<table><caption>Table: ARTD and ARDI (n=69)</caption><thead><tr><th>Based on 6 cycles of I-R-mini-CHOP</th><th>Median ARTD % (IQR)</th><th>Median ARDI % (IQR)</th><th>Mean ARTD % (SD)</th><th>Mean ARDI % (SD)</th></tr></thead><tbody><tr><td>Entire regimen</td><td>96.5 (80.2, 100.1)</td><td>96.8 (88.4, 100.4)</td><td>85.2 (30.3)</td><td>94.5 (15.6)</td></tr><tr><td>Rituximab alone</td><td>99.9 (87.1, 103.5)</td><td>99.6 (94.3, 104.0)</td><td>88.4 (27.5)</td><td>97.8 (9.9)</td></tr><tr><td>Chemotherapy (mini-CHOP) alone</td><td>96.5 (80.2, 100.1)</td><td>98.2 (91.9, 100.8)</td><td>85.2 (30.3)</td><td>96.7 (15.6)</td></tr><tr><td>Cyclophosphamide & doxorubicin combined</td><td>99.1 (82.6, 100.8)</td><td>99.1 (94.0, 100.9)</td><td>85.6 (26.3)</td><td>95.6 (9.2)</td></tr><tr><td>ibrutinib alone</td><td>87.3 (55.6, 100.0)</td><td>92.9 (73.4, 100.0)</td><td>74.1 (33.5)</td><td>75.4 (56.2)</td></tr></tbody></table>

efficacy. Ibrutinib (BTK inhibitor) has suggested efficacy in combination with R-CHOP in younger pts, but with significant toxicity limiting the ability to complete therapy in pts ³⁶ yrs. We present deliverability results from this prospective Phase II study of ibrutinib, rituximab and mini-CHOP in pts ≥75yrs with newly diagnosed DLBCL.

**Methods:** Pts received six 21 day cycles of ibrutinib 560mg daily and R-mini-CHOP (Rituximab 375mg/m<fnref n="2" />, cyclophosphamide 400mg/m<fnref n="2" />, doxorubicin 25mg/m<fnref n="2" />, vincristine 1mg on day 1 & prednisone 40mg/m<fnref n="2" /> or 100mg/d x 5) followed by an additional two 21 day cycles of rituximab + ibrutinib (or high dose methotrexate for CNS prophylaxis). Deliverability is measured using Average Relative Total Dose (ARTD) [Average delivered dose of the chemotherapy regimen as a % of the target dose] and Average Relative Dose Intensity (ARDI)[Average delivered dose of the chemotherapy regimen per unit time (week) as a % of the target dose intensity].

**Results:** 80 pts were recruited between Nov 2015 & Dec 2018. Of the first 70 to complete therapy by the data cut-off 14 Feb 2019, one died prior to commencing therapy. Median age was 81yrs (75-95); 51% female, 81% stage III/IV and 64% IPI 3-5. The ARTD & ARDI data are presented in the Table. Most patients received 6 cycles (75%; 52/69), with 14% (10/69) receiving <4. Treatment was discontinued in 23 pts (33%) due to: progressive disease 5/69 (7%), ibrutinib toxicity 4/69 (6%), consent withdrawal 4/69 (6%), intercurrent illness 3/69 (4%), R-mini-CHOP toxicity 2/69 (3%), other reasons 2/69 (3%), and death 2/69 (3%). Most patients 63/69 (91%) experienced an adverse event (AE), and 67% experienced a serious AE (SAE): one SAE in 15/69 (22%), 2 in 8/69 (12%) and ≥3 in 23/69(33%). The most common SAEs were infection (26 events, 24 ≥Gd 3), atrial fibrillation (8 events, 5 ≥Gd 3), febrile neutropenia (6 events, 6 ≥Gd 3). Of AEs of special interest, diarrhoea occurred in 38/69 (55% pts; 6 ≥Gd 3), atrial fibrillation in 12/69 (17%, 4 ≥Gd 3), and two pts had major bleeding (Gd 3, Gd 5). At a median follow-up of 12.7 months (IQR 5.0-22.1) there were 18/69 (26%) deaths, mostly due to lymphoma (11/69, 16%), and infection (3/69, 4%).

**Conclusions:** In this very elderly cohort the majority of pts were able to complete 6 cycles of R-mini-CHOP, maintaining a high ARDI and

ARTD of both immunochemotherapy and ibrutinib, with notable but expected toxicity. Despite limited follow-up, there remains a high rate of early progression and death, undermining the potential of this combination to improve overall survival over the use of R-mini-CHOP in very elderly patients with DLBCL.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); elderly; ibrutinib.

**Disclosures:** Verner, E: Research Funding: Janssen. Hawkes, E: Consultant Advisory Role: Celgene, Janssen-Cilag; to institution: Merck Sharpe & Dohme, Roche; Honoraria: Bristol-Myers Squibb, Janssen-Cilag, Takeda; institution: Roche/Genentech; Research Funding: Institution: Astra Zeneca, Celgene, Merck KgA, Bristol Myers Squibb, Merck Sharpe & Dohme. Janssen-Cilag, Gilead, MundiPharma; Other Remuneration: Travel expenses: Roche/Genentech, Janssen-Cilag, Bristol-Myers Squibb. Cochrane, T: Other Remuneration: Takeda and MSD (talks). Cheah, C: Consultant Advisory Role: Roche, Janssen, Takeda, MSD, Gilead, Bristol Myers Squibb, AstraZeneca; Honoraria: Roche, Janssen, Takeda, MSD, Gilead, Bristol Myers Squibb, AstraZeneca; Research Funding: Celgene, Roche, Abbvie. Enjeti, A: Consultant Advisory Role: Novartis, Abbvie; Honoraria: Roche, Bayer, Sanofi, Alexion; Other Remuneration: Novartis (Travel), Roche, Janssen and Amgen (Education). Trotman, J: Research Funding: Roche, Celgene, Beigene, PCYC, Janssen.

## 200 PROSPECTIVE MULTICENTER REGISTRY FOR SECONDARY CNS INVOLVEMENT IN MALIGNANT LYMPHOMA: AN UPDATE WITH DATA FROM 181 PATIENTS

F. Lammer<fnref n="1" /> | L. May<fnref n="1" /> | P. Martus<fnref n="2" /> | R. Schroers³ |
U. Schlegel<fnref n="4" /> | S. Hofer⁵ | O. Bairey<fnref n="6" /> | N. Schmitz<fnref n="7" /> |
F. Griesinger⁸ | M. Schmidt-Hieber<fnref n="9" /> | F. Weißinger¹⁰ |
P. Reimer<fnref n="11" /> | P. le Coutre<fnref n="1" /> | P. Fix¹² | O. Hopfer<fnref n="13" /> |
C. Junghanβ¹⁴ | H. Höffkes<fnref n="15" /> | B. Heilmeier¹⁶ |
R. Möhle¹⁷ | E. Lange¹⁸ | A. Korfel<fnref n="1" /> | U. Keller<fnref n="1" />

<footnote n="1">¹Haematology, Oncology, Charité University Medicine, Berlin, Germany;</footnote>

<footnote n="2">²Institute of Clinical Epidemiology and Applied Biostatistics, University Hospital Tübingen, Tübingen, Germany; ³Haematology, Oncology, Knappschaftskrankenhaus, Ruhr-Universität Bochum, Bochum, Germany;</footnote>

<footnote n="4">⁴Neurology, Knappschaftskrankenhaus, Ruhr-Universität Bochum, Bochum, Germany; ⁵Oncology, Luzerner Kantonsspital, Luzern, Switzerland;</footnote>

<footnote n="6">⁶Haematology, Tel Aviv University, Tel Aviv, Israel;</footnote>

<footnote n="7">⁷Haematology, Oncology, Universitätsklinikum Münster, Münster, Germany; ⁸Haematology, Oncology, Pius Hospital Oldenburg, Oldenburg, Germany;</footnote>

<footnote n="9">⁹Haematology, Oncology, Carl-Thiem-Klinikum, Cottbus, Germany; ¹⁰Haematology, Oncology, Evangelisches Klinikum Bethel, Bielefeld, Germany;</footnote>

<footnote n="11">¹¹Haematology, Oncology, St. Josef Krankenhaus Essen-Werden, Essen, Germany; ¹²Haematology, Oncology, Klinikum Weimar, Weimar, Germany;</footnote>

<footnote n="13">¹³Haematology, Oncology, Klinikum Frankfurt (Oder), Frankfurt (Oder), Germany; ¹⁴Haematology, Oncology, University Rostock, Rostock, Germany;</footnote>

<footnote n="15">¹⁵Haematology, Oncology,</footnote>
Klinikum Fulda, Fulda, Germany; ¹⁶Oncology, Krankenhaus Barmherzige Brüder, Regensburg, Germany; ¹⁷Haematology, Oncology, University Hospital Tübingen, Tübingen, Germany; ¹⁸Haematology, Oncology, Evangelisches Krankenhaus Hamm, Hamm, Germany

**Introduction:** Secondary central nervous system involvement of lymphoma (SCNSL) is a rare (<5%) complication of systemic disease. The prognosis of SCNSL is considered to be poor with median overall survival (OS) of less than 6 months. The optimal management for SCNSL is yet to be defined.

**Methods:** Since 2011, a prospective multicenter international registry for SCNSL is being conducted. Patients with secondary CNS involvement of indolent or aggressive Non-Hodgkin lymphoma (NHL, confirmed histologically or cytologically) with or without systemic involvement at the time point of CNS involvement are eligible. Since July 2011, 232 patients were included. Here, we present data of the first 181 patients with April 2018 as data cutoff.

**Results:** Median age was 63 years (range, 23-86 years). 31 patients (17%) had CNS involvement at initial diagnosis and 150 (83%) at relapse. Out of these 150 patients 66 (44%) had simultaneous systemic disease. In 180 patients with available data, 151 (84%) had aggressive B-/T-cell NHL and 29 (16%) indolent NHL. Localisation of CNS lymphoma was brain parenchyma in 103 patients (57%), meninges in 43 (24%), spinal cord in 2 (1%) and a combined manifestation in 33 patients (18%). First-line therapy (defined as therapy at diagnosis at CNS involvement) was given to 177 of the 180 patients. 83 (46%) received a combined systemic and intrathecal chemotherapy, 72 (40%) systemic therapy alone, 3 (2%) radiotherapy (RT) alone, 14 (8%) a combination of RT and systemic and/or intrathecal therapy, 2 (1%) intrathecal therapy alone and 3 patients (2%) palliative treatment or best supportive care only. Systemic chemotherapy was high-dose methotrexate-based in 139 patients (79%) and high-dose cytarabin-based in 100 (56%). Systemic rituximab was given to 111 patients (63%). Regarding all 181 patients, median progression-free survival (PFS) was 7.9 months (95% CI 6.1-9.7), and median OS 14.5 months (95% CI 8.1-21.0). As consolidation therapy within the first-line regimen, 56 patients (32%) received high-dose chemotherapy followed by autologous stem-cell transplantation (HD-ASCT). In the HD-ASCT group, median PFS was 13.2 (95% CI 1.4-25) months and median OS was 30 months.

**Conclusions:** We here report a large series of patients prospectively registered to analyse therapeutic approaches for SCNSL. The data suggest that intensive systemic (immune-) chemotherapy may improve the outcome of SCNSL patients as compared to historical controls, particularly if HD-ASCT can be applied.

**Keywords:** B-cell lymphoma.

**Disclosures:** Lammer, F: Research Funding: Mundipharma, Riemser. Korfel, A: Consultant Advisory Role: Lilly; Research Funding: Mundiparma, Riemser. Keller, U: Research Funding: Mundiparma, Riemser.

