A Complicated Neighborhood: Insights into the Hodgkin Lymphoma Microenvironment

Classical Hodgkin Lymphoma (cHL) is a heterogenous and complex biological entity. Whereas early studies focussed on characterization of the Reed-Sternberg (RS) cell, there is now increasing recognition of the importance of the tumor microenvironment (TME). This critical but only partially understood component of cHL biology is likely to impact pathogenesis, chemo-sensitivity and long-term outcome. Here, the non-malignant infiltrate is variably comprised of macrophages, regulatory T cells, and stroma, with the relative composition varying by histological sub-type. Notably, relative to other B cell lymphomas, cHL expresses high levels of immune checkpoint receptors such as PD-1 and LAG3, and immune checkpoint ligands such as PD-L1, PD-L2, the latter of which are frequently the subject of genetic amplifications. Hence the bi-directional relationship between the microenvironment and the malignant cell is now a valid target. Breakthroughs in our understanding of the TME in cHL have contributed to its status as the 'poster-child' for how checkpoint blockade can de-activate tumor-tolerance to induce meaningful clinical benefit. A further layer of complexity within the TME is the potential aetiological relationship between cHL and the Epstein-Barr virus, a ubiquitous virus found to reside within the RS cells in 40% of cases, particularly in those cases that have mixed cellularity. Unlike benign EBV-infected B cells, within RS cells the virus is in a highly aberrant latency state with expression of the viral oncoprotein LMP1, a virus that is known to induce immunosuppression and drive PD-L1 expression through the NFkB and the JAK-STAT pathways. But numerous unanswered mechanistic questions remain, not least in the light of the frequent genetically driven deficiencies in antigen presentation present in RS cells, particularly in cases of nodular sclerosing disease. This has reignited debate about the relative roles of adaptive and innate immunity in this disease. Remaining questions that need to be addressed include the evolution of the interaction between the TME and the malignant compartment during the course of cHL, the role of other immune checkpoints and their impact on combinatorial immune based strategies, and the contribution to immune-evasion played by stromal cells. Further understanding will assist the rational development of new immune-based strategies, and potentially one day a chemo-free regimen that is as clinically efficacious but less toxic than current chemotherapies. Disclosures Gandhi: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Roche: Honoraria, Other: Travel Support; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria.

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Long-Term Outcome Following B-Cell Depletion Therapy with Rituximab In Children and Adults with Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v116.21.72.72 ◽

2010 ◽

Vol 116 (21) ◽

pp. 72-72 ◽

Cited By ~ 1

Author(s):

Vivek L. Patel ◽

Matthieu Mahévas ◽

Roberto Stasi ◽

Susanna Cunningham-Rundles ◽

Bertrand Godeau ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Initial Response ◽

Response Rates ◽

Advisory Committees ◽

Term Outcome ◽

Long Term Outcome ◽

One Year

Abstract Abstract 72 Background: Studies of B-cell depletion using Rituximab in adults with ITP report responses lasting at least one year in almost all of the 30–40% of patients with complete responses (CR: platelet count >150 × 109/l) and also a small fraction of patients with partial responses (PR: platelet count 50–150 × 109/l). However data describing patients with ITP who are relapse-free and off-treatment beyond 1–2 years from initial Rituximab are almost entirely anecdotal and comparable response data are even less available for children. This study assessed the duration of unmaintained platelet response following rituximab treatment in 72 adults and 66 children with ITP, all of whom had had at least an initial response to rituximab. Long-term outcome was estimated from these data. Methods: Seventeen published studies including 486 patients, 376 adults and 110 children, were used to obtain the initial response rates to standard-dose rituximab treatment (375mg/m2 weekly for 4 weeks) in adults and children. Only 1 included study did not use the standard dose of rituximab. The Godeau study (Blood, 2008) was used to estimate the one-year response rate in adults with ITP. Only those adults whose responses persisted at least one year had follow up assessed whereas children who demonstrated even ephemeral responses were included. Only verified counts were used in this IRB-approved multicenter study. Results: 138 subjects with CR's or PR's after rituximab were included. All patients had starting platelet counts <30×109/l and 131 (95%) had ITP of > 6 months duration. Thirty-three (24%) had undergone splenectomy. Using the data from prior publications to obtain the initial response rates, children had a 56% initial response rate to rituximab treatment and adults had a 57% rate. Taking initial responders and then using the Godeau data for adults and Kaplan-Meier analysis of our data for children, 38% one-year response rates were obtained for both children and adults treated with rituximab. Both age groups also showed remarkable similarity at two years with 30% relapse-free response rates. However, all of the 26 eligible children maintained their response beyond two years whereas adults continued to relapse. Therefore the five-year response rate was 30% for children and only 21% for adults. Sex, duration of ITP, and age among adults did not affect long-term outcome. The rate of relapse was almost identical for splenectomized patients and non-splenectomized ones but the splenectomized patients appeared to relapse sooner (Figure). Patients with CR's (55 of the 72 adults with responses lasting at least one year were CR's) had better long-term outcomes than did patients with PR's even more than one year from initial treatment. B-cells returned significantly sooner to higher levels in subjects who relapsed compared to those whose responses were ongoing. No clinical long-term toxicity was observed but 2 patients were identified to have mild hypogammaglobulinemia > 30 months from initial treatment. Conclusions: In summary, only approximately 1 in 5 adults treated with rituximab will have an at least five-year relapse-free response rate which is disappointingly low; children have only a slightly higher five-year relapse-free response rate. A pilot study to improve outcomes using either R-CVP or double dose rituximab was unsuccessful (Hasan, Am J Hematol,2009) Current efforts to improve long-term response rates have focused on the combination of high dose dexamethasone and rituximab (or even by providing maintenance treatment with rituximab). A better understanding of the mechanism of effect of rituximab in patients with ITP might allow an improved treatment strategy to be developed. Fortunately, the toxicity of rituximab treatment in patients with uncomplicated ITP appears to be low; however, yearly testing for immunoglobulins for a minimum of five years might be appropriate. Disclosures: Neufeld: Novartis. Inc: Research Funding. Shenoy:Novartis Oncology: Honoraria. Bussel:Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy.

