100% vs 91.0%; p = 0.575), CD23 (21.4% vs 10.7%; p = 0.37), CD25 (28.5% vs 41.0%; p = 0.542), CD30 (14.2% vs 1.7%; p = 0.0997), sIgG(35.7% vs 30.4%; p = 0.758), sIgM (50.0% vs 67.9%; p = 0.229). 2‐year‐OS and PFS of iLCR‐positive and iLCR‐negative DLBCL were 61.2% vs 53.9% (p = 0.557) (Fig1) and 51.9% vs 55.0% (p = 0.924) respectively. There are 34 κ‐DLBCL and 22 λ‐DLBCL in 56 iLCR‐positive group. 2‐year OS and PFS of κ‐DLBCL and λ‐DLBCL were 64.3% vs 59.0% (p = 0.746) and 58.6% vs 47.8% (p = 0.255) respectively.Summary/Conclusion:In this study, we observed no difference in the clinical characteristics and outcomes between iLCR‐negative DLBCL and iLCR‐positive DLBCL. In iLCR‐positive DLBCL, the outcome of κ‐DLBCL is similar to that of λ‐DLBCL. Therefore, the presence or absence of iLCR and deviation of κ or λ light chain of DLBCL may not influence on the prognosis and selection of treatment.

Efficacy of Rituximab Maintenance for Diffuse Large B Cell Lymphoma with Transformation

<Introduction>The transformation of indolent lymphoma is biologic event leading to aggressive lymphoma status. As same de-novo diffuse large B cell lymphoma (DLBCL), the outcome of DLBCL with transformation has improved by the use of rituximab contained therapy. However, the effects of rituximab maintenance for DLBCL with transformation remain unknown. We performed a retrospective analysis to evaluate the efficacy of rituximab maintenance for DLBCL with transformation.<Patients and Methods>We studied patients newly diagnosed as transformed DLBCL from March 2005 to November 2017 in our institution. The pathological diagnosis was performed based on morphological and immunohistochemical analyses. Transformed DLBCL was defined in our study as a coexistence with components of follicular lymphoma (FL) or MALT lymphoma and DLBCL in a biopsied tissue at the diagnosis. Almost all patients were treated with R-CHOP chemotherapy (2 were treated by radiation with or without rituximab therapy, one was R-ICE chemotherapy). 15 patients received rituximab maintenance therapy for two years after achieving good PR or more by first therapy. PET-CT was used to evaluate the stage at the diagnosis and the response after therapy. The statistical analyses of characteristics of patients were performed by Fisher's exact test. The survivals were calculated by the Kaplan Meier method, and statistical analysis were performed by log rank test. Factors affecting OS and PFS were evaluated using Cox proportional hazard model.<Results>We analyzed 52 transformed patients. Median age was 64 years old (range 43-87), 35 patients were male (67%) and 17 were female (33%), 44 (84%) were transformed from FL and 8 (16%) were from MALT lymphoma. Germinal center B cell (GCB) type were 35 (67%) and activated B cell (ABC) were 16 (30%). An ECOG performance status (PS) ≧2 was only 1 patient (1.9%). 3 (5.7%) had B symptoms, 16 (30%) had LDH ≧ULN, 28 (53%) had stage of Ⅲ or Ⅳ, 5 (9.6%) had bone marrow invasion, 13 (25%) had IPI score ≧3, and 26 (50%) had one or more extranodal diseases. There were no significant differences in characteristics between rituximab maintenance group and no maintenance group. After induction therapy, CR was achieved in 48 (92%) and PR was 4 (8%). With a median follow up of 66 months (range 7-143), 5-year OS and 5-year PFS were 95.6% (range 83.3-98.9) and 71.7% (range 55.4-83.0) respectively. There were not statistically significant in OS and PFS between the rituximab maintenance group and the observation group (5-year OS: 100% vs 93.6%, p=0.0895, 5-year PFS: 100% vs 65.7%, p=0.0792). However, subgroup analyses showed that rituximab maintenance group was significantly superior to no maintenance group in PFS in the cases of stage III or more (5-year PFS 100% vs 30.7%, p=0.0137), males (100% vs 56.7%, p=0.0436), and GCB type (100% vs 60.0%, p=0.029). The rituximab maintenance (P=0.0356: HR 0.20; 95% CI 0.046-0.899) was indicated as the clinical parameters related to PFS by multivariate analysis.<Discussion and Conclusion>Generally, DLBCL with transformation have poor prognosis. There are several previous reports about rituximab maintenance for patients with aggressive B-cell lymphoma, which concluded that rituximab maintenance in first remission didn't provide an advantage to OS and PFS. NHL 13 trial demonstrated statistical benefit of rituximab maintenance for males and low IPI group. Regard to transformed lymphoma, the study for maintenance of rituximab was really few. Hany R et al reported the outcome of patients with transformation that rituximab maintenance post R-CHOP and the number of maintenance rituximab cycles were associated with better PFS. Our data provided that rituximab maintenance was effective in transformed DLBCL with regard to prolonged PFS in subgroups of progressive stage, men, and GCB. In conclusion, from our study it was suggested that rituximab maintenance therapy have possible to improve outcomes for DLBCL with transformation. DisclosuresMishima:Chugai pharmaceutical inc, Roche: Other: commissioned work. Yokoyama:Chugai pharmaceutical inc, Roche: Other: commissioned work. Nishimura:Chugai pharmaceutical inc, Roche: Other: commissioned work. Terui:Takeda pharmaceutical: Honoraria; Janssen Pharmaceutical KK: Honoraria; Celgene: Honoraria; Bristol myers Squib: Honoraria; Novartis pharma: Honoraria.

Return to work for patients with diffuse large B-cell lymphoma and transformed indolent lymphoma undergoing autologous stem cell transplantation.