201
LONG-TERM EFFICACY AND SAFETY OF
LENALIDOMIDE MAINTENANCE IN
PATIENTS WITH RELAPSED DIFFUSE
LARGE B-CELL LYMPHOMA WHO ARE NOT
ELIGIBLE FOR AUTOLOGOUS
TRANSPLANTATION (ASCT)

A.J. Ferreri<fnref n="1" /> | M.C. Sassone<fnref n="1" /> | P. Angelillo<fnref n="1" /> |
F. Zaja² | A. Re<fnref n="3" /> | M. Spina⁴ | A. Di Rocco⁵ |
A. Fabbri⁶ | C. Stelitano<fnref n="7" /> | M. Frezzato⁸ |
C. Rusconi⁹ | R. Zambello¹⁰ | A. Arcari¹¹ |
G. Bertoldero¹² | D. De Lorenzo<fnref n="1" /> | S. Volpetti<fnref n="13" /> |
T. Calimeri<fnref n="1" /> | S. Perrone<fnref n="1" /> | C. Cecchetti<fnref n="1" /> |
F. Ciceri¹⁴ | M. Ponzoni¹⁵

**Background:** A multicentre phase II trial showed that lenalidomide (LENA) maintenance was well tolerated and improved outcome in pts with chemosensitive relapse of DLBCL not eligible for or relapsed after ASCT (NCT00799513). However, late side effects and events remained undefined as median follow-up was only 25 months and LENA was ongoing in 41% of pts at time of report. Herein, we report results of the trial after LENA completion in all pts and a median follow-up of 5 years.

**Methods:** HIV-neg pts with *de novo* or transformed DLBCL responsive to conventional salvage therapy were registered and treated with LENA 25 mg/day for 21/28 days, until lymphoma progression or unacceptable toxicity. A protocol amendment in 2015 allowed physicians to interrupt LENA after a minimum duration of 2 ys. Primary endpoint was 1-yr PFS. Simon's two-stage optimal design was used. To demonstrate a 1-yr PFS improvement from 30% to 50%, 47 pts were needed. Maintenance would be considered effective if ≥19 pts were progression-free at 1 yr. Cell of origin was assessed by NanoString Technology and Hans algorithm.

<footnote n="1">¹Lymphoma Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; ²SC Ematologia, Azienda Sanitaria Universitaria Integrata, Trieste, Italy;</footnote>

<footnote n="3">³Division of Hematology, Spedali Civili, Brescia, Italy; ⁴Oncologia, Centro di Riferimento Oncologico, Aviano, Italy; ⁵Division of Hematology, University "La Sapienza", Rome, Italy; ⁶Division of Hematology, Azienda Ospedaliera Università Senese, Siena, Italy;</footnote>

<footnote n="7">⁷Division of Hematology, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria, Italy; ⁸Division of Hematology, San Bortolo Hospital, Vicenza, Italy; ⁹Division of Hematology, Niguarda Hospital, Milan, Italy; ¹⁰Division of Hematology, Azienda Ospedaliera di Padua, Padua, Italy; ¹¹Department of Oncology and Hematology, Guglielmo da Saliceto Hospital, Piacenza, Italy; ¹²U.O. di Oncologia ed Ematologia Oncologica, Ospedale di Mirano, Mirano, Italy;</footnote>

<footnote n="13">¹³Clinica Ematologia, Azienda Sanitaria Universitaria Integrata, DAME, Udine, Italy; ¹⁴Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy; ¹⁵Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy</footnote>
**Results:** Between 3/2009 and 12/2015, 48 pts were recruited; 46 were assessable (median age 72 ys; range 34-86); 36 pts had de novo DLBCL; most pts had unfavourable features, with an IPI ≥2 in 38 (83%) pts. Salvage therapy before LENA contained high doses of cytarabine or ifosfamide in two-thirds of cases; response at trial registration was complete in 26 pts and partial in 20.

LENA was well tolerated after an average of 16 courses/pt (range 3-82); 16 pts received LENA for ≥2 years. 3 pts died of toxicity during maintenance (intestinal infarction, meningitis and sudden death) and 2 died due to myelodysplastic syndrome at 31 and 62 months. LENA was interrupted due to toxicity in other 6 pts, and 25 required dose reduction (transient in 21), mostly due to neutropenia and rash. With the exception of neutropenia, 4 toxicities occurred in <1% of courses. Infections were rare and well controlled with oral antibiotics.

After 1 year from registration, 31 pts were progression free, which was significantly higher than the pre-determined efficacy threshold (n≥19). At a median follow-up of 5 years and a median observation period from LENA completion of 35 (8-101) months, 22 pts remain relapse-free, with a 1- and 5-yr PFS of 67 ± 7% and 48 ± 7%, respectively. The duration of response to LENA was longer than response to prior treatment in 30 (65%) pts, and benefit was observed both in de novo and transformed DLBCL, and in GCB and nonGCB subtypes. 27 (59%) pts are alive, with a 1- and 5-yr OS of 80 ± 6% and 58 ± 7%, respectively.

**Conclusions:** These long-term results soundly promote the use of LENA maintenance in pts with chemosensitive relapse of DLBCL not eligible for or failed after ASCT. LENA was well tolerated in this elderly population, even among pts treated for ≥2 ys. Further investigations on immunomodulatory drugs as maintenance in these high-risk pts are warranted.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); elderly; lenalidomide.

## 202 ESTIMATION OF LONG-TERM SURVIVAL WITH POLATUZUMAB VEDOTIN PLUS BENDAMUSTINE AND RITUXIMAB FOR PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA (R/R DLBCL)

L.H. Sehn<fnref n="1" /> | C. Flowers² | A. McMillan³ |
F. Morschhauser⁴ | G. Salles⁵ | F. Felizzi⁶ |
A. Launonen⁶ | N. Qayum⁷* | P.O. Thuresson⁶

F. Hoffmann-La Roche Ltd, Basel, Switzerland; ⁷Haematology, F. Hoffmann-La Roche Ltd, Basel, Switzerland

*Was employed by F. Hoffmann-La Roche Ltd at the time of the analysis

**Background:** To inform payers/HTA organisations regarding estimated survival benefits when all events have not occurred, statistical methods are used to model projected clinical benefits/costs of new interventions. We estimated overall survival (OS) benefit associated with polatuzumab vedotin (pola) + bendamustine (B) + rituximab (R) vs BR alone in patients (pts) with R/R DLBCL.

**Methods:** Data from a Ph2 randomised controlled trial (RCT; GO29365; NCT02257567; Sehn et al, ASH 2018) of pola-BR vs BR in pts with R/R DLBCL were used (N = 80; follow up 27.6 months [mo]). Most disease progression events occurred ≤12 mo from treatment initiation, after which fewer events were observed, causing Kaplan-Meier estimates of progression-free survival (PFS) and OS to plateau (Fig. A). A mixture model was therefore explored alongside standard parametric survival models (Fig. B). Mixture models combine two processes: (1) OS for pts who died from the disease; (2) OS for long-term survivors (LTS; pts who had not died from their disease, informed by life tables given pts' age/gender/nationality). The mixture model was fitted to the RCT data; from this, the proportion of LTS is estimated. We explored two survival models for each treatment arm: OS (Bansal et al. MDM 2019) and OS informed by PFS. Mean OS was estimated by the area under the curve. Two datasets were used to validate the predictions: (1) pooled Ph2 pola-BR (N = 40) and Ph1b pola-BR data (N = 6; max. follow up 45.9 mo); (2) a Ph2 trial (NCT01691898; ROMULUS; Morschhauser et al. ASH 2014) of pola-R (R/R DLBCL; N = 39; max. follow up 49.5 mo).

**Results:** Estimated mean OS (assuming a Weibull distribution) was between 1.9 yrs (parametric model) and 4.7 yrs (mixture model) for pola-BR, vs 0.8 yrs for BR (both models). When modelled, most pts who died from their disease died within ~2 yrs; those who did not, could be considered LTS. Fig. B shows the mixture model extrapolations (purple/green dashed lines). From these extrapolations, the proportion of LTS was derived: when modelled using PFS, the estimated proportion of LTS was 21% (95% CI 16-27%) for pola-BR vs 0% (95% CI 0-2%) for BR; when estimated using Ph2 OS data, the predicted proportion of LTS was 38% for pola-BR (95% CI 31-42%) vs 9% for BR (95% CI 1-21%). Survival predictions were in line with those from the pooled GO29365 dataset (Fig. B solid lines) and ROMULUS (not shown). Of the extrapolation methods tested, mixture model predictions were best aligned with pooled pola-BR survival data over parametric survival analysis. Sensitivity analysis showed that censoring (at time of initiation) pts who had received stem-cell transplant/chimeric antigen receptor T-cell therapy had no impact on the estimates, suggesting the effects were due to pola-BR and not subsequent therapy.

**Conclusion:** These models suggest that pola-BR is associated with a 4-year increase in life-years and at least a fourfold increase in the proportion of LTS vs BR alone.

<footnote n="1">¹Department of Medical Oncology, BC Cancer Agency, Vancouver, BC, Canada; ²Hematology and Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States; ³Centre for Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; ⁴Institute of Hematology-Transfusion, University of Lille, CHU Lille, Lille Cedex, France; ⁵Clinical Haematology, Hospices Civils de Lyon, Université Lyon-1, Lyon, France; ⁶Global Access - Center of Excellence,</footnote>
<figure><img src="image_146.png" /><figcaption>Figure: (A) GO29365 Ph2 survival data (N=40 per arm) and parametric extrapolations;
(B) Comparison of pola-BR extrapolation models and pooled Ph1b/2 GO29365 data (N=46)</figcaption></figure>

**Keywords:** diffuse large B-cell lymphoma (DLBCL); non-Hodgkin lymphoma (NHL); polatuzumab.

**Disclosures:** **Sehn, L:** Consultant Advisory Role: Celgene, AbbVie, Seattle Genetics, TG Therapeutics, Janssen, Amgen, Roche/Genentech, Inc., Gilead Sciences, Lundbeck, Amgen, Apobiologix, Karyopharm Therapeutics, Kite Pharma, Merck, Takeda, Teva, AstraZeneca, Acerta Pharma, MorphoSys; **Honoraria:** Amgen, Apobiologix, AbbVie, Celgene, Gilead Sciences, Janssen-Ortho, Karyopharm Therapeutics, Kite Pharma, Lundbeck, Merck, Roche/Genentech, Inc., Seattle Genetics, Takeda, Teva, TG Therapeutics; **Research Funding:** Roche/Genentech, Inc.
**Flowers, C:** Consultant Advisory Role: AbbVie, AstraZeneca, Bayer, BeiGene, Celgene (unpaid), Denovo Biopharma, Genentech/Roche (unpaid), Gilead, OptumRx, Karyopharm, Pharmacyclics/Janssen, Spectrum; **Research Funding:** AbbVie, Acerta, BeiGene, Celgene, Gilead, Genentech/Roche, Janssen Pharmaceutical, Millennium/Takeda, Pharmacyclics, TG Therapeutics.
**McMillan, A:** **Honoraria:** Roche, Celgene, Novartis, MSD, BMS, Sandoz; **Research Funding:** Pfizer; **Other Remuneration:** Roche, Celgene (speakers' bureau; travel,

accommodation and expenses). **Morschhauser, F:** Consultant Advisory Role: Gilead; **Honoraria:** Celgene, Roche, Janssen, Bristol-Myers Squibb, Servier, Epizyme. **Salles, G:** Consultant Advisory Role: Roche/Genentech, Inc., Gilead Sciences, Janssen, Celgene, Novartis, Merck, Pfizer, Acerta Pharma, Kite Pharma, Servier, MorphoSys, Epizyme; **Honoraria:** Roche/Genentech, Inc., Amgen, Janssen, Celgene, Servier, Gilead Sciences, Novartis, AbbVie, Merck, Takeda, MorphoSys.
**Felizzi, F:** Employment Leadership Position: Roche. **Launonen, A:** Employment Leadership Position: Roche; **Stock Ownership:** Novartis.
**Qayum*, N:** Employment Leadership Position: Roche. **Thuresson, P:** Employment Leadership Position: Roche.