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The Tumor Microenvironment of Nodular Lymphocyte Predominant Hodgkin Lymphoma Is a Unique Immunobiological Entity Distinct from Classical Hodgkin Lymphoma

Blood ◽

10.1182/blood-2018-99-115836 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4123-4123

Author(s):

Jay Gunawardana ◽

Karolina Bednarska ◽

Soi C Law ◽

Justina Lee ◽

Muhammed Bilal Sabdia ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Host Immunity ◽

Immune Checkpoints ◽

Classical Hodgkin Lymphoma ◽

Advisory Committees ◽

Immune Effector

Abstract There is proven pre-clinical and clinical efficacy of mono or combinatorial immune strategies to boost host anti-lymphoma immunity, with classical Hodgkin Lymphoma (cHL) seen as the 'poster child'. Approaches include blockade of immune-checkpoints on exhausted tumor-specific T-cells (via mAb blockade of PD-1, TIM3, LAG3, TIGIT or their ligands), activation of T-cells via mAbs agonistic to CD137, and finally modulation of FOXP3, CTLA-4 and/or LAG3 regulatory T-cells (Tregs) or immunosuppressive tumor-associated macrophages (TAMs). In contrast, studies characterizing the circulating and intra-tumoral microenvironment (TME) of the distinct but rare CD20+ Hodgkin Lymphoma entity (5-8% of HL), Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL), are minimal. Furthermore, to our knowledge no functional profiling studies comparing the host immunity of NLPHL with cHL has been performed. We compared host immunity in 29 NLPHL patients, 30 cHL patients and 10 healthy individuals, with a focus on pertinent and clinically actionable immune parameters. Paraffin-embedded tissue and paired (pre- and post-therapy) peripheral blood mononuclear cells samples were interrogated by digital multiplex hybridization (Nanostring Cancer Immune Profiling Panel) and flow cytometry. Although cytotoxic T-cell gene counts (CD8a, CD8b) were similar, compared to cHL there were higher levels of the immune effector activation marker CD137 (gene counts 439 vs. 287; P<0.01). Consistent with this, CD4 and the Treg markers LAG3, FOXP3 and CTLA-4 were lower in NLPHL (2-4 fold lower, all P<0.05), with no difference in T-helper cell activation markers CD40L and CD30L seen between tumors. TAMs and dendritic cell markers MARCO, CD36, CD68, CD163, COLEC12 and CD11b were all lower in NLPHL than cHL (all P<0.05). In line with the known 'rossette' formed around LP cells by PD-1+ T-lymphocytes, we observed strikingly elevated PD-1 and the other T-cell checkpoints TIM3 and TIGIT in NLPHL (all 2-3 fold, P<0.001). However, in line with the known gene amplification of PD-L1 on HRS cells and its presence on TAMs, gene counts of this checkpoint ligand were 2-fold higher in cHL (P<0.001). Flow cytometry profiling of immune subsets in peripheral blood showed findings consistent with findings in the TME. Specifically, there was elevation of multiple exhaustion markers within CD4, CD8, and NK immune effector cells, with a striking proportion of highly anergic dual-LAG3/PD-1 positive CD8+ T-cells. Also there was elevation of immune-suppressive monocyte/macrophages in cHL relative to NLPHL. Relative to healthy lymph nodes, there was prominent up-regulation of a range of T-cell associated exhaustion markers in both NLPHL and cHL, indicating dysregulated priming of effector immune responses and host immune homeostasis. Comparison between NLPHL and cHL illustrated that NLPHL had a myriad of features that marked its intratumoral TME as a unique immunobiological entity typified by elevated immune checkpoint markers and T-cells with a highly anergic phenotype. Put together, these findings indicate that distinct immune evasion mechanisms are operative within the TME of NLPHL, including markedly higher levels of multiple immune-checkpoints relative to cHL. In contrast, Treg subsets and immune-suppressive monocyte/macrophages were relatively lower than that seen in cHL. T-cells frequently had dual immune-checkpoint expression. The findings from this study provides a compelling pre-clinical rationale for targeting PD-1 or combinatory checkpoint inhibition in NLPHL and sets the basis for future 'chemo-free' rituximab + checkpoint inhibitor clinical trials. Disclosures Tobin: Amgen: Other: Educational Travel; Celgene: Research Funding. Birch:Medadvance: Equity Ownership. Keane:Takeda: Other: Educational Meeting; BMS: Research Funding; Roche: Other: Education Support, Speakers Bureau; Celgene: Consultancy, Research Funding; Merck: Consultancy. Gandhi:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Long-Term Outcome of Myelodysplastic Syndromes (MDS) Patients Treated with Erythropoiesis Stimulating Agents (ESAs)

Blood ◽

10.1182/blood.v126.23.1696.1696 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1696-1696 ◽

Cited By ~ 1

Author(s):

Mikkael A. Sekeres ◽

Katrina Zell ◽

John Barnard ◽

Amy E. DeZern ◽

David P. Steensma ◽

...