BackgroundAutologous stem cell transplantation (ASCT) is the standard treatment for patients with relapsed diffuse large B-cell lymphoma (DLBCL) or transformed indolent lymphoma (TIL). The treatment is mainly considered for younger patients still available for the work market. In this study, social outcomes after ASCT in terms of return to work (RTW) are described.Patients and methodsInformation from national administrative registers was combined with clinical information on patients, who received ASCT for relapse of DLBCL or TIL between 2000 and 2012. A total of 164 patients were followed until RTW, disability or old-age pension, death, or December 31, 2015, whichever came first. A total of 205 patients were followed with disability pension as the event of interest. Cox models were used to determine cause-specific hazards.ResultsDuring follow-up, 82 (50%) patients returned to work. The rate of returning to work in the first year following ASCT was decreased for patients being on sick leave at the time of relapse (hazard ratio [HR] 0.3 [0.2;0.5]) and increased for patients aged ≥55 years (HR 1.9 [1.1;3.3]). In all, 56 (27%) patients were granted disability pension. Being on sick leave at the time of relapse was positively associated with receiving a disability pension in the first 2 years after ASCT (HR 3.7 [1.8;7.7]).ConclusionPatients on sick leave at the time of relapse have a poorer prognosis regarding RTW and have a higher rate of disability pension. Furthermore, patients >55 are more likely to RTW compared to younger patients. These results indicate an unmet need for focused social rehabilitation.

Double-Hit and Double-Expressor Lymphomas Are Not Associated with an Adverse Outcome after Allogeneic Stem Cell Transplantation

Double-Hit and Double-Expressor Lymphomas Are Not Associated with an Adverse Outcome after Allogeneic Stem Cell Transplantation

Social Outcomes after High Dose Chemotherapy with Autologous Stem Cell Transplant

Introduction:Diffuse large B-cell lymphoma (DLBCL) is the largest subgroup of malignant lymphoma. Prognosis has increased after introduction of rituximab, and today more than 80% of the patients will achieve partial or complete remission after standard immunochemotherapy. However, approximately 30% will either present with refractory disease or develop relapse. The standard approach for younger patients with relapsed disease and without major comorbidity is salvage treatment followed by high dose therapy with autologous stem cell transplant (ASCT). This potentially curative treatment is toxic with many side effects, and social outcomes for patients need to be investigated.Objectives:Patients with relapse of de novo DLBCL and transformed indolent lymphoma (TIL) were included. The aim was to describe social outcome after ASCT in form of return to work (RTW).Methods: Patients with B-cell lymphoma in the period 2000-2012, who received ASCT as relapse treatment, were extracted from the Danish National Lymphoma Registry. Medical records were reviewed for clinical, pathological, and treatment information. Individual information on socioeconomic factors and social outcomes were achieved by cross-reference to national administrative registries. Patients were included in RTW analyses, if they received public welfare benefits in at least four weeks including the week of stem cell reinfusion. RTW was defined as four consecutive weeks without receiving welfare benefits; retirement, disability pension and death was regarded as competing events. Patients were followed until RTW, emigration, permanent withdrawal from the labour market, death, or December 31, 2015, whichever came first.Results: A total of 369 patients were identified. At the time of ASCT, 164 (44%) patients received public welfare benefits in form of either sick leave or unemployment benefits. Furthermore, 61 (17%) received disability pension or similar, 102 (28%) received old age pension, and 41(11%) patients did not receive any welfare benefits.The 164 patients receiving sick leave or unemployment benefits were included in the analysis. Median age was 54 years (25-65), 16 patients were above the age of 60, and 104 were male (64%). A total of 54 patients had primary refractory disease; median time to relapse was 1.7 years. Both diagnoses were equally represented with 78 (48%) patients with TIL, IPI score at relapse was available for 118 patients, 22 % had a score of high-intermediate or high. Furthermore, socioeconomic factors at time of relapse showed, that 36 (22%) patients had only basic (mandatory) education, 39 (24%) patients lived alone and 60 (37%) patients had a low disposable income, corresponding to the 1st or 2nd quintile of the Danish population with the same gender and in the same age-group. Most of the patients, n=118 (72%), did not have comorbidities, but 46 patients had one or more at time of relapse. (Table 1)Median time to return to work was 420 days, ranging from 13 to 909 days. One year after year after ASCT, 57 (35%) patients had returned to work, 15 (10%) received disability pension, and 7 (4%) received old age pension. A total of 48 (29%) were still on sick leave, and 37 (23%) had died. (Figure 1)Conclusion: In this nationwide population based study we found that after one year only 35% of the patients had returned to work, 14% had been retired and 23% had died. This emphasizes that this patient group is at risk of impaired social status. There is an unmet need of focused social rehabilitation. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic Factors for Patients with Diffuse Large B Cell Lymphoma and Transformed Indolent Lymphoma Undergoing Autologous Stem Cell Transplantation in Denmark 2000-2012