<footnote>*Estimations of LTS proportions are in line with plateaus shown in the mixture models, these do not directly refer to a particular time point on the curve</footnote>
L. de la Cruz-Merino<fnref n="1" /> | A. Martín García-Sancho² |
E. Nogales Fernández<fnref n="1" /> | F. Carnicero González³ |
E. Ríos Herranz⁴ | F. de la Cruz Vicente⁵ |
G. Rodríguez García⁵ | C. Nicolás García⁶ |
N. Martínez Benaclocha⁷ | J. Gumà Padrò⁸ |
J. Gómez Codina⁹ | A. Salar Silvestre¹⁰ |
D. Rodríguez Abreu¹¹ | C. Quero Blanco¹² |
J. Labrador Gómez¹³ | M. Guirado Risueño¹⁴ |
M. Provencio Pulla¹⁵ | A. Rueda Domínguez¹⁶

¹Clinical Oncology, Hospital Universitario Virgen Macarena, Seville, Spain;

²Hematology, Hospital Universitario de Salamanca, Salamanca, Spain;

³Hematology, Hospital San Pedro de Alcántara de Cáceres, Cáceres, Spain; ⁴Hematology, Hospital Universitario de Valme, Seville, Spain;

⁵Hematology, Hospital Universitario Virgen del Rocío, Seville, Spain;

⁶Hematology, Hospital Universitario Central de Asturias, Oviedo, Spain;

⁷Clinical Oncology, Hospital General Universitario de Alicante, Alicante, Spain; ⁸Clinical Oncology, Hospital Universitario Sant Joan de Reus, Reus, Spain; ⁹Clinical Oncology, Hospital Universitario La Fé, Valencia, Spain;

¹⁰Hematology, Hospital del Mar, Barcelona, Spain; ¹¹Clinical Oncology, Hospital Universitario Insular, Las Palmas de Gran Canaria, Spain;

¹²Clinical Oncology, Hospital Clínico Virgen de la Victoria, Málaga, Spain;

¹³Hematology, Hospital Universitario de Burgos, Burgos, Spain; ¹⁴Clinical Oncology, Hospital General Universitario de Elche, Elche, Spain; ¹⁵Clinical Oncology, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain; ¹⁶Hematology/Clinical Oncology, Hospital Costa del Sol, Marbella, Spain

**Introduction:** Lenalidomide is an immunomodulatory drug that can reverse rituximab refractoriness in lymphoma patients (pts). We conducted an open label multicenter phase 2 trial testing the synergism of a combination of lenalidomide and rituximab (R2) plus GDP schedule (R2-GDP) in Relapsed/Refractory Diffuse Large B Cell Lymphoma (R/R DLBCL) pts, not suitable for autologous stem cell transplant (ASCT).

**Methods:** Patients > 18 years of age with R/R DLBCL, ECOG performance status 0-2, adequate organ function, having received previously at least 1 prior therapy including rituximab, and not candidates for ASCT were eligible. Treatment consisted in an induction phase up to a maximum of 6 cycles with lenalidomide 10 mg administered po days 1-14, rituximab 375 mg/m2 iv day 1, cisplatin 60 mg/m2 iv day 1, gemcitabine 750 mg/m2 iv d1 and 8 and dexamethasone 20 mg d1-3. Pts without disease progression (DP) entered into a

<table><caption>TABLE 1</caption><thead><tr><td>Response status</td><td>R/R DLBCL</td><td>Primary Refractory DLBCL</td></tr></thead><tbody><tr><td>ORR</td><td>59,21%</td><td>45,16%</td></tr><tr><td>CR</td><td>31,58%</td><td>22,58%</td></tr><tr><td>PR</td><td>27,63%</td><td>22,58%</td></tr><tr><td>SD</td><td>9,21%</td><td>12,90%</td></tr><tr><td>PD</td><td>31,58%</td><td>41,94%</td></tr></tbody></table>

maintenance phase with lenalidomide (LEN) 10 mg, or last LEN dose received in the induction phase, d1-21 in cycles every 28 days. Primary endpoint was overall response rate (ORR) by investigator assessment. Secondary endpoints included disease free survival (DFS), event free survival (EFS), median overall survival (OS), safety and response by cell of origin (COO), type of DLBCL (double-triple hit, double expressors) and other microenvironment and genomic biomarkers.

**Results:** 79 pts with R/R DLBCL were enrolled between April 2015 and September 2018. Median age was 71 years, 48,7% women. Primary refractory DLBCL in 31 cases (39,2%). 76 pts were considered for efficacy in the intention to treat (ITT) analysis and 78 for safety. With a median follow-up of 13 months at the time of cut-off (December 2018), ORR was 59,21% with 31,58% complete responses (CR) and 27,63% partial responses (PR). In the primary refractory population ORR was 45,16% with 22,58% CR and 22,58% PR. Median event free survival (EFS) was 12,0 months (7,8-16,1 months). Most common grade 3/4 (G3/4) events were thrombocytopenia (60,26%), neutropenia (56,1%) and anemia (26,92%). Febrile neutropenia occurred in 14,10% pts. Most frequent non-hematologic G3/4 events were asthenia (16,67%), respiratory infection (6,41%) and hypocalcemia (5,13%). There were 4 toxic deaths related to the R2-GDP schedule.

**Conclusions:** LEN with Rituximab and GDP (R2-GDP schedule) is feasible and highly active in R/R DLBCL. Results in the primary refractory DLBCL population are particularly appealing. Analysis of COO and immune and genomic biomarkers are pending to ascertain if there are subpopulations that may obtain greater benefit with this combination.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); gemcitabine; lenalidomide.

**Disclosures:** de la Cruz-Merino, L: Research Funding: Celgene.

## 204 MSKCC EARLY EXPERIENCE USING RADIOTHERAPY AS A BRIDGING STRATEGY FOR RELAPSED DIFFUSE LARGE B CELL LYMPHOMA BEFORE CD19 CAR T THERAPY

B.S. Imber<fnref n="1" /> | M.L. Palomba² | C. DeSelm³ |

C. Batlevi² | P.B. Dahi⁴ | S. Giralt⁴ | A.M. Noy⁵ |

J.H. Park⁶ | C.S. Sauter⁴ | M. Scordo⁴ | G. Shah⁴ |

M. Sadelain⁷ | M. Perales⁴ | J. Yahalom<fnref n="1" />

<footnote n="1">¹Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States; ²Lymphoma Service & Center for Cellular Therapeutics, Memorial Sloan Kettering Cancer Center, New York, NY, United States; ³Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States; ⁴Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States; ⁵Lymphoma</footnote>
<table><thead><tr><th>Patient</th><th>Age at RT</th><th>Diagnosis</th><th>Original stage</th><th>Prior therapies</th><th>Staging prior to RT bridging</th><th>Irradiated sites</th><th>RT dose (Gy)</th><th>RT fractions</th><th>In field response after RT bridge</th><th>CAR product</th><th>CRS</th><th>Neurotox</th><th>Day +30 response</th><th>Day +90 response</th></tr></thead><tbody><tr><td>1</td><td>66</td><td>DLBCL - CD5+</td><td>IV</td><td>4</td><td>IV</td><td>R leg</td><td>20</td><td>5</td><td>PMR</td><td>JCAR017</td><td></td><td></td><td>PMR (near CMR)</td><td>PD</td></tr><tr><td>2</td><td>77</td><td>DLBCL - CD5+</td><td>IV</td><td>4</td><td>bulky IV</td><td>Right sciatic nerve and pelvis</td><td>20</td><td>5</td><td>PMR</td><td>EGFRt/19-28z/4-1BBL "Armored"</td><td>Grade 1</td><td>Grade 3</td><td>CMR</td><td>PD</td></tr><tr><td>3</td><td>69</td><td>DLBCL - ABC (tFL)</td><td>IIIA</td><td>2</td><td>III</td><td>Bilateral neck</td><td>33</td><td>11</td><td>PMR</td><td>JCAR017</td><td></td><td></td><td>CMR</td><td>CMR</td></tr><tr><td>4</td><td>61</td><td>DLBCL - GC</td><td>I*</td><td>2</td><td>IIA</td><td>Right groin</td><td>46.8</td><td>26</td><td>PD</td><td>AxiCel</td><td>Grade 1</td><td>Grade 1</td><td>CMR</td><td>CMR</td></tr><tr><td>5</td><td>34</td><td>DLBCL - EBV+</td><td>IVB*</td><td>3</td><td>IV</td><td>Left iliac bone and sacrum</td><td>20</td><td>5</td><td>PMR</td><td>AxiCel</td><td>Grade 2</td><td>Grade 3**</td><td>CMR</td><td>CMR</td></tr><tr><td>6</td><td>54</td><td>DLBCL - GC</td><td>IV</td><td>2</td><td>IV</td><td>1. R wrist<br>2. R femur<br>3. R femur</td><td>1, 27<br>2-3, 30</td><td>1, 9<br>2-3, 10</td><td>PMR</td><td>AxiCel</td><td>Grade 3</td><td>Grade 3</td><td>CMR</td><td>CMR</td></tr><tr><td>7†</td><td>72</td><td>DLBCL - GC (tFL)</td><td>IV*</td><td>8</td><td>IV</td><td>L abdomen</td><td>20</td><td>5</td><td>PMR</td><td>JCAR017</td><td></td><td></td><td></td><td></td></tr><tr><td>8†</td><td>48</td><td>DLBCL - GC (tFL)</td><td>IV</td><td>5</td><td>IV</td><td>Larynx</td><td>20</td><td>5</td><td>SD</td><td>AxiCel</td><td>Grade 1</td><td></td><td></td><td></td></tr><tr><td>9†</td><td>72</td><td>DLBCL - GC</td><td>IV</td><td>1</td><td>IV</td><td>L scapula and soft tissue</td><td>20</td><td>5</td><td></td><td>tisagen-lecleucel</td><td></td><td></td><td></td><td></td></tr><tr><td>10†</td><td>39</td><td>DLBCL - ABC</td><td>II</td><td>2</td><td>III</td><td>Right neck</td><td>30</td><td>20 (BID)</td><td></td><td>AxiCel</td><td></td><td></td><td></td><td></td></tr><tr><td>11†</td><td>55</td><td>DLBCL - ABC</td><td>IIIS*</td><td>2</td><td>I</td><td>Spleen</td><td>30</td><td>20 (BID)</td><td></td><td>AxiCel</td><td></td><td></td><td></td><td></td></tr></tbody></table>

**Figure:** Cohort details of patients who received RT bridge therapy prior to CD19 CAR T. Abbreviations: ABC – reflects non-germinal center histology by Hans algorithm; GC – germinal center histology by Hans algorithm; tFL – suspected transformed follicular lymphoma; PMR – partial metabolic response; SD – stable disease, PD – progressive disease; AxiCel – axicabtagene ciloleucel; CRS – cytokine release syndrome. For original stage, * reflects primary refractory. ** Patient developed severe, generalized cord edema and lower extremity paresis that ultimately improved with rehabilitation, this was felt to be potentially attributable to prior checkpoint inhibitor exposure along with RT. †Patient currently undergoing or recently completed treatment and updated results will be presented at ICML Meeting.

Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States; ⁶Center for Cellular Therapeutics, Memorial Sloan Kettering Cancer Center, New York, NY, United States; ⁷Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States

**Introduction:** CD19-targeted chimeric antigen receptor T cell (CAR T) therapies have remarkable overall response rates (ORR) for relapsed diffuse large B cell lymphoma (DLBCL). There is strong rationale to use a radiotherapy (RT) bridge during cellular manufacturing including palliation, local control and cytoreduction with limited count impact. Recent data from our institution suggests RT may also augment an immune response and sensitize antigen negative cells to CAR-mediated death. This series details our early experience using RT conditioning.

**Methods:** 11 patients (median age 61 years) with DLBCL (n = 8) or transformed follicular lymphoma (n = 3) were analyzed. Overall, patients had a median of 2 prior therapies (range 1-8) including 3 with auto transplant, 3 with distant RT and 1 with CAR T infusion. Several CAR products were used, including axicabtagene ciloleucel (n = 6), JCAR017 (n = 3, per NCT02631044), tisagenlecleucel (n = 1) and EGFRt/19-28z/4-1BBL "armored" CAR (n = 1, per NCT03085173). Most patients began RT (n = 8) post apheresis with median duration between RT and CAR infusion of 20d (range 13-80). The most common RT regimen (n = 6) was 20 Gy in 5 fractions (range 20-47 Gy) but 2 received our pre-transplant regimen of 30 Gy in 20 BID fractions.

None received concurrent chemotherapy with RT but one had a cycle post RT and pre CAR. All had cy/flu lymphodepletion. PET response was evaluated by Lugano criteria.

**Results:** 2 patients (18%) had limited stage PET avid disease at RT and were treated comprehensively pre-CAR. The remaining 9 were advanced stage, and were treated palliatively to limited sites. Irradiated sites included the neck (n = 4), pelvis/groin (n = 3), intra-abdominal (n = 2) and extremity (n = 2). Most (n = 9) had intensity modulated RT. RT fields were large (median planning treatment volume of 887 cc, range 163-1641). Post RT PET interpretation was challenging given a short interval since RT completion (median 11d) but of 8 evaluable patients, many (n = 6, 75%) had partial response (PR). Though locally controlled, most (n = 7, 88%) had out of field progressive disease (PD) pre CAR. Of 7 evaluable patients post CAR T, no severe adverse events in the RT field were noted, 5 had cytokine release syndrome (n = 1 grade 3) and 4 had neurotoxicity (n = 3 grade 3). At day 30, ORR was 100%; of 6 evaluable patients, 5 had complete metabolic response (CMR) and 1 had near CMR. Of the 5 evaluable patients at day 90, 3 (60%) had continued CMR and the other 2 (40%) had PD and subsequently died from DLBCL. One relapsed at 95d post armored CAR both in and out of the RT field, and the other relapsed at 64d post JCAR017 primarily out of field.

**Conclusions:** Use of RT as a CAR T bridging strategy is feasible and associated with excellent pre CAR local control and initial post CAR ORR in a cohort of heavily pre-treated DLBCL patients. We observed moderate serious CAR toxicity that did not appear to be clearly
augmented by RT. Future efforts should clarify the optimal RT
timing/dose and assess the potential for incremental immunogenicity
with combined therapy.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); immune system; salvage treatment.

**Disclosures:** Palomba, M: Consultant Advisory Role: Merck, Pharmacyclics; Stock Ownership: Seres (spouse); Honoraria: Flagship Ventures, Novartis, Evelo, Seres, Jazz Pharmaceuticals, Therakos, Amgen, Merck (all spouse); Other Remuneration: Royalties: Seres, Juno (both spouse). DeSelm, C: Consultant Advisory Role: Merck, Pharmacyclics; Stock Ownership: Seres (spouse); Honoraria: Flagship Ventures, Novartis, Evelo, Seres, Jazz Pharmaceuticals, Therakos, Amgen, Merck (all spouse); Other Remuneration: Royalties: Seres, Juno (both spouse). Batlevi, C: Consultant Advisory Role: Life Sci, GLG, Juno/Celgene, Seattle Genetics; Honoraria: Dava Oncology; Research Funding: Janssen, Novartis, Epizyme, Xynomics, Bayer, Juno, BMS. Giralt, S: Consultant Advisory Role: Amgen, Actinuum, Celgene, Johnson & Johnson, Jazz Pharmaceuticals, Takeda, Novartis, Kite, Spectrum Pharma; Research Funding: Amgen, Actinuum, Celgene, Johnson & Johnson, Miltenyi, Takeda. Shah, G: Research Funding: Janssen and Amgen. Sadelain, M: Consultant Advisory Role: Berkeley Lights; Research Funding: Juno Therapeutics, Fate Therapeutics, Atara Biotherapeutics, Takeda. Perales, M: Consultant Advisory Role: Servier, Medigene, MolMed and NexImmune; Honoraria: Abbvie, Bellicum, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, and Takeda; Research Funding: Incyte and Miltenyi Biotec.

205
HIGHLY FAVORABLE OUTCOMES WITH RT
FOLLOWED BY ASCT IN LOW/LOW-
INTERMEDIATE SECONDARY AGE
ADJUSTED IPI REL/REF DLBCL PATIENTS
REFRACTORY TO SALVAGE
CHEMOTHERAPY

J.C. Yang¹ | K.W. Chau² | M. Scordo³ |

C.S. Sauter³ | J. Yahalom²

¹Radiation Oncology, University of California San Francisco, San Francisco, United States; ²Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, United States; ³Medicine, Memorial Sloan Kettering Cancer Center, New York, United States

**Introduction:** For patients with relapsed or primary refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) who respond to salvage chemotherapy (ST), high-dose chemotherapy and autologous stem cell transplantation (ASCT) is considered standard of care. Patients with refractory disease to ST, defined as stable disease (SD) or progressive disease (PD), by functional imaging are ineligible for ASCT, and have a dismal prognosis. In practice, we have attempted to salvage these patients with radiation therapy (RT) to

residual sites of active disease prior to consolidative ASCT. The out-
come of this unique combined modality therapy has not been previ-
ously reported.

**Methods:** We retrospectively reviewed all patients with rel/ref DLBCL who received ST followed by RT and ASCT between the years of 2000 and 2017 at a single center. Only patients with SD or PD as defined by Deauville 5 on the 5-point scale after ST and who had at least 1 year of follow-up were included in this analysis. Survival functions were estimated by the Kaplan-Meier method and compared using a log-rank test.

**Results:** Thirty-six patients, 12 with rel and 24 with ref disease, with a median age of 43 years (range: 18-66 years) were analyzed. Twenty-three patients had DLBCL while 13 had primary mediastinal B-cell lymphoma (PMBCL). The secondary age-adjusted International Prognostic Index (sAAIPI) for this cohort was as follows: 0 (n = 10), 1 (n = 21), 2 (n = 4), and 3 (n = 1). All patients received ST with subsequent functional imaging showing SD (n = 32) and PD (n = 4) and then went on to receive RT to the sites of disease. Median RT dose was 39.6Gy (range: 30-54Gy). Six patients also received TBI as part of their conditioning regimen prior to ASCT.

With median follow up of 4.0 years (range: 1.0-12.3 years) for survivors, 4-year relapse-free survival (RFS) was 76% and 4-year overall survival (OS) was 80%. There was no significant difference in 4-year RFS for rel versus ref disease (80% v 75%, p = 0.59) nor for DLBCL versus PMBCL (68% v 92%, p = 0.12). By sAAIPI score, 4-year RFS was 80% for a score of 0, 90% for a score of 1, and 0% for scores of 2 and 3. Patients with low- and low-intermediate risk sAAIPI scores of 0 and 1 had improved RFS as compared to patients with sAAIPI scores of 2 and 3 (87% v 0%, p<0.0001).

**Conclusions:** Patients with chemorefractory rel/ref DLBCL who have had minimal or no response to systemic salvage therapy may benefit from salvage RT to the residual PET-avid disease followed by ASCT, particularly if their sAAIPI score is ≤ 1. The outcome of this retrospective cohort is markedly superior to outcomes described in the literature for this high-risk population and represents a promising treatment paradigm to be further explored. We suggest there may be a role for sequencing this salvage paradigm prior to CAR T-cell therapy.

**Keywords:** autologous stem cell transplantation (ASCT); diffuse large B-cell lymphoma (DLBCL); salvage treatment.

206
POST-TRANSPLANT
LYMPHOPROLIFERATIVE DISORDER IN
PATIENTS WITH LYMPHOMA AFTER
ALLOGENEIC HEMATOPOIETIC STEM CELL
TRANSPLANTATION

A. Fujimoto¹ | N. Hiramoto² | S. Yamasaki³ |

Y. Inamoto⁴ | M. Ogata⁵ | T. Fukuda⁴ |

N. Uchida⁶ | K. Ikegame⁷ | K. Matsuoka⁸ |
S. Shiratori⁹ | T. Kondo¹⁰ | T. Miyamoto¹¹ |
T. Ichinohe¹² | Y. Kanda¹³ | Y. Atsuta¹⁴ | R. Suzuki¹

¹Department of Oncology and Hematology, Shimane University Hospital, Izumo, Japan; ²Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan; ³Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan; ⁴Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan; ⁵Department of Hematology and Clinical Research Institute, Oita University Faculty of Medicine, Oita, Japan; ⁶Department of Hematology, Federation of National Public Service Personnel Mutual Aid Association Toranomon Hospital, Tokyo, Japan; ⁷Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan; ⁸Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan; ⁹Department of Hematology, Hokkaido University Hospital, Sapporo, Japan;

¹⁰Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; ¹¹Hematology, Oncology and Cardiovascular medicine, Kyushu University Hospital, Fukuoka, Japan;

¹²Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan;

¹³Division of Hematology, Saitama Medical Center Jichi Medical University, Saitama, Japan; ¹⁴Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya University Graduate School of Medicine, Nagoya, Japan

**Introduction:** Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication after hematopoietic stem cell transplantation (HSCT). PTLD represents a heterogeneous group of abnormal lymphoid proliferations and is generally associated with Epstein-Barr virus infection. Several risk factors for PTLD have been reported, but no studies regarding risk factors in patients with lymphoma have been conducted to date.

**Methods:** In the national Japanese transplant registry database, 5,270 patients with lymphoma and 34,922 patients with other

diseases underwent allogeneic HSCT between 1990 and 2015. Data for these patients were used for analysis. The most common primary disease in patients with other diseases was acute myeloid leukemia or myelodysplastic syndrome (N = 20,472), followed by acute lymphoblastic leukemia (N = 6,808) and chronic myeloid leukemia or myeloproliferative disorder (N = 2,827).