Keyword(s):

Board Of Directors ◽

Median Survival ◽

Lower Risk ◽

Research Funding ◽

Advisory Committees ◽

Term Outcome ◽

Median Response ◽

Long Term Outcome ◽

Medical Need

Abstract Background: The majority of MDS patients (pts) have anemia and are treated initially with ESAs. Particularly for lower-risk MDS pts (International Prognostic Scoring System (IPSS) Low and Int-1), once ESAs are no longer effective, treatment options are limited to drugs commonly used for higher-risk MDS, such as hypomethylating agents, or off-label use of immunomodulatory drugs. As a result, most pts receive only transfusion support post-ESA, representing a pt group with an unmet medical need frequently targeted for drug development, for whom long-term outcome is unknown. Methods: We studied pts diagnosed with lower-risk MDS from 1997-2014 at MDS CRC institutions and treated with ESAs (epoetin alpha (epo) or darbepoetin (darb)). The best response to treatment was categorized per International Working Group 2006 response criteria (hematological improvement (HI), complete response (CR), or partial response (PR)). The primary endpoint was overall survival (OS) at the time of ESA failure, defined as cessation of treatment due to relapse or refractoriness; a secondary endpoint was time to AML transformation or death, from time of response (for responders) or failure (for nonresponders) determination. Descriptive statistics were used for baseline characteristics. The Kaplan Meier method was used to estimate OS and a log rank analysis was used to compare response categories. Cox regression analysis was performed for multivariable analysis. Results: Of 206 patients included in analyses, median age was 71.6 years (range: 25.3-88.1), 36% were female, 5% were African-American, and 11% had t-MDS. WHO categories included RA (14%), RARS (16%), RCMD (42%), MDS-u (6%), del (5q) (4%), RAEB-1 (9%), RAEB-2 (2%), RARS-T (2%), MDS/MPN-u (3%), and CMML-1 (2%), with pts classified as IPSS Low (39%), Int-1 (61%), or IPSS-R Very Low (16%), Low (55%), Intermediate (26%), and High (4%). IPSS cytogenetic risk groups were Good (72%), Intermediate (22%), and Poor (6%). Baseline median hemoglobin was 9.4 g/dl (range: 5.5-14.2), serum epo level was 97.2 (range: 14.2-3899.0), and 11% were transfusion-dependent. Treatment included darb (59%) and epo (41%) at median doses of 300 mcg (range: 100-500) and 40,000 units (range: 5,000-80,000), respectively. Pts remained on therapy for a median of 30.4 weeks (range: 0.0-447.7) and had a median follow-up of 28.4 months (95% confidence interval (CI): 24.5, 45.4). First treatments following ESA failure included azacitidine (41.7%), decitabine (10.2%), lenalidomide (16.6%), experimental drugs (3.1%), other growth factors (13.6%), ATG and/or other immunosuppressants (8%), chemotherapy (0.1%) , transplant (0.1%) and others (6.6%). The overall response rate (ORR) to ESAs was 18.8%, with 0% achieving CR; 0.1% PR; and 18.7% HI. Responses for epo were 17.3% and for darb were 19.8% (p=.67 for difference). For both ESAs, 81.2% of patients had disease refractory to treatment: 69.4% with stable disease and 12% with progressive disease with no significant differences between epo and darb by responder status. Median response duration for epo and darb were 21.9 weeks (range: 3.0 - 447.7) and 39.1 weeks (range: 0.0 - 350.7) respectively (p=0.045). Median survival from the date of diagnosis was 28.4 months (95% CI: 24.5, 45.4), and from ESA failure was 23.9 months (95% CI: 19.9, 33.0): 21.6 months (95% CI: 15.6, 39.2) for epo and 28.8 months (95% CI: 21.2, 39.7) for darb (p=0.99) (Figure). Median time to AML transformation or death was 17.4 Months (95% CI: 14.1, 22.9): 25.4 months for responders and 16.8 months for non-responders (p=.069). For patients who received ESAs for a minimum of 4 months (39% of pts for epo and 61% for darb), ORR was 16.5%, and median survival from ESA failure was 23.0 months (95% CI: 14.7, 33.0): 22.3 months (95% CI: 13.1, NA) for epo and 24.7 months (95% CI: 14.3, 39.7) for darb (p=0.87). Conclusion: In this large, but uncontrolled cohort, response rates were similar for lower-risk MDS patients treated with epo and darb, though duration was longer for darb. There was a trend for improved outcomes in patients who responded to ESAs. Lower-risk MDS patients treated with ESAs have an OS of less than 2 years from the time of failure, and can thus be considered a high-risk MDS group for whom subsequent therapies are not standardized, representing an unmet medical need. Figure 1. Figure 1. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Komrokji:Incyte: Consultancy, Honoraria, Research Funding; Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Speakers Bureau.

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Strong Expression of the Immune Checkpoint Regulators LAG3 and Tim3 in Hodgkin Lymphoma

Blood ◽

10.1182/blood.v128.22.2952.2952 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2952-2952 ◽

Cited By ~ 5

Author(s):

Layal el Halabi ◽

Julien Adam ◽

Virginie Marty ◽

Jacques Bosq ◽

Julien Lazarovici ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Board Of Directors ◽