▪Introduction: Diffuse large B-cell lymphoma (DLBCL) is the largest subgroup of malignant lymphoma. Today more than 80% of the patients will achieve partial or complete remission. However more than 20 % will either relapse or present with refractory disease. The standard approach for patients without major comorbidity is salvage treatment followed by high dose therapy with autologous stem cell transplant (HDT). This potentially curative treatment is toxic with many side effects and procedure related mortality, and therefore identification of patients eligible for HDT is a difficult challenge.Objectives: Patients with relapse of de novo DLBCL and transformed indolent lymphoma (TIL) were included. The aim was to identify clinical prognostic markers that can identify patients who will not benefit from HDT.Methods: From the national lymphoma registry patients with relapse of B-cell lymphoma in Denmark in the period 2000-2012, who underwent HDT, were extracted. Medical records were reviewed for clinical, pathological, and treatment information, and outcome. Patients were followed until death or emigration or until February 1, 2015. The Kaplan-Meier method was used to estimate overall survival (OS) and progression free survival (PFS). Cox regression models were used to assess prognostic factors.Results: A total of 370 patients were included, 174 with de novo DLBCL, and 196 with TIL, 143 of the 196 had histologically confirmed transformation. Median age was 58 (22-73), and 59% of the patients were male.With a median follow-up of 82 months from HDT, the 5-year OS was 52% and the 5-year PFS was 44% (median PFS 3.2 years). For the DLBCL patients the 5-year OS was 43% and the 5-year PFS was 38%. For TIL patients the OS was 62% and the PFS 49% (figure 1).During the first 100 days, 29 patients (8%) were admitted to the intensive care unit (14 DLBCL), and only four of these patients were alive at six months. The non-relapse mortality (NRM) at day 100 was 6 % for both groups, after five years 25% for DLBCL and 15% for TIL.No significant difference in 5-year PFS was seen between sexes or age, but patients younger than 58 had better 5-year OS compared to patients aged 58 or above (p=0.047).There was no difference in relapse treatment (DHAP vs ICE). Smoking (ever vs. never) caused a significantly worse OS (p=0.034). All IPI-factors, except Ann Arbor stage, was of prognostic importance (PFS). Primary refractory disease was of poor prognostic importance (p=0.001), and in patients, for whom the time from last salvage treatment to reinfusion of stem cells was more than 2 months, had a worse outcome (p=0.006). Patients, with less than 20 days of hospital admission in the period from the date of relapse to start of HDT, had a significantly higher survival (OS and PFS) (p>0.001).In a multivariate analysis (PFS), LDH above upper normal reference, HR 1.4 (95% CI: 1.0;2.1), involvement of more than one extranodal site, HR 1.6 (1.1;2.3) primary refractory disease, HR 1.6 (1.1;2.3) and more than two earlier relapses, HR 1.9 (1.1;3.5) were all factors associated with adverse outcome.For OS, the multivariate analysis showed, that patients with TIL had a better outcome, HR 0.7 (0.5;0.9), compared to DLBCL. Age above 58, HR 1.5 (1.1;2.1), involvement of more than one extranodal site, HR 1.9 (1.4;2.8), and primary refractory disease, HR 1.6 (1.1;2.3) were factors associated with adverse outcome.Discussion:In this population based study we find a 5-year OS of 52% after HDT and a 5-year PFS of 44%. Patients with TIL have a significantly higher 5-year PS (49%) than patients with de novo DLBCL (38%) whereas NRM is identical for the two groups at day 100 (6%). However, NRM increases subsequently more for DLBCL than for TIL over time to 25% and 15 % respectively after five years. Furthermore we show that hospitalization days less than 20 and postponement of stem cell infusion beyond 2 month after harvest may be useful parameters that can identify patients that have better or worse outcome after HDT.This nationwide study cohort with the long follow-up period is applicable to a general population of patients, and this may explain the somewhat lower outcome compared to other published HDT cohorts. [Display omitted] DisclosuresBrown:Bayer: Consultancy; Roche: Consultancy, Speakers Bureau.

Sequencing-Based Detection of Circulating Tumor DNA in the Autologous Stem Cell Grafts of Patients with Diffuse Large B-Cell Lymphoma Undergoing Hematopoietic Stem Cell Transplantation

▪Introduction: High dose chemotherapy followed by autologous stem cell transplantation (ASCT) cures a subset of patients with chemosensitive relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL). Several factors associated with post-ASCT outcome have been identified, including pre-ASCT PET status, but better biomarkers are needed in order to optimally select candidates for the procedure. In other lymphoma subtypes with defining chromosomal translocations, PCR detection of pre- and post-ASCT minimal residual disease (MRD) in peripheral blood and of tumor contamination in the stem cell product is associated with inferior outcome. Until recently, MRD detection in DLBCL was limited by the rarity of detectable circulating disease using conventional techniques. The immunosequencing platform (Adaptive Biotechnologies, Corp.) is a next-generation-sequencing (NGS)-based MRD assay that detects small amounts of circulating tumor DNA (CTD) in patients with lymphoid malignancies. The assay detects CTD at diagnosis in most DLBCL patients and CTD levels track with response to induction therapy (Armand, 2013). Persistence of CTD or recurrence of CTD after completion of therapy is highly associated with DLBCL relapse (Kurtz, 2015; Roschewski, 2015). We evaluated whether CTD in autologous stem cell grafts was predictive of outcome in patients with rel/ref DLBCL undergoing ASCT.Methods: We retrospectively studied patients with rel/ref DLBCL, including transformed indolent lymphoma (TIL), who had paired archival tumor and autologous stem cell specimens and underwent ASCT at Brigham and Women's Hospital/Dana-Farber Cancer Institute from 2003-2013. Genomic tumor DNA was extracted from archival formalin-fixed paraffin-embedded (FFPE) tissue and analyzed using the NGS-based MRD assay. PCR amplification of IGH-VDJ, IGH-DJ,and IGK regions using universal consensus primers was performed followed by NGS to determine the tumor clonotype(s), defined as having a frequency > 5% in the tumor specimen. DNA from all available autologous peripheral blood or bone marrow stem cell specimens from each patient was amplified using universal consensus primers and sequenced to determine the level of CTD, defined as the number of lymphoma molecules per diploid genome.Results: We identified 98 eligible patients with rel/ref DLBCL/TIL. The median age was 60 (range 22-77) years; 63% were male; 65% had DLBCL, 29% had TIL, and 5% had primary mediastinal DLBCL; the median number of prior lines of therapy was 2 (range 2-5); all had received prior rituximab; 38% had primary refractory disease; 60% were in complete remission at ASCT; 96% received CBV conditioning. Median follow-up was 56 (range 19-123) months. The 4y progression-free survival (PFS) and overall survival (OS) in the entire cohort were 46% and 64%, respectively.Among 83 patients (85%) with sufficient DNA for clonotype determination, a clonotype was identified in 59 (71%). CTD data was complete in 53 patients (52 received peripheral blood stem cells (PBSC) and 1 received bone marrow). Eight patients (15%) had detectable CTD (CTD+) in the stem cell autografts (all PBSC) and 6/8 relapsed after ASCT. One CTD+ patient had early non-relapse mortality less than 1 month after ASCT and was never restaged. Seven of 8 CTD+ patients had TIL histology, 5 of whom relapsed (4 with aggressive lymphoma). The 4y PFS and OS in CTD+ v CTD- patients were 13% v 48% (P =0.01), and 38% v 67% (P =0.013), respectively [Figure 1]. In multivariable models including CTD status and pre-ASCT characteristics, CTD+ was the only factor associated with OS (HR 3.1, p=0.018), but was not significantly associated with PFS.Discussion: In patients with rel/ref DLBCL undergoing ASCT, the presence of CTD in the autologous stem cell graft is associated with inferior survival. CTD detection in the autograft may be more common in patients with TIL. In studies evaluating CTD detection in DLBCL, the plasma compartment has been more sensitive for detecting CTD than mononuclear cells. The use of concentrated cell specimens in this study may have decreased the sensitivity of the assay. Nevertheless, if the present findings are confirmed in a larger population, CTD detection may permit the identification of a subgroup of patients with a particularly poor outcome after ASCT, for whom alternative approaches could be considered. [Display omitted] [Display omitted] DisclosuresHerrera:Sequenta, Inc.: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Kong:Adaptive Biotechnologies, Corp.: Employment, Other: Stockholder. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy. Rodig:Perkin Elmer: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding. Faham:Adaptive Biotechnologies Corp.: Employment, Other: Stockholder. Armand:BMS: Research Funding; Infinity: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Sequenta, Inc.: Research Funding.