**Results:** The median age was 47 years (range, 16 to 88) for lymphoma patients and 45 years (range, 16 to 85) for those with other diseases. A total of 31 lymphoma patients and 236 patients with other diseases developed PTLD. The probability of PTLD 2 years after HSCT was 0.77% with a median onset of 217 days (range, 48 to 2,210) for lymphoma patients and 0.80% with a median onset of 127 days (range, 15 to 6,356) for those with other diseases. No difference in the probability of PTLD was found between patients with lymphoma and those with other diseases (P = 0.98). In the univariate analysis, the significant factors associated with PTLD development in lymphoma patients were the year of HSCT, donor type, graft-versus-host disease prophylaxis, use of antithymocyte globulin (ATG) in the conditioning regimen, and use of rituximab before HSCT. Among these factors, the year of HSCT (hazard ratio (HR) = 5.6, P = 0.01), ATG use (HR = 4.5, P = 0.004), and rituximab use (HR = 0.32, P = 0.01) were identified as significant variables by multivariate analysis. The probability of PTLD at 1 year was 0.23% for patients who received rituximab but not ATG, 0.74% for those who did not receive either rituximab or ATG, 1.25% for those who received both rituximab and ATG, and 3.99% for those who received only ATG (Figure). The patients who received both ATG and rituximab had a trend of lower probability of PTLD than those who received only ATG (HR = 0.24, P = 0.08). Regarding lymphoma subtypes, patients with mature B cell lymphoma had the lowest incidence of PTLD.

**Conclusion:** Rituximab use before HSCT significantly reduced the risk of PTLD in patients with lymphoma. As patients who receive ATG have a high risk of developing PTLD, adding rituximab to ATG in the conditioning regimen is a good candidate strategy to reduce the risk of PTLD.

**Keywords:** allogeneic stem cell transplant (alloSCT); post-transplant lymphoproliferative disorders (PTLDs); rituximab.

**Disclosures:** Kanda, Y: Consultant Advisory Role: Chugai, Shionogi, Ono, Bristol-Myers Squibb, Kyowa-Hakko Kirin, Astellas, Eisai, Dainippon-Sumitomo, Takeda, Celgene, Mochida, Alexion, Takara-bio; Honoraria: Chugai, Shionogi, Ono, Bristol-Myers Squibb, Kyowa-Hakko Kirin, Astellas, Eisai, Dainippon-Sumitomo, Takeda, Celgene, Mochida, Alexion, Takara-bio; Research Funding: Chugai, Shionogi, Nippon-Shinyaku, Ono, MSD, Pfizer, CSL Behring, Kyowa-Hakko Kirin, Asahi-Kasei, Tanabe-Mitsubishi, Novartis, Astellas, Eisai, Otsuka, Dainippon-Sumitomo, Sanofi, Taisho-Toyama, Taiho, Takeda. Suzuki, R: Honoraria: Kyowa-kirin Chugai Bristol-Meyers-Squib Eisai MSD Takeda Meiji-Seika Ono-Pharma Novartis.

<figure><img src="image_147.png" /></figure>
## EXTRANODAL LYMPHOMAS

# 207
## DEPTH OF REMISSION FOLLOWING FIRST LINE HP-ERADICATION IS AN INDEPENDENT PROGNOSTIC FACTOR IN GASTRIC MALT LYMPHOMA

M. Raderer<fnref n="1" /> | W. Dolak² | I. Simonitsch-Klupp<fnref n="3" /> | B. Kiesewetter<fnref n="1" />

Patients with gastric MALT lymphoma responding to initial HP-eradication have an excellent outcome, and no further oncological therapy is recommended even in the presence of residual disease after antibiotic therapy due to excellent long term prognosis. However, no long term data exist on the influence of initial depth of remission (i.e. CR versus residual disease after response) on PFS in such patients.

In view of this, we have retrospectively analysed the course of patients with gastric MALT lymphoma following initial treatment with focus on HP-eradication. In total, 137 patients with gastric MALT lymphoma (70 f / 67 m) were treated at our institution: 66% had stage I, 23% stage II while the remaining patients had disseminated disease. The MALT-IPI was 0 in 61%, 1 in 33%, 2 in 5% and 3 in 1% of cases. Out of those patients, 69% were found positive for HP, while 31% were negative by means of histology, breath test and serology. Consequently, 70% were given antibiotics for first line therapy, 24% systemic therapy and 4% local therapy; 4 patients were only watched and were excluded from this analysis. Response was assessed based on histology as defined in the GELA-criteria for no change, responding residual disease (rRD) and probable minimal residual disease (pMRD) as well as complete remission (CR) based on regular follow up biopsies every 3 months for the first two years after therapy and every 6 months afterwards. The median follow-up was 56 months for our cohort. In total, 67% responded to first line therapy as assessed by histology according to the GELA-criteria (48% CR, 19% PR including rRD and pMRD) as judged by best outcome, while 30% had stable disease/no change. Overall, the median PFS for all responders was 68 months and significantly better than for patients with stable disease/no change at 17 months (p < 0.01); furthermore, patients achieving CR had a significantly longer PFS at 95 months versus 29 months for the PR group (p = 0.01); and all differences remained significant after correction for MALT-IPI. Also among the subgroup of HP-positive patients undergoing eradication for first line therapy, the difference between CR and PR remained significant for PFS at 109 months vs 28 months (p = 0.02). However, in terms of overall survival, no difference between CR and PR after initial therapy could be demonstrated.

These data suggest that patients with gastric MALT lymphoma achieving a CR after initial therapy, especially HP-eradication have a significantly longer PFS than patients with residual disease after initial response. In view of these results, patients with PR should probably be followed more closely than after CR.

**Keywords:** extranodal marginal zone lymphoma of MALT type.

# 208
## ⁹⁰Y-IBRITUMOMAB TIUXETAN IN PATIENTS WITH EXTRA-NODAL MARGINAL ZONE B-CELL LYMPHOMA OF MUCOSA ASSOCIATED LYMPHOID TISSUE (MALT LYMPHOMA) – THE ZENO STUDY

M. Marangon | A. Morigi | B. Casadei |

A. Broccoli | L. Nanni | V. Stefoni | L. Argnani |

G. Lolli | M. Carella | P. Zinzani

Institute of Hematology "L. e A. Serågnoli", University of Bologna, Bologna, Italy

**Introduction:** Currently, no standard treatments are available for extra-nodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma), which appears to be a radiosensitive tumor. ⁹⁰Y-ibritumomab tiuxetan (YIT) delivers targeted radiotherapy in specific MALT localizations, avoiding the exposure of other tissues and consequent organ toxicities.

**Methods:** The aim of this phase II trial was to evaluate the efficacy of a single course of YIT in generating clinical responses in patients with MALT lymphoma in first line or with relapsed/refractory disease. The radioimmunotherapy treatment plan consisted of an initial infusion of rituximab on day 1, then repeated on day 8, immediately followed by a weight-based dose of YIT.

**Results:** Seventeen patients were enrolled and 16 were evaluable for efficacy analysis as 1 patient refused to undergo YIT due to a drug infusion reaction after the first administration of rituximab. Four out of 16 patients were previously untreated. For the other 12 patients, the median duration of the last response was 13 months. All but 2 (IE,

<table><caption>TABLE 1</caption><thead><tr><th></th><th>Baseline</th><th>Nadir (range)</th><th>Days from Baseline to nadir</th></tr></thead><tbody><tr><td>Absolute neutrophil count, cells/mm<fnref n="3" /></td><td>3400 (1500-6000)</td><td>700 (210-2950)</td><td>36 (19-52)</td></tr><tr><td>Platelets, cells x10³/mm<fnref n="3" /></td><td>216 (118-338)</td><td>159 (89-121)</td><td>33 (19-38)</td></tr><tr><td>Hemoglobin, g/dL</td><td>13.6 (9.9-16.2)</td><td>11.9 (8.8-13.0)</td><td>39 (19-56)</td></tr></tbody></table>

<footnote n="1">¹Internal Medicine I, Oncology, Medical University Vienna, Vienna, Austria; ²Gastroenterology, Medical University Vienna, Vienna, Austria;</footnote>

<footnote n="3">³Pathology, Medical University Vienna, Vienna, Austria</footnote>
intraorbital) presented with a stage IV disease. At 3 months after YIT 10 complete responses (CR, 62.5%), 5 partial responses (PR) and 1 sta- ble disease were observed, leading to an overall response rate of 94%. With a median follow up of 1 year, only 4 patients relapsed (3 from CR and 1 PR). Seven patients are in continuous CR with a median duration of response of 18 months. Adverse events after YIT were only hematologic and transient. The severity of hematologic toxicities (expressed as the lowest, i.e. nadir, concentration of granulocytes, platelets, and hemoglobin reached after radioimmunotherapy) are reported in the table. Grade 3 to 4 thrombocytopenia and neutropenia occurred in 7 patients (43.8%). Four patients (25.0%) received G-CSF; no patients received transfusions.

**Conclusions:** YIT represents a highly effective and tolerable treatment option for MALT lymphoma, both in first-line and in relapsed/refractory disease setting.

**Keywords:** extranodal marginal zone lymphoma of MALT type; radioimmunotherapy (RIT).

**Disclosures:** Zinzani, P: Consultant Advisory Role: Verastem, MSD, EUSAPHARMA, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, Immune Designa, Celgene, Portola, Roche, Kyowa Kirin.

209
TRANSFORMED MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMAS: A SINGLE INSTITUTION RETROSPECTIVE STUDY INCLUDING PCR-BASED CLONALITY ANALYSIS

**B. Kiesewetter**¹ | **W. Lamm**¹ | **W. Dolak**² |
**J. Lukas**³ | **M.E. Mayerhoefer**⁴ | **M. Weber**⁴ |
**C. Kornauth**⁵ | **A.I. Schiefer**⁵ | **G. Bayer**⁵ |
**I. Simonitsch-Klupp**⁵ | **M. Raderer**¹

¹Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria; ²Department of Medicine III, Clinical Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; ³Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria; ⁴Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; ⁵Department of Pathology, Medical University of Vienna, Vienna, Austria

**Background:** The natural course of mucosa-associated lymphoid tissue (MALT) lymphoma is favorable but histological transformation (HT) to diffuse large B-cell lymphoma (DLBCL) may occur in a small proportion of patients and drastically worsen prognosis. However, only little is known about clonal lymphomagenesis and disease behavior in these patients.

**Patients and methods:** Given the lack of consistent data on clinicopathological features and clonal relationship of patients with MALT lymphoma and HT, we have systematically analyzed 379 patients (32% gastric, 68% extragastric; median follow-up 52 months)

diagnosed at the Medical University of Vienna 1999 - 2017 for HT, and reassessed tissues of identified patients by PCR-based clonality analysis of both, indolent and aggressive lymphoma.

**Results:** HT was documented in 12/379 patients (3.2%) and occurred at a median time of 22 months (range; 6-202 months) after initial diagnosis of MALT lymphoma. Development of HT was significantly associated with presence of lymph node- (p<0.001) and bone marrow involvement (p = 0.029). By PCR-based clonality analysis, we detected a clear-cut clonal relationship of MALT lymphoma and DLBCL in 8 of 11 analyzed cases proving that the large majority of DLBCL following MALT lymphoma are clonally-related and constitute a real transformation. Interestingly, HT occurred within the first 2.5 years after diagnosis in patients with clonal relationship, whereas time to aggressive lymphoma was longer in patients identified as clonally-unrelated (most likely secondary) lymphoma (82-202 months), suggesting that HT is an early event in this disease. Survival of patients with HT was poor with 6/12 dying at 1.5-33 months after transformation, however, patients with localized gastric transformation had a superior outcome with only 1/6 dying due to progression of lymphoma.

**Conclusion:** These data show clearly that the large majority of DLBCL following MALT lymphoma are clonally-related and constitute a real transformation of indolent to aggressive lymphoma. With the exception of localized gastric transformation, however, prognosis is poor in patients with HT.