Hodgkin Lymphoma ◽

Immune Checkpoint ◽

Single Case ◽

Immune Checkpoint Blockade ◽

Immune Checkpoints ◽

Advisory Committees ◽

Secondary Resistance

Abstract Background: Recent results of immune checkpoint blockade trials have provided a proof of concept for immunotherapy in classical Hodgkin lymphoma (cHL) with more than two third of relapsed/refractory patients responding to blockade of the PD1/PDL1 axis. Unfortunately, there is still a proportion of patients who will present primary or secondary resistance to immunotherapy. Besides the PD1/PDL1 axis, several other molecules are critical regulators of the immune response and may be the target of therapeutic intervention. Combined immune checkpoint targeting has shown interesting results in preclinical and clinical trials in several types of tumors. Methods: Patients with initially diagnosed or relapsed cHL for whom formalin fixed paraffin embedded (FFPE) tissue was available at our institution were identified. Fifty-seven cases were selected depending solely on the availability and the quality of the FFPE blocks. Expression of the following immune checkpoints PD1, PDL1, LAG3, TIM3 was assessed using immunohistochemical methods with a threshold of 5% set for positivity. Results: Complete results for 25 cases were available at the time the abstract was written. Hodgkin and Reed Sternberg cells (HRS) were identified morphologically upon microscopic examination. Consistently with data published in the literature, HRS stained positively and intensely for PDL1 in 100% of the cases (25/25). HRS were positive for Tim3 in 36% (9/25) of cases but with more varying intensities. No PD1 or LAG3 expression was found on HRS cells except for a single case where 5% of HRS stained weakly for LAG3. In the tumor microenvironment, PD1 expression was detected in 65% of cases (15/23) and PDL1 in 60% of cases (15/25). Impressively, LAG3 and TIM3 stained positively in 96% (23/24) and 92% (24/25) of cases respectively. Lymphocyte-rosetting was present in 9/25 cases. These CD4+ FoxP3- T cells surrounding HRS were positive for PD1 in 5 cases, for LAG3 in 2 cases and for both PD1 and LAG3 in 2 cases, suggesting they represented exhausted T-cells. Concomitant expression of PD1 and PDL1 in the tumor microenvironment was present in 43% of cases (10/23). Conclusion: LAG3 and TIM3 are nearly universally expressed in the tumor microenvironment of cHL. These findings provide a strong rationale for their blockade alone or in combination in relapsed/refractory patients with cHL. The role of TIM3 expression by HRS remains unclear. Correlation of these findings with clinical data and survival outcome of the patients will be done for the whole sample. Disclosures Ribrag: NanoString: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

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Incidence, Risk Factors, Treatment and Long Term Outcome of Refractory and First Relapse AML Patients in the OSHO Studies

Blood ◽

10.1182/blood-2019-125262 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1358-1358

Author(s):

Dietger Niederwieser ◽

Rainer Krahl ◽

Christoph Kahl ◽

Hans-Heinrich Wolf ◽

Sebastian Scholl ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

Remission Induction ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

Term Outcome ◽

Long Term Outcome ◽

Advisory Boards

Introduction: Outcome of patients (pts) with refractory AML or following relapse is considered dismal and usually reported as refractory/relapsed. Here we analyzed long term outcome of refractory and relapsing pts separately over a 10 year (y) period from two prospective, non-age-limited, adult AML studies. Results have been published or presented previously as part of the German AML Intergroup studies1,2. However, incidence, characteristics, treatment and outcome of refractory and relapsed pts have not been evaluated. Patients and Methods: A total of 1621 pts from the OSHO 2002 ≤60 y (n=740) and 2004 >60 y (n=881) with newly diagnosed AML (except acute promyelocytic leukemia) and eligible for chemotherapy were analyzed. The gender was male in 51.7% of pts. AML type was de novo in 66.6%, followed by secondary AML in 25.8% and therapy related in 7.6%. Cytogenetic risk status was normal in 47.9%, intermediate in 16.3%, unfavorable in 15.3%, monosomal in 12.6% and favorable in 7.9%. Molecular analysis revealed wildtype (wt) FLT3 in 80.9% and FLT3 ITD mutated (mut) in 19.1% of pts. NPM was mutated in 30.2% of 1124 pts. In the AML 2002 and 2004 studies (NCT 01414231; NCT 01497002; NCT00266136), pts were randomly (9:1) assigned to remission induction by cytarabine (1 g/m2 bid d 1, 3, 5, 7) and Idarubicin (AML 2002) 12 mg/m2/d d 1-31 or mitoxantrone (AML 2004) 10 mg/m2/d iv d 1 - 32 or to a common arm consisting of a 3+7 scheme 3. Pts in complete remission (CR) received consolidation and stem cell transplantation (HSCT) according to cytogenetic risk and donor availability1,2. Pts with partial remission (PR) or non-response (NR) to two induction cycles were considered refractory. Pts achieving CR and relapsing thereafter were considered relapses and treated with MitoFlag or Flag-Ida4. Results: The majority of pts [median age 62 (range 17-87) y] entered CR or CRi after one or two induction cycles (n=1144; 70.6%). OS was 31.9 (29.5-34.4) % @5y and 26.0 (23.4-28.9) % @10y. Results were age dependent and superior in younger pts with an OS of 46.8 (43.1-50.7) % @5y compared to 19.3 (16.7-22.4) % @ 5y in elderly. Age, cytogenetics and NPM1 were determinants for CR and WBC (p<0,001), gender (p<0,05) and AML type (p<0,01) for OS. FLT3-ITD mut was an important determinant for relapse free survival in pts ≤60y. A total of 238 (14.7%) of 1621 pts, 23.5% in the younger and 76.5% in the elderly study, were refractory (PR 60.1%, NR 39.9%). Pts had a median age of 66 (range 23-83)y. OS of refractory pts was 11.4 (7.9-16.6)% @5y, and dependent upon PR [(13.1 (8.1-21.1) % @10y] and NR [5.2 (2.1-12.6) % @5y; p=0.0003]. Intensive chemotherapy ± HSCT and hypomethylating agents (HMA) were able to induce CR in 24.8% of pts. CR and non-CR pts had an OS of 42.7 (31.4-58.2) % @5y and an OS of 3.7 (1.7-8.0) % @2y, respectively. Risk factors for OS in refractory pts were age and type of therapy (p<0.0001). Almost all long term survivors were treated with HSCT. Of the 1144 CR/CRi pts, 582 relapsed 1-121 months (mts) after CR. Relapse occurred in 34.0% ≤6 mts, in 38,8% between 7-18 mts and in 12,2% >18 mts. Age, cytogenetic risk, type of AML, interval CR to relapse and HSCT were the dominant factors for relapse. CR2 was achieved after intensive chemotherapy ± HSCT, ± DLI and HMA in 227 pts (39.0%), 54.5% in the AML 2002 and 28.4% in the AML 2004. OS of relapsed pts was 13.8 (11.1 - 17.3) % @5y and 10.9 (7.4 - 16.2) % @10y and was higher in the younger with 23.4 (18.2-29.9) % @5y as compared to elderly pts 6.9 (4.4 - 11.0) % @5y. Pts with CR2 had a LFS of 24.9 (19.5-31.7) % @5y and was highest in patients <60y when intensive chemotherapy followed by HSCT was involved. Independent risk factors for OS in relapsed pts were age, cytogenetic risk, interval CR1 to relapse and type of therapy. Relapsed pts with HSCT in CR1 showed a trend for reduced survival. Conclusions Outcome of pts with refractory and relapsed AML is unsatisfactory but consistent >10% @5y. A differential response is observed in refractory and relapsed pts and is dependent upon PR, NR and the achievement of CR. Increase of CR rate in younger but especially in elderly pts with second generation TKI, reduction of TRM using FLT3-inhibitor monotherapy and the option to treat pts ineligible to chemotherapy promise better outcome in refractory and relapsed AML. 1Büchner et al. JCO 2012; 2Niederwieser et al Blood 2016; 3Mayer et al. NEJM 1994; 4Thiel et al. Ann Oncology 2015 Disclosures Niederwieser: Daichii: Speakers Bureau; Cellectis: Consultancy. Scholl:Gilead: Other: Project funding; Daiichi Sankyo: Other: Advisory boards; AbbVie: Other: Advisory boards; Pfizer: Other: Advisory boards; Novartis: Other: Project funding. Zojer:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sayer:Novartis: Other: none. Schwind:Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding. Maschmeyer:Gilead, Janssen Cilag, Astra Zeneca; BMS, Merk-Serono: Honoraria. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Al-Ali:Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CTI: Honoraria.