Double Expressing (MYC/BCL2) and Double-Hit Diffuse Large B-Cell Lymphomas Have Inferior Survival Following Autologous Stem Cell Transplantation

Background: Double-hit lymphomas (DHL) are a subset of diffuse large B-cell lymphoma (DLBCL) with concurrent chromosomal rearrangements involving the MYC and BCL2 or BCL6 genes, and are associated with dismal outcomes with standard upfront therapy. Double expressing lymphomas (DEL) are a subset of DLBCL with co-expression of MYC and BCL2 by immunohistochemistry (IHC), and also have a poor prognosis with standard therapy. While DHL status may be associated with inferior outcomes in patients with relapsed or refractory (rel/ref) disease (Cuccuini, Blood, 2012), little is known about the outcome of DHL patients with rel/ref disease who proceed to autologous stem cell transplantation (ASCT), and no study to date has examined the outcome of patients with DEL following ASCT. We evaluated the prognostic impact of DHL and DEL status in patients with rel/ref DLBCL who underwent ASCT at 2 centers.Methods: We retrospectively studied patients with rel/ref DLBCL, including transformed indolent lymphoma (TIL), who underwent ASCT at Brigham and Women's Hospital/Dana-Farber Cancer Institute (DFCI) and City of Hope (COH) between 1/2000 and 7/2013. The most recent biopsy prior to ASCT was used for testing when possible. IHC for MYC and BCL2 were performed using the Ventana (MYC: DFCI) and Leica BOND III (MYC: COH; BCL2: DFCI, COH) platforms according to standard protocols. For DEL, IHC cutoffs of ≥ 40% MYC-positive and ≥ 50% BCL2-positive cells were used (Johnson, JCO, 2012). Fluorescence in situ hybridization (FISH) for MYC was performed using LSI MYC dual-color break-apart probes (Abbott Molecular, Des Plaines, IL). MYC -rearranged cases had FISH for BCL2 and BCL6 performed using LSI BCL2 and BCL6 dual-color break-apart probes. DHL was defined as > 20% nuclei with break-apart signals for MYC and BCL-2 and/or BCL-6.Results: 201 patients with available archival tissue and clinical data were included. The median age was 60 (range 30-77) years; 60% were male; 26% had TIL; the median number of prior lines of therapy was 2 (range 2-5); 99% had prior rituximab; 53% had primary refractory disease or early (< 6 mo) relapse; 60% were in CR by PET at ASCT; and conditioning regimens were: 66% CBV v 16% BEAM v 10% rituximab and/or ibritumomab tiuxetan-BEAM v 8% other. Overall, the 4y progression-free survival (PFS) and overall survival (OS) were 44% and 61%, respectively.Among 185 patients with complete IHC data, 38% were DEL. The 4y PFS and OS in patients with DEL compared to non-DEL patients were 37% v 52% (p =0.001), and 51% v 69% (p =0.005), respectively [Figure 1]. Results were similar using other reported IHC cutoffs for DEL (e.g. MYC ≥ 40%/BCL2 ≥ 70%, Green, JCO, 2012). Among 93 patients with complete FISH and IHC data available, 13% had MYC rearrangement: 4% were MYC/BCL2 DHL, 3% were MYC/BCL6 DHL, and 2% had rearrangements of all 3 loci. The 4y PFS and OS in DHL v non-DHL were 30% v 42% (p =0.042), and 40% v 57% (p =0.026), respectively. Patients with DEL (excluding DHL) and patients with DHL had similar PFS, which was inferior to non-DEL/non-DHL patients (4y PFS 35% v 30% v 45%, respectively, p =0.026) [Figure 2]. In multivariable models testing pre-ASCT variables, including PET response to salvage, DEL (HR 2.1, p=0.0002), TIL histology (HR 1.8, p=0.009), and SD/PD at ASCT (HR 2.9, p=0.025) were associated with poorer PFS, while DEL (HR 2.0, p=0.004) and SD/PD (HR 3.1, p=0.021) were associated with poorer OS. Neither MYC (≥ 40%) nor BCL2 (≥ 50%) expression alone was independently associated with PFS or OS. When analysis was restricted to the subset of patients with complete IHC and FISH data, DEL (HR 1.9, p=0.023), DHL (HR 2.4, p =0.048), and SD/PD at ASCT (HR 7.6, p =0.009) were associated with inferior PFS. No center effect was observed.Conclusions: DEL and DHL status are both associated with inferior PFS in patients with rel/ref DLBCL who undergo ASCT, regardless of remission status. Although ASCT remains a potentially curative approach, these patients should be targeted for study of pre- or post-ASCT relapse risk reduction strategies. [Display omitted] [Display omitted] [Display omitted] DisclosuresHerrera:Genentech: Research Funding; Pharmacyclics: Research Funding; Sequenta, Inc.: Research Funding. Budde:Atara Biotherapeutics: Consultancy; Seattle Genetics, Inc.: Research Funding; Merck: Research Funding; Ikara Inc: Patents & Royalties. Chen:Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau. Davids:Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Other: ad board. Nademanee:Seattle Genetics Inc.: Research Funding; Celgene: Consultancy; Gilead: Consultancy; Spectrum: Research Funding. Siddiqi:Pharmacyclics: Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Forman:Mustang: Research Funding; Amgen: Consultancy. Rodig:Perkin Elmer: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding. Krishnan:Onyx: Speakers Bureau; Janssen: Consultancy; Millenium: Speakers Bureau; BMS: Consultancy; Jazz: Consultancy; Celgene: Consultancy, Speakers Bureau. Armand:Merck: Consultancy, Research Funding; Infinity: Consultancy, Research Funding; BMS: Research Funding; Sequenta, Inc.: Research Funding.