**Keywords:** extranodal lymphomas; extranodal marginal zone lymphoma of MALT type; indolent lymphoma.

210
INCIDENCE AND TREATMENT OUTCOMES OF PATIENTS WITH TRANSFORMED MARGINAL ZONE LYMPHOMA TREATED WITH RCHOP-LIKE REGIMENS

**S. Rajeeve**¹ | **S.V. Bobillo**² | **A.D. Zelenetz**² |
**D.J. Straus**² | **M.L. Palomba**² | **A. Noy**² |
**S.M. Horwitz**² | **A.J. Moskowitz**² | **P.A. Hamlin**² |
**M.J. Matasar**² | **A. Kumar**² | **C.L. Batlevi**² |
**G. von Keudell**² | **J. Yahalom**² | **A. Dogan**³ |
**E. Drill**⁴ | **A. Younes**² | **E. Joffe**²

¹Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States; ²Lymphoma service, Memorial Sloan-Kettering Cancer Center, New York, United States; ³Hematopathology service, Memorial Sloan-Kettering Cancer Center, New York, United States; ⁴Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, United States

**Introduction:** Transformed marginal zone lymphoma (tMZL) is frequently included among diffuse large B cell lymphoma (DLBCL) cases and is treated in a similar manner. We aimed to define the prevalence of tMZL and compare treatment outcomes to those of patients with non-transformed DLBCL treated with RCHOP-like regimens.
<table><caption>**TABLE 1** Baseline tMZL cohort and matching characteristics</caption><thead><tr><th></th><th>tMZL</th><th>non-GCB (matched)</th><th>p value</th></tr></thead><tbody><tr><td></td><td>80</td><td>240</td><td></td></tr><tr><td>Age</td><td>64.5 [35;91]</td><td>68.0 [23;94]</td><td>0.2</td></tr><tr><td>Sex (F)</td><td>47 (59%)</td><td>121 (50%)</td><td>0.3</td></tr><tr><td>ECOG &gt;=2</td><td>7 (9%)</td><td>22 (9%)</td><td>1.0</td></tr><tr><td>Stage</td><td></td><td></td><td></td></tr><tr><td>I-II</td><td>21 (26%)</td><td>67 (28%)</td><td>0.9</td></tr><tr><td>III</td><td>14 (18%)</td><td>45 (19%)</td><td></td></tr><tr><td>IV</td><td>45 (56%)</td><td>128 (53%)</td><td></td></tr><tr><td>Elevated LDH</td><td>42 (53%)</td><td>126 (53%)</td><td>0.9</td></tr><tr><td>Treatment regimen</td><td></td><td></td><td></td></tr><tr><td>R-CHOP</td><td>65 (81%)</td><td>196 (82%)</td><td>0.8</td></tr><tr><td>R-CHOP/RICE</td><td>5 (6%)</td><td>11 (5%)</td><td></td></tr><tr><td>R-EPOCH</td><td>10 (13%)</td><td>33 (14%)</td><td></td></tr></tbody></table>

**Methods:** We included all cases of DLBCL who were treated with RCHOP/RCHOP-like regimens at Memorial Sloan Kettering Cancer Center between 2001 and 2015. Among these we identified all patients with a pathology-confirmed diagnosis of MZL prior-to or at the time of presentation with DLBCL, divided into treatment-naïve and those who received systemic immunotherapy or chemotherapy prior to transformation. PFS was defined as the time from initiation of

RCHOP until progression or death from any cause. We also conducted an event free survival analysis (EFS), excluding progression as indolent MZL not requiring systemic chemotherapy. Survival was compared to all DLBCL cases (data not shown), and to a cohort of non-germinal-center DLBCL matched on age, stage, LDH, ECOG, and treatment regimen, excluding transformed histologies.

**Results:** We identified 1986 patients with newly diagnosed DLBCL treated with frontline RCHOP, of whom 63 (3.2%) had treatment-naïve tMZL. Of these 23 (37%) had pre-existing MZL (median time to transformation 33m). An additional 17 patients treated with RCHOP at the time of transformation, but with prior systemic therapy for MZL, were analyzed as a separate group (tMZL-Chemo). Fifty-four had ENMZL (68%), 16 (20%) nodal and 10 (13%) splenic. tMZL patients were matched with 240 non-GCB DLBCL cases (table 1). With a median follow-up of 76m from initiation of RCHOP, patients with tMZL had a trend towards a higher rate of progression (7yPFS of 44% for tMZL vs. 60% for DLBCL, p = 0.09). However, EFS, which excluded progressions as indolent MZL not requiring systemic chemotherapy, was similar (7yEFS 59% tMZL vs. 60% DLBCL, p = 0.64). Patients with tMZL who had received prior systemic rituximab or chemotherapy had a worse PFS and EFS (7yPFS 15% 7yEFS 35%, p<0.0001 vs. DLBCL). OS was similar between the groups (7yOS 72% tMZL vs. 68% DLBCL vs. 53% MZL-Chemo, p = 0.2) (figure 1).

**Conclusions:** tMZL represents 3% of newly diagnosed DLBCL cases and has a similar overall survival compared with non-transformed DLBCL non-GCB. To the best of our knowledge this is the largest tMZL cohort to be reported and the first to evaluate the prevalence and natural course of tMZL as compared to DLBCL.

<figure><img src="image_148.png" /></figure>
**Keywords:** diffuse large B-cell lymphoma (DLBCL); marginal zone lymphoma (MZL); R-CHOP.

## 211 ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA PATIENTS RELAPSING AFTER HIGH DOSE CHEMOTHERAPY WITH AUTOLOGOUS STEM CELL TRANSPLANTATION: DATA FROM THE JAPAN SOCIETY FOR HEMATOPOIETIC CELL TRANSPLANTATION (JSHCT) REGISTRY

E. Kondo<fnref n="1" /> | R. Shimizu-Koresawa<fnref n="1" /> | D. Chihara<fnref n="2" /> |

S. Mizuta³ | K. Izutsu<fnref n="4" /> | K. Ikegame⁵ | N. Uchida⁶ |

T. Fukuda⁷ | T. Ichinohe⁸ | Y. Atsuta⁹ | R. Suzuki¹⁰

**Introduction:** The outcome of primary mediastinal large B-cell lymphoma (PMLB) has been significantly improved by the addition of rituximab to CHOP-like or dose adjusted EPOCH. And high dose chemotherapy with autologous stem cell transplantation (HDT/ASCT) has been reported to be effective for relapsed or refractory (rel/ref) PMLB patients. However, PMLB patients relapsing after HDT/ASCT have few options of cure.

**Methods:** We have retrospectively analyzed the detailed records on allogeneic hematopoietic stem cell transplantation (AlloSCT) in PMLB patients relapsing after HDT/ASCT in the JSHCT registry. The objectives were to determine overall survival (OS), relapse rate, progression-free survival (PFS), non-relapse mortality (NRM) and GVHD rate following AlloSCT.

**Results:** Between 2004 and 2016, 23 PMLB patients relapsing after HDT/ASCT underwent AlloSCT. The median patient age was 33 years (range, 21 to 63 years). The median time from diagnosis to AlloSCT and HDT/ASCT to AlloSCT were 23 months (range, 11 to 168) and 11 months (range, 3 to 120), respectively. Disease status at AlloSCT were CR (or CRu) for 2 patients(pts), PR for 6 pts and

refractory for 15 pts. Five, 4 or 7 pts received transplants from matched related, mismatched related or matched unrelated donors, respectively. Seven pts had cord blood transplantation. Myeloablative conditioning regimen was used in 7 pts, whereas reduced intensity regimen was used in 16 pts. Two out of 6 pts in PR prior AlloSCT and 6 out of 15 pts in refractory prior AlloSCT achieved CR following AlloSCT. Grade II-IV acute GVHD occurred in 11 pts and chronic GVHD occurred in 3 pts. After a median follow-up of 3.1 years among surviving patients, the estimated 3-year OS and PFS were 48.8% (95% CI, 26.3-68.1%) and 32.6% (95% CI, 14.2-52.6%), respectively. The 1-year relapse rate was 46.3% (95% CI, 24.9-65.2%), whereas NRM was 17.3% at 100 days. Patients in CR after AlloSCT had significantly better OS and PFS (P = 0.001 and P<0.001, respectively)

**Conclusions:** AlloSCT may provide durable response even in the chemo-refractory patients with PMLB relapsing after HDT/ASCT. The remission status after AlloSCT correlated with a prolonged OS and PFS.

**Keywords:** allogeneic stem cell transplant (alloSCT); primary mediastinal large B-cell lymphoma (PMLBCL).

## 212 PROGNOSTIC FACTORS (PFs) IN PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA (PMLBCL) TREATED WITH RITUXIMAB-CHOP (RCHOP) ± RADIOTHERAPY (RT)

T.P. Vassilakopoulos<fnref n="1" /> | S.G. Papageorgiou<fnref n="2" /> |

M. Michail³ | M.K. Angelopoulou<fnref n="1" /> | G. Kourti<fnref n="4" /> |

C. Kalpadakis⁵ | M. Kotsopoulou⁶ | T. Leonidopoulou⁷ |

P. Konstantinidou⁸ | I. Kotsianidis⁹ | D. Boutsis¹⁰ |

E. Michali¹¹ | S. Sachanas¹² | E. Terpos¹³ |

G. Karianakis¹⁴ | C. Poziopoulos¹⁵ | C. Vadikolia¹⁶ |

A. Pigaditou¹⁷ | E. Vrakidou¹⁸ | K. Anargyrou¹⁹ |

A. Symeonidis²⁰ | E. Stefanoudaki²¹ | E. Hadjiharissi²² |

M. Papaioannou²² | G. Gainaru¹⁴ | M. Tsirogianni²³ |

E. Katodritou⁸ | T. Karmiris²⁴ | E. Variami²⁵ |

V. Pappa<fnref n="2" /> | M. Dimopoulos¹³ | P. Roussou<fnref n="4" /> |

P. Panayitidis²⁶ | K. Konstantopoulos<fnref n="1" /> | G.A. Pangalis¹²

<footnote n="1">¹Dept. of Hematology, Kawasaki Medical School, Kurashiki, Japan;</footnote>

<footnote n="2">²Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, United States; ³Department of Hematology and Immunology, Kanazawa Medical University, Uchinada, Japan;</footnote>

<footnote n="4">⁴Department of Hematology, National Cancer Center Hospital, Tokyo, Japan; ⁵Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan; ⁶Department of Hematology, Toranomon Hospital, Tokyo, Japan; ⁷Department of Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan; ⁸Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; ⁹Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan; ¹⁰Department of Oncology/Haematology, Shimane University Hospital, Izumo, Japan</footnote>