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The NLPHL Tumor Microenvironment Is Markedly Enriched in the Tigit and PD-1 Signalling Axes Compared to Classical Hodgkin Lymphoma

Blood ◽

10.1182/blood-2021-145840 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3513-3513

Author(s):

Jay Gunawardana ◽

Muhammed B. Sabdia ◽

Karolina Bednarska ◽

Soi C. Law ◽

Sandra Brosda ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Immune Checkpoint ◽

Research Funding ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Immune Checkpoints ◽

Advisory Committees ◽

Tcr Repertoire

Abstract Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) comprises 5% of all Hodgkin lymphomas (HL). Its biology remains poorly characterized. Like classical HL (cHL), it contains minimal malignant cells embedded within a T cell rich intra-tumoral microenvironment (TME). Unlike cHL, it can transform to diffuse large B cell lymphoma (DLBCL). Immune-checkpoint blockade is effective in cHL but has minimal activity in DLBCL. No data is currently available regarding the potential to reactivate host anti-tumoral activity via immune-checkpoint blockade in NLPHL. Diagnostic FFPE samples from 49 NLPHL patients retrospectively collected from 4 Australian centres were interrogated. Inclusion criteria were sample availability and centrally confirmed histological NLPHL. Characteristics were in line with the literature: median age 45 years, range 13-82 years; F:M 1:3.5; stage I/II 55%, III/IV 35% (10% stage unknown) with the majority of cases were of immuno-architectural types A or C. RNA was digitally quantified using the NanoString 770-gene PanCancer Immune panel. Multi-spectral immunofluorescent (mIF) microscopy, plasma soluble PD-1 quantification, cell sorting, T cell receptor (TCR) repertoire analysis and functional immuno-assays were also performed. Results were compared with samples from 38 cHL and 35 DLBCL patients. We initially compared gene expression of NLPHL and cHL, looking for molecular similarities and differences. Ten non-lymphomatous nodes (NLN) were included as controls. Unsupervised clustering showed all but 3 NLPHL cases segregated from the cHL cluster. All NLN congregated in a discrete sub-cluster. As expected, RNA analysis showed significant enrichment for CD20 in NLPHL and CD30 in HL. Volcano plots (Fig. 1a), corrected for false-discovery showed marked variation in gene expression. For NLPHL (vs. cHL) there were 105 upregulated and 337 down regulated genes. Strikingly, the most significantly differentially over-expressed genes in NLPHL were all T cell related (CD247: CD3 zeta chain; CD3D: CD3 delta chain; GZMK: granzyme K; EOMES: marker of CD8 + T cell tolerance; and the immune checkpoints PDCD1: encodes for PD-1; and TIGIT). CD8B expression was increased in NLPHL. For cHL, the most over-expressed genes included macrophage-derived chemokines CCL17 and CCL22. Gene set enrichment analysis revealed activation of the PD-L1 expression and PD-1 checkpoint pathway and 9 of the top 10 Gene Ontology (GO) term enrichment scores involved lymphocyte signalling in NLPHL (Fig. 1b). To better appreciate the impact of the relevant immune checkpoints on their signalling axis, we compared gene ratios for PD-1 and TIGIT receptors with their ligands (PD-L1/L2 and PVR, respectively). NLPHL showed the highest enrichment ratios of these signalling pathways vs. cHL, DLBCL and NLN (Fig. 1c). Although it is known that CD4 +PD-1 +T cells form rosettes around NLPHL cells, the differential cellular localization of immune proteins has not been compared between HL entities. Using mIF, the proportion of intra-tumoral PD-1 + was markedly higher for CD4 + (~7-fold; p<0.0001) and CD8 + (~5-fold; p<0.001) T cells in NLPHL. However, the proportion of T cells expressing LAG3 was similar. Soluble PD-1 was elevated for both NLPHL and cHL, indicating circulating blood is influenced by the TME. For both HL entities over 80% of circulating CD4 + and CD8 + T cells expressed PD-1 alone or in combination with TIGIT. TCR repertoire analysis of sorted T cell subsets showed large intra-tumoral clonal T cell expansions were also detectable in circulating T cells. T cell clones were predominantly PD1 +CD4 + T cells in both HL types. Finally, we developed a functional assay using PD-L1/PD-L2 expressing NLPHL and cHL cell lines. These were co-cultured with genetically engineered PD-1 +CD4 + T cells that express a luciferase reporter. Similar levels of heightened T cell activation were seen with immune-checkpoint blockade for both HL entities, indicating that immune-checkpoint inhibition may also be of benefit in NLPHL. In conclusion, our multi-faceted analysis of the immunobiological features of the TME in NLPHL, provides a compelling rationale for early phase clinical studies that incorporate immune-checkpoint blockade in NLPHL. Figure 1 Figure 1. Disclosures Hawkes: Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Specialised Therapeutics: Consultancy; Merck KgA: Research Funding; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Antigene: Membership on an entity's Board of Directors or advisory committees; Regeneron: Speakers Bureau; Janssen: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau. Swain: Janssen: Other: Travel expenses paid; Novartis: Other: Travel expenses paid. Keane: BMS: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Karyopharm: Consultancy; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Talaulikar: Takeda: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jansenn: Honoraria, Research Funding; Roche: Honoraria, Research Funding; EUSA Pharma: Honoraria, Research Funding. Gandhi: janssen: Research Funding; novartis: Honoraria.