Salvage chemotherapy and autologous stem cell transplantation for transformed indolent lymphoma: a subset analysis of NCIC CTG LY12

AbstractThe treatment of transformed indolent lymphoma (TRIL) often includes salvage chemotherapy (SC) and autologous stem cell transplant (ASCT). NCIC CTG LY12 is a randomized phase 3 trial comparing gemcitabine, dexamethasone, and cisplatin (GDP) with dexamethasone, cytarabine, and cisplatin (DHAP) before ASCT. This analysis compares the results of SC and ASCT for TRIL with de novo diffuse large B-cell lymphoma (DLBCL). Six-hundred nineteen patients with relapsed/refractory aggressive non-Hodgkin lymphoma were randomized to GDP or DHAP; 87 patients (14%) had TRIL and 429 (69%) had DLBCL. The response rate to SC was 47% in TRIL and 45% in DL (P = .81). Transplantation rates were similar: TRIL 53% and DL 52% (P = 1.0). With a median follow-up of 53 months, 4 year overall survival was 39% for TRIL and 41% for DL (P = .78); 4 year event-free survival (EFS) was 27% for TRIL and 27% for DL (P = .83). Post-ASCT, 4-year EFS was 45% for TRIL and 46% for DL. Histology (TRIL or DL) was not a predictor of any outcome in multivariate models. Patients with relapsed or refractory TRIL and DLBCL have similar outcomes with SC and ASCT; this therapy should be considered the standard of care for patients with TRIL who have received prior systemic chemotherapy. NCIC CTG LY12 is registered at ClinicalTrials.gov as #NCT00078949.

Outcome determinants for transformed indolent lymphomas treated with or without autologous stem-cell transplantation

Transformation of indolent lymphomas (IL) to an aggressive histology (TIL) often results in a rapid clinical course, treatment refractoriness and shortened survival. Although rituximab-containing regimens (R-chemo) have become standard of care in CD20-positive TIL, the role of autologous stem-cell transplantation (ASCT) is still debated. The purpose of this study was to determine whether the outcome of TIL patients improved if they, at transformation, also received ASCT. Furthermore, we investigated the outcome of cases with histologically low- and high-grade components diagnosed either simultaneously or after a period of overt indolent disease. We also analyzed, whether prior rituximab treatment during the indolent course of the disease affected outcome after transformation. Eighty-five patients (≤68 years) with histologically confirmed TIL were included. Five-year overall (OS) and progression-free survival (PFS) were calculated. Selected parameters were tested in a multivariate analysis. All analyses were conducted on three cohorts: (i) whole cohort (all TIL), (ii) patients with co-existing evidence of both indolent and aggressive histology at diagnosis (Composite/discordant TIL) and (iii) patients transformed after prolonged prior indolent disease (sequential TIL). Fifty-four patients (64%) received ASCT consolidation and 31 (36%) did not. Within the 'all TIL' cohort, the 5-year OS and PFS for R-chemo + ASCT versus R-chemo alone, were 67% versus 48% (P = 0.11) and 60% versus 30% (P = 0.02), respectively. Furthermore, in 'Composite/discordant TIL' R-chemo + ASCT showed no impact on OS (76% versus 67%; P = 0.66) or PFS (71% versus 62%; P = 0.54). Conversely, R-chemo + ASCT improved the outcome of 'sequential TIL' (OS 62% versus 36%; P = 0.07; PFS 53% versus 6%; P = 0.002), regardless of prior rituximab therapy. The beneficial effect of ASCT was significantly higher in patients who had not received rituximab at IL stage. ASCT improved the outcome in sequential, but not composite/discordant TIL. The beneficial impact of ASCT was greater in patients, who were rituximab-naïve at transformation.