<footnote n="1">¹Dept of Haematology, National & Kapodistrian University of Athens, Athens, Greece; ²2nd Department of Internal Medicine and Research Institute, University General Hospital "Attikon", Haidari, Greece; ³Hematology, General Hospital of Nicosia, Nicosia, Cyprus; ⁴3rd Dept of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece; ⁵Dept of Haematology, University of Crete, Heraclion, Crete, Greece; ⁶Dept of Haematology, Metaxa Anticancer Hospital, Piraeus, Greece; ⁷Dept of Haematology, Sismanoglion Hospital, Marousi, Greece; ⁸Dept of Haematology, Theagenion Anticancer Hospital, Thessaloniki, Greece; ⁹Dept of Haematology, Democritus University of Thrace, Alexandroupolis, Greece; ¹⁰Dept of Haematology, Navy Hospital Athens, Athens, Greece; ¹¹Dept of Haematology, Athens General</footnote>
<table><caption>TABLE 1</caption><thead><tr><th colspan="4">FFP: Multivariate Analysis</th><th colspan="4">LSS: Multivariate Analysis</th></tr><tr><th>Factor</th><th>HR</th><th>95% CI</th><th>p-value</th><th>Factor</th><th>HR</th><th>95% CI</th><th>p-value</th></tr></thead><tbody><tr><td>E/IV</td><td>2.52</td><td>1.50-4.23</td><td>&lt;0.001</td><td>E/IV</td><td>2.71</td><td>1.26-5.86</td><td>0.011</td></tr><tr><td>LDH ≥2x</td><td>1.68</td><td>1.00-2.82</td><td>0.05</td><td>Bulk</td><td>4.40</td><td>1.32-14.64</td><td>0.016</td></tr><tr><th colspan="4">FFP: Prognostic Models</th><th colspan="4">LSS: Prognostic Models</th></tr><tr><th>Factors (#)</th><th>Pts [# (%)]</th><th>5-year FFP</th><th>p-value</th><th>Factors (#)</th><th>Pts [# (%)]</th><th>5-year LSS</th><th>p-value</th></tr><tr><th colspan="4">Model 1: E/IV and LDH ≥2x</th><th colspan="4">Model 1: E/IV and LDH ≥2x</th></tr><tr><td>0</td><td>151 (48%)</td><td>89.5%</td><td></td><td>0</td><td>151 (48%)</td><td>96.4%</td><td></td></tr><tr><td>1</td><td>121 (39%)</td><td>72.9%</td><td>&lt;0.0001</td><td>1</td><td>121 (39%)</td><td>83.6%</td><td>0.0014</td></tr><tr><td>2</td><td>41 (13%)</td><td>62.0%</td><td></td><td>2</td><td>41 (13%)</td><td>80.8%</td><td></td></tr><tr><th colspan="4">Model 2: E/IV and Bulk</th><th colspan="4">Model 2: E/IV and Bulk</th></tr><tr><td>0</td><td>74 (26%)</td><td>88.7%</td><td></td><td>0</td><td>74 (26%)</td><td>98.6%</td><td></td></tr><tr><td>1</td><td>134 (47%)</td><td>81.2%</td><td>0.0009</td><td>1</td><td>134 (47%)</td><td>90.8%</td><td>0.0002</td></tr><tr><td>2</td><td>78 (27%)</td><td>64.5%</td><td></td><td>2</td><td>78 (27%)</td><td>76.6%</td><td></td></tr></tbody></table>

HR = Hazard Ratio; 95% CI = 95% Confidence Intervals; E/IV = any extranodal involvement

Hospital, "Gennimatas, Athens, Greece; ¹²Dept of Haematology, Athens Medical Center, Psychikon Branch, Athens, Greece; ¹³Dept of Therapeutics, National and Kapodistrian University of Athens, Athens, Greece; ¹⁴Dept of Haematology, HYGEIA Hospital, Athens, Greece; ¹⁵Dept of Haematology, Metropolitan Hospital, Piraeus, Greece; ¹⁶Dept of Haematology, 424 Army Hospital, Thessaloniki, Greece; ¹⁷Dept of Haematology, Athens Medical Center, Marousi, Greece; ¹⁸Dept of Haematology, HyGEIA Hospital, Athens, Greece; ¹⁹Dept of Haematology, 251 Air Force Hospital, Athens, Greece; ²⁰Dept of Haematology, University of Patras, Patras, Greece; ²¹Dept of Haematology, Al. Fleming Hospital, Athens, Greece; ²²¹st Dept of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece; ²³Dept of Haematology, AGIOS SAVVAS Anticancer Hospital, Athens, Greece; ²⁴Dept of Haematology, Evangelismos Hospital, Athens, Greece; ²⁵¹st Dept of Internal Medicine, National & Kapodistrian University of Athens, Athens, Greece; ²⁶¹st Propedeutic Dept of Internal Medicine, National & Kapodistrian University of Athens, Athens, Greece

**Introduction:** RCHOP provides satisfactory results in PMLBCL, minimizing failure rates, but PFs have not been sufficiently evaluated, since only 2 moderately-sized studies have appeared so far including 96 and 123 patients (pts) from British Columbia and Japan, respectively. In the presence of R-da-EPOCH, a potentially better but also more toxic regimen compared to RCHOP, a reliable prognostic classification of PMLBCL is urgently needed, in order to define subgroups of pts at high- or very low-risk for treatment failure and death.

**Aims:** The identification of PFs for the outcome of pts with PMLBCL treated with RCHOP±RT.

**Methods:** 325 pts with PMLBCL ≤65 years old were treated with RCHOP±RT (usually 6-8 cycles) in a multicenter setting in Greece and Cyprus. The following potential PFs were evaluated: Age (median 32; range 16-65), gender (female 65%), B-symptoms (32%), stage III/IV (14%), infradiaphragmatic disease (10%), any extranodal involvement

(E/IV, 37%), any serositis (45%), bulky disease (≥10 cm; 63%), performance status (PS) ≥2 (14%), LDH levels (elevated 83%; ≥2x, 27%), anemia (38%), leukocytosis ≥10x10⁹/L (26%), ESR ≥50 mm/h (39%), albumin <4 g/dL (46%), age-adjusted IPI (aalPI; ≥2 in 22%).

**Results:** At amedian follow-up of 64 months (2-198), 68 failures and 34 deaths were recorded (including 2 unrelated deaths) for a 5-yearfreedom from progression (FFP) of 78% and both 5-year overall survival (OS) and lymphoma specific survival (LSS) of 89%. The aalPI was moderately predictive with 5-year FFP of 82% vs. 71% for aalPI 0-1 vs 2-3 (p = 0.04). On univariate analysis, extranodal involvement (E/IV), bulky disease, and low albumin were significantly associated with both inferior FFP and LSS, infradiaphragmatic disease and LDH ≥2x only with FFP, while any serositis and anemia only with LSS. The results of multivariate analysis and the respective prognostic models are shown in the table.

**Conclusions:** In the largest pt series with PMLBCL reported so far, RCHOP±RT provided long-term disease control and LSS rates of 78% and 89%. The combination of any extranodal involvement (E/IV) with either bulky disease or LDH ≥2x defined high-risk subgroups (13-27% of pts) with ~20-23% mortality. More importantly, their absence defined subgroups comprising ~1/4 or 1/2 of the pts, with 10-11% risk of failure and only 1.5% or 3.5% 5-year mortality, who might not benefit from intensified treatment as R-da-EPOCH.

**Keywords:** primary mediastinal large B-cell lymphoma (PMLBCL); prognostic indices.

213
IS IT RADIOTHERAPY NECESSARY FOR PRIMARY MEDIASTINAL B-CELL LYMPHOMA (PMBL) PATIENTS ACHIEVING PET NEGATIVITY AFTER IMMUNOCHEMOTHERAPY?
M. Trneny¹ | K. Polgarova¹ | A. Janikova² |

D. Belada³ | V. Prochazka⁴ | J. Duras⁵ |

H. Mocikova⁶ | K. Steinerova⁷ | V. Campr⁸ |

P. Blahovcova⁹ | M. Petrova⁹ | D. Zogala¹⁰ |

V. Ptacnik¹⁰

¹Ist Dept Med, Charles University General Hospital, Praha, Czech Republic; ²Dept Hemato-Oncology, University Hospital Brno, Brno, Czech Republic; ³Dept Hematology, University Hospital, Hradec Kralove, Czech Republic; ⁴Dept Hematology, University Hospital, Olomouc, Czech Republic; ⁵Dept Hematology, University Hospital, Ostrava, Czech Republic; ⁶Dept Hematology, University Hospital Kralovske Vinohrady, Praha, Czech Republic; ⁷Dept Hematology, University Hospital, Plzen, Czech Republic; ⁸Dept Pathology, University Hospital Motol, Praha, Czech Republic; ⁹Data Center, Czech Lymphoma Study Group, Praha, Czech Republic; ¹⁰Dept Nuclear Medicine, Charles University General Hospital, Praha, Czech Republic

**Introduction:** Primary mediastinal B-cell lymphoma (PMBL) has specific clinical and biological characteristics. The current standard of therapy is based on immunochemotherapy which means rituximab and anthracycline based chemotherapy (R-CHT), either CHOP, CHOEP or DA-EPOCH or more intensive chemotherapy. Radiotherapy (RT) consolidation has been a standard especially in pre PET era. Although the RT has started to be skipped now in situation of complete metabolic response after R-CHT, there is lack of data to answer this question. Primary objective of this analysis is to compare PFS and OS of PMBL patients who achieved PET negative response after R-CHT according to RT.

**Methods:** Patients (pts) with confirmed diagnosis of PMBL observed in NiHiL project (NCT03199066) were included. Pts have to be treated with R-CHT and PET/CT has to be performed at the end of the immunochemotherapy. Response criteria according to Cheson 2007 were used. Only pts who achieved PET negativity could be included for primary analysis. The indication of RT was based on center/physician decision. PFS and OS were calculated since the time of dg.

**Results:** Altogether 190 PMBL pts diagnosed between 6/2002 and 8/2017 fulfilled the inclusion criteria and were included. The age median was 36 years (range 18-78) with slight female predominance (56.8%). The localized stage I-II was observed in 69.5%; low or low-intermed IPI in 79.5% pts. All patients received R-CHT (CHOP 57.9%, DA-EPOCH or CHOEP 8.9%, intensive regimens 32.6% and 1pt received ICE as primary CHT). High dose therapy and ASCT as part of the induction was performed in 27.9% pts. At the end of R-CHT (including ASCT) 136 (71.6%) pts. achieved PET negative remission (PET-neg), 43 (22.6%) were PET positive (PET-pos) and the finding was inconclusive (PET-un) for 11 (5.8%) pts. Median follow up was 4.5 years. OS probability at 5y was 89.4% vs 80.0% vs 70.0% for PET-neg vs PET-un vs PET-pos resp. (p = 0.002). Out of 136 PET-neg pts the radiotherapy was used in 54 (39.0%) and 83 (61.0%) were observed (OBS). There was insignificant trend for better PFS

probability at 5y for RT group (95.5%) vs OBS group (85.4%) with 3.85 times increased risk for progression or death in OBS arm (HR 3.86; 95%CI; 0.96-8.77; p = 0.0585). There was insignificant trend for better 5y OS probability for RT group (97.6%) vs OBS group (90.2%) with 4.7 times increased risk of death in OBS arm (HR 4.71; 95%CI; 0.77-13.02; p = 0.1098).

**Conclusion:** The radiotherapy use in PMBL patients who achieve PET negativity at the end of immunochemotherapy remains controversial. Our observational analysis failed to show statistically significant benefit of radiotherapy, however from the clinical point of view, the numeric difference 10% and 7.5% resp. in 5 years progression free survival and overall survival probability resp. could be viewed as the important one esp. when therapy de-escalation is discussed. The results of randomized IELSG-37 study (NCT01599559) could bring more information in the future.

**Keywords:** positron emission tomography (PET); primary mediastinal large B-cell lymphoma (PMLBCL).

Q. Mei | W. Zhang | Y. Liu | J. Liu | Q. Yang |

W. Han

Bio-therapeutic Department, Molecule & Immunology Department, Chinese PLA General Hospital, Beijing, China

**Background:** Primary mediastinal large B-cell lymphoma (PMLBCL) is an aggressive type of diffuse large B-cell lymphoma (DLBCL) and represents a molecular signature reminiscent of classical Hodgkin's lymphoma (cHL). The frontline therapy is very effective in PMBCL, but relapsed/refractory PMLBCL (rrPMLBCL) generally has limited treatment options and dismal prognosis. Monotherapy of PD-1 inhibitor was reported to induce an effective clinical response and was approved for the treatment of patients with rrPMLBCL by FDA in 2018. However, PD-1 inhibitor is not recommended for treatment of rrPMLBCL patients with life-threatening tumor burden (bulky disease) who require urgent cytoreductive therapy. We aimed to develop a salvage therapy for patients with aggressive bulky disease.