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Identification of Novel Immune-Checkpoint Molecules on Multiple Myeloma Cells Using a High-Throughput Discovery Platform

Blood ◽

10.1182/blood.v128.22.380.380 ◽

2016 ◽

Vol 128 (22) ◽

pp. 380-380

Author(s):

Valentina Volpin ◽

Till Michels ◽

Antonio Sorrentino ◽

Dirk Hose ◽

Anthony D. Ho ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

Board Of Directors ◽

High Throughput ◽

Immune Checkpoint ◽

Research Funding ◽

Immune Checkpoints ◽

Advisory Committees ◽

Myeloma Cells ◽

Immune Checkpoint Molecules

Abstract Introduction: Multiple myeloma (MM) is a B-cell malignancy, characterized by accumulation of plasma cell clones in the bone marrow. While novel therapeutic agents like immunomodulatory drugs and proteasome inhibitors have improved overall survival of MM patients, the disease remains incurable in most patients. Several studies showed that immune-checkpoint molecules are expressed by myeloma cells and induce tumor-related immune suppression. Despite the promising results achieved by blocking CTLA4 and the PD-1/PD-L1 axis in the treatment of various solid tumors and Hodgkin's lymphoma, targeting these checkpoints did not induce objective responses in Phase I/II trials in MM patients. Therefore, identification of novel immune-checkpoints and defining the subsequent molecular mechanisms of inhibition are essential for further improvement. Methods: Our main goal is to identify novel MM-related immune-checkpoint molecules by taking advantage of a high-throughput (HT) RNAi screen and sequentially validate the role of candidate molecules, whose blockade could potentially induce anti-tumor immunity in MM patients. Methods: High-throughput RNAi screens offer a possibility to systemically search for immune-checkpoint molecules. Therefore, we established a high-throughput screening system to discern candidate molecules and evaluate their use as potential targets for multiple myeloma immunotherapy. We established a luciferase based read-out system by generating a stable luciferase expressing MM cell line (KMM-1-luc). To test the effect of immune-checkpoint molecules, KMM-1-luc cells were transfected with a siRNAs library targeting 2514 genes encoding for cell surface proteins, kinases and GPCRs. Transfected tumor cells were subsequently co-cultured with patient-derived HLA-matched Myeloma Infiltrating T Lymphocytes (MILs) and the effect of gene knock-down on T-cell mediated tumor lysis was measured. Results: Based on our primary HT-screening, we have identified 132 candidate molecules (hits) whose knockdown increased T-cell mediated killing more efficiently than the established checkpoint genes CCR9. To confirm the hits and the robustness of the screening, we re-tested the identified candidates in a secondary screening. Among these potential immune-checkpoints we selected 10 hits for further validation. So far, we were able to confirm expression of the hits at mRNA level and to validate siRNAs on-target effect by qPCR and luciferase-based cytotoxicity assay. Detailed results will be presented at the meeting. Conclusion: Altogether we optimized a high-throughput RNAi screen to discover novel immune-checkpoints that are potential immunotherapeutic targets for the treatment of multiple myeloma. We are currently investigating the mode of action of the candidate hits in vitro. Further in vivo validation of these immune-checkpoint molecules is still required for clinical studies. Disclosures Goldschmidt: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Witzens-Harig:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Long-Term Follow-up of the Randomized Controlled Study in Patients with Newly Diagnosed Severe Aplastic Anemia Treated with ATG, Cyclosporine, with or without G-CSF: On Behalf of the SAA Working Party of the EBMT

Blood ◽

10.1182/blood-2018-99-111811 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1307-1307

Author(s):

André Tichelli ◽

Regis Peffault De Latour ◽

Jakob R. Passweg ◽

Cora Knol ◽

Gérard Socié ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Late Complications ◽