Sequencing-Based Detection of Minimal Residual Disease Is Associated with Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Lymphoid Malignancies

Introduction: Monitoring for minimal residual disease (MRD) in hematologic malignancies can identify patients at high risk of relapse after standard therapy and hematopoietic stem cell transplantation (HSCT). However, techniques are limited for MRD monitoring of most lymphoma subtypes. The LymphoSIGHTTM method (Sequenta, Inc.) is a high-throughput sequencing-based MRD assay that detects small amounts of circulating tumor DNA (CTD) in patients with lymphoid malignancies. This assayhas shown promise in the monitoring of patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). We evaluated whether CTD measured by LymphoSIGHTTM pre- and post-allogeneic HSCT predicts relapse and outcome in patients with lymphoid malignancies.Methods: We retrospectively studied patients enrolled between 2009-2012 on a multicenter phase 3 trial comparing sirolimus-containing to non-sirolimus containing GVHD prophylaxis regimens in patients with lymphoma undergoing allogeneic HSCT. Only patients with available archival tumor tissue were included. Patients underwent conventional restaging at 3, 6, 12, 18 and 24 months per protocol. Genomic tumor DNA was extracted from formalin-fixed paraffin-embedded tissue or bone marrow aspirate mononuclear cells. PCR amplification of IGH and IGK regions was performed followed by high-throughput sequencing to determine the tumor clonotype(s). As part of the trial, peripheral blood mononuclear cell (PBMC) and plasma samples were collected pre-HSCT and at days 30, 60, 100, 180, 270, 365, 545 and 730 after HSCT. DNA from plasma (DLBCL) and PBMCs (other histologies) was amplified and sequenced to determine the level of CTD per million diploid genomes.Results: We studied 68 patients with B-cell non-Hodgkin lymphoma, classical Hodgkin lymphoma (HL), or CLL. Clonotype calibration was successful in 51 patients (75%; 82% when excluding diagnostic samples with insufficient DNA). MRD evaluation was performed at >=1 time point in 40 patients (13 CLL, 4 DLBCL, 4 transformed indolent lymphoma (TIL), 8 follicular lymphoma (FL), 7 MCL, 4 HL). Overall, 9/40 patients in the cohort relapsed, with a 2y cumulative incidence of relapse/progression (CIR) of 18%. Thirteen of 26 patients (50%) tested were MRD+ pre-HSCT, including 27% of patients in complete remission (CR) and 71% of patients in partial remission (PR) by conventional criteria. The 2y CIR in MRD+ vs MRD- patients at baseline was 38% vs 7% (p=0.2), 2y non-relapse mortality (NRM) was 15% vs 8% (p=0.6), and 2y progression-free survival (PFS) was 46% vs 85% (p=0.12). At day 100, 12 of 32 patients (38%) tested were MRD+. The 2y CIR in day 100 MRD+ patients was 25% vs 0% for MRD- patients (p=0.25), 2y NRM was 25% vs 5% (p=0.05), and 2y PFS was 50% vs 95% (p=0.01). In multivariable models with histology and disease status at HSCT as covariates, the hazard ratio (HR) for progression or death associated with baseline MRD+ was 2.8 (p=0.3); for day 30 MRD+, HR=6.0 (p=0.1); and for day 100 MRD+, HR=8.3 (p=0.07). When entered into the models as a time-dependent covariate, MRD-positivity was associated with a significantly increased risk of progression or death (HR 5.2, 95% CI 1.8-15.4; p=0.03) and of disease relapse/progression (HR 12.7, 95% CI 2.5-64.3, p=0.002). Histology and disease status were not significantly associated with either outcome in the models.Nine patients relapsed or progressed at a median of 4 (range 1-28) months post-HSCT and 7 (78%) had an MRD+ PB sample at a median of 6 months prior to relapse (Figure). Five patients were persistently MRD+ in all PB samples tested prior to relapse and 2 were initially MRD- then became MRD+. All 5 patients who relapsed after day 100 were MRD+ prior to relapse. Among 31 patients who did not relapse: 16 were MRD- in all PB samples tested; 9 were initially MRD+ then became MRD- by day 365 (4 by d100, 3 by d180, 2 by d365); 2 had a mixed MRD pattern, initially MRD-, then MRD+, then MRD- thereafter; the remaining 4 patients, all of whom had CLL, were persistently MRD+ but had marrow or PB evidence of persistent disease without progression at MRD+ time points.Conclusions: MRD status based on CTD detection in patients with lymphoid malignancies is predictive of outcome after allogeneic HSCT. This technique may provide important prognostic information throughout the HSCT course and identify a target population for early intervention to prevent disease relapse. [Display omitted] DisclosuresFaham:Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

Consolidative Radioimmunotherapy after Chemoimmunotherapy in Patients with Histologic Transformation of Indolent Lymphoma

Abstract Introduction:Histologic transformation (HT) has been well characterized in follicular lymphoma (FL), and has historically carried a poor prognosis with median overall survival (OS) of 1.2-1.8 years (yrs) in the pre-rituximab era (Montoto et al, 2007; Al-Tourah et al 2008). Despite improved outcomes in the rituximab era (Link et al, 2013), HT still represents a major source of mortality and morbidity in these patients (pts). While there is emerging evidence that autologous stem cell transplant (ASCT) confers a survival advantage compared to chemotherapy with rituximab alone (Ban-Hoefen et al, 2013; Villa et al, 2013), many of these patients have contraindications such as advanced age and frailty precluding ASCT as an option. We report a strategy of radioimmunotherapy (RIT) consolidation after chemoimmunotherapy to address this unmet need. Methods: Consecutive pts ≥ 18 yrs old, who received RIT as consolidation after chemoimmunotherapy for HT at the Wilmot Cancer Institute were identified who had been deemed ineligible for ASCT. Inclusion criteria were as follows: 1) clinical, composite or pathologic diagnosis of HT, and 2) receipt of RIT after response to rituximab and chemotherapy. HT was defined as biopsy confirmed diffuse large B cell or Burkitt-like lymphoma by the WHO classification ≥6 months following a biopsy establishing indolent lymphoma diagnosis (pathologic HT), or clinical evidence of transformation as defined in previous cohorts (Al-Tourah et al, 2008; Link et al, 2013) in the absence of biopsy confirmation (clinical HT). Composite diagnosis of HT was defined as concurrent indolent and large cell lymphoma. The primary endpoint was overall survival (OS). Progression free survival (PFS) was a secondary outcome. Kaplan-Meier survival estimation curves were generated using SAS (SAS Institute Inc., Cary, NC, USA), and p values were generated using the log rank test. Results: 21 consecutive pts who had a clinical, composite, or pathologic HT diagnosis were included in this analysis. All of these pts responded to rituximab and chemotherapy (CHOP like n=18, other n=3), and were treated with RIT for consolidation. The median age at the time of HT was 66 yrs (44-90). Nine pts received I-131 tositumomab and 12 received Y-90 ibritumomab tiuxetan. The median OS from HT was 6.9 yrs in the entire cohort with a median follow up of 3.5 yrs (Figure). There were no statistical differences in outcomes between the pathologic (n=11) and clinical/composite (n=10) HT pts (p=0.33). There was also no difference between those who received rituximab prior to HT (n=13), and those who did not (n=8; p=0.88). Twelve pts experienced grade 3-4 thrombocytopenia, which was the most common adverse event (AE). Nine deaths occurred. Disease-related death was the most common cause (n=4), followed by death unrelated to disease or treatment (n=3) and treatment-related death (n=2). Figure: Kaplan-Meier estimate of OS after HT in pts receiving RIT after chemoimmunotherapy (n=21) Figure:. Kaplan-Meier estimate of OS after HT in pts receiving RIT after chemoimmunotherapy (n=21) Conclusions: We report the use of RIT as consolidation of response to chemoimmunotherapy in pts with HT. This represents one of the largest series focused on pts with HT who were deemed unfit for ASCT. The RIT was well tolerated in this analysis with only 2 treatment related deaths, one of which was secondary to therapy related acute myeloid leukemia. Our observed median OS compares favorably to published reports of pts with HT who are younger and able to tolerate more aggressive therapeutic options. Consolidative RIT should be considered as a treatment approach in this vulnerable population of pts, and can serve as a platform for the incorporation of novel agents into prospective clinical trials. Disclosures Barr: Pharmacyclics: Research Funding.

Limited clinical benefit for surveillance PET-CT scanning in patients with histologically transformed lymphoma in complete metabolic remission following primary therapy

The optimum follow-up of patients with transformed indolent lymphoma (TrIL) is not well defined. We sought to determine the utility of surveillance positron emission tomography-computed tomography (PET-CT) in patients with TrIL achieving complete metabolic remission (CMR) after primary therapy. We performed a retrospective analysis of patients with TrIL treated at Peter MacCallum Cancer Centre between 2002 and 2012 who achieved CMR after primary therapy who had ≥1 subsequent surveillance PET-CT. Of 55 patients with TrIL, 37 (67%) received autologous stem cell transplantation as consolidation following chemoimmunotherapy. After a median follow-up of 34 (range 3-101) months, the actuarial 3-year progression-free (PFS) and overall survival (OS) were 77% (95%CI 62-86%) and 88% (75-94%), respectively. Of 180 surveillance PET-CT scans, there were 153 true negatives, 4 false positives, 1 false negative, 7 indeterminate and 15 true positives. Considering indeterminate scans as false positives, the specificity of PET-CT for detecting relapse was 94%, sensitivity was 83%, positive predictive value was 63% and negative predictive value was 98%. All seven subclinical (PET detected) relapses were of low-grade histology; in contrast, all nine relapses with diffuse large B cell lymphoma (DLBCL) were symptomatic. In our cohort of patients with TrIL achieving CMR, PET-CT detected subclinical low-grade relapses but all DLBCL relapses were accompanied by clinical symptoms. Thus, surveillance imaging of patients with TrIL achieving CMR is of limited clinical benefit. PET-CT should be reserved for evaluation of clinically suspected relapse.

Prognostic factors for patients with diffuse large B cell lymphoma and transformed indolent lymphoma undergoing autologous stem cell transplantation in the positron emission tomography era

In the positron emission tomography (PET) era, traditional prognostic factors may not apply for patients with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) undergoing autologous stem cell transplantation (ASCT). Moreover, little is known about prognostic factors in patients transplanted for transformed indolent lymphoma (TIL). We conducted a retrospective study of 143 patients with R/R DLBCL and TIL who were transplanted in the last decade and had a post-salvage PET scan. We examined prognostic factors in both groups, and constructed a prognostic score for DLBCL patients. For patients with DLBCL, post-salvage PET response was an important prognostic factor. Advanced age and symptomatic relapse were also significantly associated with outcome. A simple score could stratify patients into three risk groups with 4-year post-ASCT overall survival of 84%, 59%, and 10%, and 4-year progression-free survival of 67%, 41% and 0% (P<0.0001 for both). However, none of those factors (including PET response to salvage) appeared relevant for patients with TIL, despite their comparable overall outcome. Our prognostic score for DLBCL patients undergoing ASCT may be useful for prognostication, for stratification in clinical trials, and to motivate the design of new strategies for patients in the high-risk group, who may not derive benefit from standard ASCT.