Solid Cancer ◽

Advisory Committees ◽

Term Outcome ◽

Long Term Outcome ◽

Secondary Mds

Abstract Introduction The prospective randomized study on treatment of 192 severe aplastic anemia (SAA) patients with ATG and Cyclosporine (CSA) with and without G-CSF showed that G-CSF added to ATG/CSA decreases the rate of early infection episodes and days of hospitalization in very SAA (vSAA) patients, but has no significant impact on overall survival (OS), event free survival (EFS), relapse, or death rates (Blood, 2011;17:4434). The number of secondary MDS/AML was low, however with a short observation time. Now, 16 years after initiation of the study, a follow-up was planned to evaluate long-term outcome, comparing patients with and without G-CSF. Patients and Methods A total of 192 patients with newly diagnosed SAA, not eligible for stem cell transplantation (SCT) were entered into this prospective randomized multi-center study to receive ATG/CSA with (49.5%) or without G-CSF (50.5%). In 2011, 44 of the 192 patients had died. For the present study the follow-up of the 148 patients alive at time of first publication were requested. There were 49% males (49% G-CSF; 48% no G-CSF), 36% with vSAA (32% G-CSF; 41% no G-CSF). The median age at randomization was 46 years (2-80), 47 (2-80) for the G-CSF and 44 (7-80) for the non-G-CSF group. The median follow-up using reverse KM method was 11.7 years (10.9-12.5). Results Among the 110 survivors (17 missing), 71 (65%) were in CR, 33 (30%) in PR and 6 not in remission (5%), without any difference between the G-CSF and non-G-CSF group (P=0.523). At last follow-up 65 (34%) of the patients have died. Causes of death were infection (26), bleeding (3), SAA unspecified (3), MDS/AML (4), solid cancer (3), transplant related mortality (8), cardiovascular/aging (7), or unspecified (11). There was no difference in the causes of death between patients treated with or without G-CSF. OS at 15 years was 57±12% for the G-CSF and 63±12% for the non-G-CSF group (P=0.927). EFS, including SCT, relapse, non-response at day 120, second MDS/AML, PNH or death as an event, was 24±10% for the G-CSF, and 23±10% for the non-G-CSF group (P=0.367). Nine patients developed florid or morphological signs of MDS/AML, 9 clonal cytogenetic anomaly only, 7 a solid cancer, 18 clinical PNH, 8 avascular osteonecrosis, and 12 chronic kidney disease (No difference between patients treated with or without G-CSF). Cumulative incidence (CI) at 15 years of MDS/AML (isolated cytogenetic anomalies not included) was 5.0±2% (G-CSF) and 7.3±3% (no G-CSF), respectively (P=0.693); for clinical PNH it was 10.1±5% and 13.3±7% (P=0.499), for relapse of responding patients at day 120, 29.8±22% and 25.1±17% (P=0.545), and for chronic kidney failure 16%±12% and 13%±12% (P=0.513), respectively. Forty patients needed a second line immunosuppressive therapy (IST) for relapse (17), refractory disease (8), cyclosporine dependence (6) or isolated cytopenia (9) (G-CSF 26; no G-CSF 16; P=0.291); 16 patients needed a third line IST for relapse (5), refractory disease (7), isolated cytopenia (4) (G-CSF 12; no G-CSF 4; P=0.647). Twenty-eight patients were treated with allogeneic SCT in second or subsequent line (G-CSF 12; no G-CSF 16). CI at 15 years of SCT (competing risk, death without SCT) was 14±8% (G-CSF) and 22%±10% (no G-CSF), respectively (P=0.380). OS at 10 years since SCT was 46±24%. The most important risk factors for patients treated with ATG/CSA with or without G-CSF were age and severity of the disease at randomization: OS at 15 years was 89±12% (<20 years), 81±13% (20-40 years), 55±15% (40-60 years), and 32±16% (>60 years of age), respectively (P>0.001), and 64±5% and 52±7% for patients with SAA and vSAA, respectively (P=0.021). There was no difference between patients treated with or without G-CSF. Finally, the lack of neutrophil response by day 30, which was significant at first evaluation, is still associated with borderline lower survival (46.6±14% versus 67.1±9%; P=0.058). Conclusion: Long-term outcome of SAA patients treated with ATG/CSA was not influenced by supplementing G-CSF in term of OS, EFS, death rates, relapse, PNH, secondary MDS/AML, solid cancer and non-malignant late complications. Due to the pre-cancer nature of the disease and its long-lasting treatment, patients treated with IST are at risk for a number of malignant and non-malignant late complications. It is somewhat disappointing that in this careful followed cohort less than 25% of patients are alive and event-free 10-15 years after initial treatment. Disclosures Peffault De Latour: Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hoechsmann:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Schrezenmeier:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Kulasekararaj:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support . Bader:Neovii: Research Funding; Cellgene: Consultancy; Riemser: Research Funding; Medac: Patents & Royalties, Research Funding; Novartis: Consultancy, Speakers Bureau. Risitano:Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amyndas Pharmaceuticals: Consultancy; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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A Phase II Single Arm Study of Nivolumab As Maintenance Therapy after Autologous Stem Cell Transplantation in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression

Blood ◽

10.1182/blood-2021-148139 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2455-2455

Author(s):

Carlos Bachier ◽

Henning Schade ◽

Behyar Zoghi ◽

Aravind Ramakrishnan ◽

Nirav N. Shah

Keyword(s):

Stem Cell ◽

High Risk ◽

Maintenance Therapy ◽

Board Of Directors ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Residual Disease ◽

Refractory Disease ◽

Advisory Committees ◽

Extranodal Disease

Abstract Introduction: Autologous stem cell transplants (ASCT) are standard of care for patients with primary refractory or recurrent Hodgkin lymphoma (HL). While transplant results in cure for some patients, others relapse and succumb from their disease. Studies have found high expression of programmed death ligand 1 (PD-L1) in HL cells. The anti-PD-1 monoclonal antibody, nivolumab, has been safe and efficacious in the treatment of relapsed, refractory HL (Ansell et al. 2015). We evaluated the safety and efficacy of nivolumab maintenance therapy post-ASCT in high risk for relapse Hodgkin disease. Methods: Patients with HL with high risk of residual disease following ASCT ( high risk defined as refractory disease, relapse <12 months, or relapse ≥12 months with extranodal disease after frontline therapy) received nivolumab (240 mg IV every 2 weeks) starting 45-180 days post-transplant for a maximum of 6 months of treatment. Patients were followed for AEs through 100 days after the last dose of drug. PET-CT response assessments were performed 1-3 month, 6 month, and 12 month post-ASCT. The primary objective was to evaluate the safety and tolerability of nivolumab as maintenance therapy early after ASCT. The secondary objective was to evaluate progression-free survival (PFS) at 12 months post-transplant. Results: To date, 37 patients were enrolled; median age 36 years; 25 patients (68%) male. The median number of prior systemic regimens was 2 (range 2-4). 25 patients (68%) had relapsed disease, and 12 patients (32%) had primary refractory disease. 18 patients (49%) had extranodal disease at relapse, 6 patients (16%) had B-symptoms at relapse, and 11 patients (30%) had residual disease after salvage, including 10 patients (27%) of whom had 2-3 prior salvage therapies. 22 patients (60%) had received prior brentuximab, and 3 patients (8%) had received prior nivolumab or pembrolizumab. 36 patients received ASCT and 1 patient received tandem ASCT. At the time of data cutoff, 28 patients (76%) had discontinued nivolumab treatment, 22 patients (60%) because they had completed the 6-month treatment course, 4 patients (11%) due to an adverse event (AE) (1 patient each with pain, pneumonitis, rhabdomyolysis, or hypothyroidism), and 2 patients (5%) due to disease progression. The median duration of treatment was 22.1 weeks. 17 patients (46%) experienced a treatment-related AE (TRAE), of which 5 patients (14%) experienced a ≥Grade 3 TRAE. The most common (≥5%) TRAEs were diarrhea, fatigue, bone pain, neutrophil count decreased, pruritus, rash, and vomiting. 2 patients experienced a treatment-related serious AE (pneumonitis, rhabdomyolysis). There were no treatment-related deaths. With a median follow up of 9.2 months, the median PFS and overall survival (OS) have not been reached. The 6 month PFS is 92.1% and the 12-month OS is 100%. There were no differences in OS when stratified based on prior treatment. Conclusions: The use of nivolumab maintenance early after ASCT is safe and tolerable in this high risk patient population. Early efficacy data is promising, but data need to mature to determine the 12 month PFS. Figure 1 Figure 1. Disclosures Bachier: CRISPR: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Shah: Umoja: Consultancy; Incyte: Consultancy; Legend: Consultancy; Kite: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy.

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Clinicopathological Features of Nodular Sclerosis-Type Classical Hodgkin Lymphoma In the Elderly: Multicenter Study of Hodgkin Lymphoma In Japan

Blood ◽

10.1182/blood.v116.21.2677.2677 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2677-2677

Author(s):

Naoko Asano ◽

Tomohiro Kinoshita ◽

Koichi Ohshima ◽

Tadashi Yoshino ◽

Nozomi Niitsu ◽

...

Keyword(s):

Board Of Directors ◽

Hodgkin Lymphoma ◽

Research Funding ◽

The Elderly ◽

Clinicopathological Features ◽

Line Treatment ◽

Classical Hodgkin Lymphoma ◽

First Line ◽

Advisory Committees ◽

First Line Treatment

Abstract Abstract 2677 Background: Classical Hodgkin lymphoma (CHL), which is characterized by the presence of Hodgkin and Reed Sternberg (H-RS) cells in a background of non-neoplastic inflammatory cells, is divided into four histological subgroups, nodular sclerosis (NSCHL), mixed cellularity (MCCHL), lymphocyte-rich, and lymphocyte depletion. While NSCHL in young adults is characterized by a mediastinal mass and good prognosis, the clinicopathological characteristics of NSCHL in the elderly (NSCHL-e) remain uncertain. Patients and methods: Enrolled patients were diagnosed with CHL between 1986 and 2006 as part of the Hodgkin Lymphoma's Multicenter Study Group. To better characterize NSCHL-e, we compared the clinicopathological profiles of 84 NSCHL-e patients aged 50 or over with 237 NSCHL-y patients aged 49 or younger and 302 with MCCHL. Results: The total of 743 CHL patients consisted of 496 men and 247 women with a median age of 48 years (range, 15– 89 years). The pathological diagnoses were NSCHL in 324 patients (43%) and MCCHL in 303 (41%). NSCHL patients showed a bimodal age distribution, with an initial peak in their 20s and a second small peak in their 60s. We categorized the former as NSCHL-y (49 or younger) and the latter as NSCHL-e (50 and over). NSCHL-e patients were characterized by male predominance and a more advanced clinical stage (53%) than NSCHL-y. Immunophenotypically, H-RS cells had the prototypic immunophenotype of CD15+ CD30+ and Pax5+. NSCHL-e cases showed a significantly higher rate of CD20 (24%) than NSCHL-y (8%, P = 0.001). Furthermore, H-RS cells in 29 of 75 (39%) patients with NSCHL-e were positive for EBV RNA transcripts by in situ hybridization, whereas only 7% of NSCHL-y cases were EBER-positive (P < 0.0001) (Table). Regarding NSCHL-e and MCCHL, no significant difference between these patients was seen in clinical characteristics. Immunophenotypically, NSCHL-e patients showed significantly higher rates for CD3 and TIA-1, while MCCHL patients showed higher EBV positivity (75%). Fifty-five of 63 patients received systemic multi-agent chemotherapy as first-line treatment, consisting of doxorubicin, bleomycin, vinblastine, and dacarbacin (ABVD) in 38 patients; CHOP in 8; C-MOPP in 8; and BEACOPP in 1. Overall, 51 patients responded to first-line treatment, 39 with complete response and 12 with partial response. Disease-specific survival of NSCHL-e was poorer than that of NSCHL-y (P < 0.001) but similar to that of MCCHL (P = 0.43) (Figure). Conclusion: NSCHL-e is characterized by an unfavorable prognosis and different clinicopathological features to NSCHL-y, which is considered as typical NSCHL. A number of cases of NSCHL-e might have been associated with MCCHL, with most being EBV-positive. These results suggest the limitations of current histological subgroupings for CHL. Disclosures: Matsushita: Pfizer CO.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter Co.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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