Prognostic Factors for Patients with Diffuse Large B Cell Lymphoma and Transformed Indolent Lymphoma Undergoing Autologous Stem Cell Transplantation in the PET Era

Abstract 1980▪▪This icon denotes a clinically relevant abstractHigh dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) who are chemosensitive to salvage therapy. There is now evidence that the achievement of complete remission by PET scan (PET-CR) after salvage therapy is a favorable determinant of ASCT outcome, implying that PET response should be part of the prognostic assessment for patients considering ASCT. However, it is unclear whether other prognostic factors are still relevant in patients getting post-salvage PET scanning. Moreover, while ASCT is often also used for patients with R/R transformed indolent lymphoma (TIL), there are no data on whether prognostic factors that are important for DLBCL patients, especially PET response to salvage, are similarly prognostic in this population.We studied 163 consecutive adult patients who underwent ASCT at 2 institutions over the last decade for R/R DLBCL (122 patients) or R/R TIL (41 patients) and had a post-salvage PET scan. 98% were chemosensitive after salvage by conventional criteria. Among the 122 patients with DLBCL, 52 (43%) remained PET positive after salvage. PET-positivity was more likely for patients with advanced stage at relapse, and for those whose first remission duration was less than 6 months. After a median follow-up of 49 months from ASCT, the 4-year overall survival (OS) for PET-positive patients was 54% versus 74% for PET-negative patients (p=0.016), while the corresponding 4-year progression-free survival (PFS) was 30% versus 63% (p<0.0001). In multivariable models, the following were adverse prognostic factors for OS and PFS: PET positivity after salvage, age ≥60 years, CNS involvement at relapse, symptomatic relapse, and advanced stage at relapse (for OS only). Based on those factors, we constructed a prognostic score, assigning 1 point for each of the above factors (except for CNS relapse which was assigned 3 points). Patients in the low-risk group (0–1 points) had a 4y OS of 90% and 4y PFS of 74%, compared to 63% and 45% for patients in the intermediate-risk group (2–3 points), and 19% and 0% for patients in the high-risk group (4+ points) (p<0.0001 for both OS and PFS differences) (Figure 1A).The post-ASCT outcome of patients with TIL was not significantly different from that of DLBCL patients (4y OS 53% versus 69%, p=0.23, and 4y PFS 44% versus 54%, p=0.4). Notably, in this group, PET status after salvage had no prognostic relevance (Figure 1B). In fact, in multivariable models for OS and PFS, only short duration of 1st remission and elevated LDH at relapse (for OS only) were significant. [Display omitted] This study confirms the prognostic importance of post-salvage PET remission status. However, If PET response is included in the prognostic assessment, traditional risk factors such as receipt of 1st line rituximab, short duration of 1st remission, or elevated second-line aaIPI appear to lose their prognostic importance. Instead, we identified 4 other clinical factors that were strongly associated with outcome: advanced age, CNS relapse, advanced stage at relapse, and symptomatic relapse. Our prognostic score is simple to calculate and stratifies patients into 3 groups with significantly different OS and PFS. An important potential use of this score, if further validated, could be to identify a high-risk population whose outcomes after ASCT are dismal (0% PFS and 19% OS at 4 years), and who should be considered for alternative treatment approaches. Moreover, our results suggest that prognostic factors for patients with TIL may be entirely different; in particular, PET response to salvage may not be prognostically important. This is important to consider when designing clinical trials or interpreting their results in this patient population. Disclosures:No relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation Is Associated with Prolonged Disease Control in Chemosensitive Aggressive Histology Lymphoma Patients When Done Early

Abstract 4525 IntroductionAllogeneic stem cell transplantation (Allo-SCT) is a treatment option in aggressive histology lymphoma (AG-NHL) patients who have either failed or relapsed after autologous SCT (ASCT) or if the potential for long term disease control after ASCT is limited. There is limited data in literature regarding the long term outcome of allo-SCT in AG-NHL. MethodsWe did a retrospective analysis of all aggressive histology patients who underwent Allo-SCT between 1989 and 2009 at our centre. A total of 41 patients with AG-NHL [diffuse large B cell lymphoma (DLBCL) and variants, follicular lymphoma grade 3 (FL3), biopsy proven aggressive transformation of indolent lymphoma (TRIL)] underwent Allo-SCT. All patients were in a chemosensitive remission at time of transplantation. The conditioning regimen was BU-CY in the majority (36 or 88%) of patients and 3 patients had reduced intensity transplantation (RIC) with fludarabine-based regimens. GVHD prophylaxis was cyclosporine and methotrexate until 2009 and was cyclosporine and mycophenolate mofetil after that. Alemtuzumab was used in matched unrelated donor (MUD) transplants in 5 (12%) cases. ResultsThere were 22 (54%) males and 19 (46%) females. The median age at BMT was 48 years (range: 20–65). Fifteen (37%) had DLBCL, 19 (46%) had TRIL and 7 (17%) had FL3. Fifteen (37%) patients had received 2 or less lines of chemotherapy and 26 (63%) had received more than 2 lines of therapy at time of transplantation. The median number of chemo regimens was 3 (range: 1–7). The chemotherapy regimens included prior anthracyclines in 40 (98%), prior platinum in 26 (63%) and prior mini BEAM in 19 (46%). Six (15%) patients had received Rituximab and 9 (22%) had received prior RT. Seven (17%) patients had prior ASCT. Thirty-five (85%) of patients received matched related donor transplant whereas 5 (12%) received MUD transplant. The graft source was bone marrow in 33 (80%) and peripheral blood stem cells in 8 (20%). Grade 1–2 acute GVHD was seen in 53% and grade 3–4 in 9%. Chronic GVHD was seen in 51% patients. With a median follow up of 49 months and 96 months in those who are alive, five (12%) patients have relapsed, 20 (49%) patients are alive and in remission. Non relapse mortality (NRM) was 16/41 (39%) and predominantly related to infection. The overall survival (OS) and progression free survival (PFS) of the entire cohort at 60 months was 55% (Fig-1). Patients, who had achieved CR pre-allo-SCT (compared to PR) had a statistically significantly improved PFS and OS (100% survival for those who were in CR). In multivariate analysis, number of chemotherapy regimens (≤2) was associated with improved OS (p=0.015) and presence of chronic GVHD showed a trend towards significant OS (p=0.052) ConclusionsWith a median follow up of 96 months in survivors, myeloablative allo-SCT is associated with durable remission in patients with chemosensitive AG-NHL. Results are less favourable in patients who have received multiple prior regimens. NRM remains a significant concern with myeloablative regimens. We believe there is a role for myeloablative regimens and research should focus on ways to reduce NRM in this setting. Disclosures:Gupta:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. [Display omitted]