**Methods:** This ongoing trial is enrolling patients with rrPMLBCL who have bulky disease (minimum measurement must be >5 cm in the longest diameter) with aggressive phenotype, rapid progression and fatal prediction. All patients have been heavily treated with rituximab-containing regimens, and have relapsed or refractory disease after ≥ 2 lines of prior therapy. Enrolled patients received GVD chemotherapy regimen (Gemcitabine, Vinorelbine and Doxorubicin, day 1) plus PD-1 antibody SHR-1210 (4 mg/kg, day 2) every 3 weeks. Treatment
duration was up to completion of 12 cycles or until progressive disease (PD) or unacceptable adverse events (AEs) occurred or upon patient request to discontinue therapy. Safety was assessed by CTCAEv4.0 in the population consisted of all patients who received ≥ 1 dose of study drug. Clinical response was evaluated by computed tomography (CT) every two cycles and by positron emission tomography-computed tomography (PET-CT) every 4 cycles using International Working Group (IWG) Response Criteria. Peripheral blood samples were collected before every cycle and tumors were biopsied prior to initiation of therapy for relevant biomarker analysis. The primary end points were safety/tolerability and objective response rate (ORR). Key secondary end points were complete response rate (CRR), progression-free survival (PFS) and overall survival (OS).

**Interim Results:** At the analysis cutoff date (March 10, 2019), 29 rrPMLBCL patients were enrolled: median age 30 years (range: 16 - 45), 52% female (15/29), median 3 lines of prior therapy (range: 2 - 6), median 6 cycles of rituximab-containing regimens (range: 2 - 10), median aalPI score 2 (range: 1 - 4). Median follow-up duration was 11.8 mos (range: 6.2 - 19.9). 26 patients had completed the first efficacy assessment: 12 CR, 7 PR, 3 SD and 4 PD; ORR 73% and CRR 46%. median PFS and OS were not reached, and all responders were still alive at data cutoff.

ClinicalTrials.gov (NCT03346642)

**Keywords:** chemotherapy; PD-1; primary mediastinal large B-cell lymphoma (PMLBCL).

## 215 TEMOZOLOMIDE IN RELAPSE/REFRACTORY PRIMARY VITREORETINAL LYMPHOMA (R/R PVRL): A SIMPLE, CHEAP, EFFECTIVE AND WELL TOLERATED TREATMENT. RESULT OF THE LARGEST STUDY ON R/R PVRL, FROM THE LOC NETWORK

S. Choquet<fnref n="1" /> | M. Baron<fnref n="1" /> | C. Soussain² |

C. Houillier<fnref n="3" /> | E. Gyan⁴ | P. Soubeyran⁵ |

N. Cassoux⁶ | V. Touitou⁷ | B. Bodaghi⁷ |

K. Hoang-Xuan<fnref n="3" /> | V. Leblond<fnref n="1" />

**Background:** Primary vitreoretinal lymphoma (PVRL) is a very rare subset of non Hodgkin lymphoma. The main adverse evolution is central-nervous system localization which arise in more than 1/3 of

<figure><img src="image_149.png" /></figure>

patients at 4 years. Publications in this field are very limited and no consensus or recommendations exist. Temozolomide is used in first line gliobastoma and has been described effective in some cases of CNS lymphoma.

**Purpose:** To evaluate the efficacy and safety of temozolomide for the treatment of relapsed or refractory (R/R) primary vitreoretinal lymphoma or as front-line therapy in patients not eligible for intensive treatment.

**Patients and methods:** From March 2008 to January 2018, immunocompetent adults with R/R PVRL or patients not eligible for intensive treatment were treated with oral temozolomide (TMZ) monotherapy at a dose of 150 or 200 mg/m² for 5 days a month every 4 weeks.

**Results:** Twenty-one patients were treated. Two patients received TMZ as first-line therapy, two patients had undergone autologous stem cell transplantation (ASCT) prior to treatment with TMZ, one patient had relapsed after treatment with lenalidomide and two other patients had relapsed after treatment with ibrutinib. Median age was 75 years (range: 35-90) and median follow-up was 42 months. Overall response rate was 81%: 15 patients (71%) achieved complete remission and two (10%) had a partial response. The median duration of response was 10.9 months (range: 3-109) and median progression-free survival was 12 months [95%CI: 8-NR]. TMZ was well tolerated and there was no unexpected toxicity.

**Conclusion:** TMZ is an attractive therapeutic option in patients with R/R PVRL or as front-line therapy in patients not eligible for intensive treatment, with a high response rates and good tolerance, even in patients who have become resistant to treatment with ibrutinib, lenalidomide or ASCT. In economic terms, this treatment is far less expensive than other new medications.

**Keywords:** B-cell lymphoma; primary CNS lymphoma (PCNSL); temozolomide.

## 216 CLINICAL FEATURES, TREATMENT AND OUTCOME OF NEUROLYMPHOMATOSIS: SINGLE INSTITUTION EXPERIENCE

<footnote n="1">¹Clinical Haematology, APHP, Pitie-Salpetriere, Paris, France; ²Clinical Haematology, Institut Curie, Rene Huguenin, Saint-Cloud, France;</footnote>

<footnote n="3">³Neuro-Oncology, Pitie Salpetriere Hospital, Paris, France; ⁴Clinical Haematology, CHRU Trousseau, Chambray-lès-Tours, France; ⁵Clinical Haematology, Institut Bergonié, Bordeaux, France; ⁶Ophtalmology, Institut Curie, Paris, Paris, France; ⁷Ophtalmology, Pitie Salpetriere Hospital, Paris, France</footnote>
**M. Novo** | **G.S. Nowakowski** | **I.N. Micallef** |

**K. Ristow** | **T.M. Habermann** | **P.B. Johnston** |

*Hematology, Mayo Clinic, Rochester, MN, United States*

**Introduction:** Neurolymphomatosis (NL) is a highly rare disorder defined as infiltration of peripheral nervous system by a lympho-proliferative neoplasm, both presented as the first manifestation of the malignancy (primary NL) or as a site of disease progression or relapse (secondary NL). Clinical features of NL and best approach are still widely unknown.

**Methods:** We retrospectively reviewed clinical records of all histologically confirmed-NL, diagnosed and treated at the Hematology Department of Mayo Clinic in Rochester MN between January 2002 and December 2018.

**Results:** Over a 16-year period 40 patients were diagnosed with NL. Primary and secondary NL were 18 (45%) and 22 (55%) respectively, with a median age of 60.5 years (range 37-83) and male sex 24/40 (60%). The majority had B-cell lymphomas (39/40 patients): 27/40 (60%) with diffuse large B-cell lymphoma (DLBCL) and only 1 case of T-cell lymphoma. The affected structures included peripheral nerves in 16/40 cases, spinal nerves (12/40), neural plexus (14/40),

cranial nerves (4/40), cauda equine (6/40); multiple sites were involved in 13/40. 4/40 cases had brain involvement and cerebrospinal fluid (CSF) was positive in 7/29. NL clinical manifestations included muscular weakness (33/40 patients), sensory deficit (32/40), pain (28/40) and autonomic dysfunction (3/40). Magnetic resonance imaging (MRI) detected neural abnormalities in 35/36 cases (97%), CT imaging identified disease in 3/8 (37%) and FDG-PET scan was positive in 22/31 (71%); electromyography showed some grade of neuropathy in 28/29 cases. Treatment included systemic chemotherapy in 38/40 patients, containing high dose methotrexate (HD-MTX) in 26/40 (65%) and rituximab in 20/40 (50%); 11/39 (28%) patients underwent consolidative autologous stem cell transplant; 4/40 received consolidative radiotherapy (RT) and 1/40 was managed with RT alone; intrathecal chemotherapy was infused in 1/40 cases; one patient with solely great auricular nerve NL involvement was cured with surgery only. Treatment efficacy evaluated by imaging and clinical improvement consisted with an overall response rate of 73% (27/37) with a 51% (19/37) rate of complete remission (CR); the rates of CR reached with HD-MTX regimens and other systemic treatments were 56% (13/24) and 42% (5/13) respectively. The median overall survival (OS) was 137.8 months with a 48-months OS 73%. A trend of longer survival rate for primary NL, although no statistically

<figure><img src="image_150.png" /><figcaption>**Figure 1.** Kaplan-Meier Curves of Overall survival (OS) of global population (median OS 137.8 months; 40 patients) (A), and patients with either primary NL (median OS not reached; 18 patients) or secondary NL (median OS 80.7 months; 22 patients) (B). Median Follow-up 45.1 months.</figcaption></figure>
significance, was observed, with a 48-month OS of 94% vs 56% for secondary NL (p 0.134). (Figure 1)

**Conclusions:** In our retrospective cohort of NL, DLBCL represent the predominant histologic subtype; MRI appeared to be the most accurate radiological tool to detect relevant neural disease; primary NL showed a trend of better prognosis with high rates of prolonged survival; HD-MTX - containing regimens are associated with higher rates of deep response.

**Keywords:** extranodal lymphomas; immunochemotherapy; non-Hodgkin lymphoma (NHL).

## 217
BICENTRIC PILOT STUDY ON AGE-ADAPTED HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS STEM CELL TRANSPLANT IN NEWLY DIAGNOSED PRIMARY CNS LYMPHOMA PATIENTS > 65 YEARS - MARITA TRIAL

E. Schorb<fnref n="1" /> | B. Kasenda<fnref n="2" /> | G. Ihorst<fnref n="3" /> | H. Fricker<fnref n="1" /> |

H. Holl<fnref n="2" /> | J. Finke<fnref n="1" /> | G. Illerhaus<fnref n="2" />

**Introduction:** Intensive chemo(immuno)therapy followed by high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) is widely regarded standard treatment for younger patients with primary central nervous system lymphoma (PCNSL). Although elderly PCNSL patients are able to tolerate intensive systemic therapy, such approaches are often only offered to patients younger than 65-70 years. However, similar to experience in myeloma and systemic lymphoma, it has been shown that a selected subgroup of elderly patients is eligible for HCT-ASCT (Schorb et al. BMT 2017). The rationale of this study is to prospectively determine efficacy and safety of HCT-ASCT in elderly PCNSL patients.

**Methods:** This is a prospective, single-arm, pilot study conducted at two German centers (DRKS 00008900). Main eligibility criteria included newly diagnosed PCNSL, immunocompetency, age > 65 years, ECOG PS ≤ 2, and adequate organ function. Induction treatment consisted of 2 cycles (21 days): methotrexate 3.5 mg/m<fnref n="2" /> (day 1), cytarabine 2 g/m<fnref n="2" /> twice daily (days 2 and 3) and rituximab 375 mg/m<fnref n="2" /> before and after each chemotherapy; stem cell harvest after 1st cycle. Subsequent consolidation with HCT-ASCT included: Busulfan 3.2 mg/kg on day -7 and -6, thiotepa 5 mg/kg/d on day -5 and -4 and reinfusion of stem cells on day 0. Main endpoints included toxicity, lymphoma response, progression free survival (PFS) and overall survival (OS).

**Results:** Fourteen patients were included between Dec 2015, and Sept 2017. Median age and Karnofsky performance score were 73 years (range 69-79 years) and 80% (range 30-90%), respectively. 13 of 14 patients responded to induction treatment (2 with complete remission (CR), 11 with partial remission (PR), 1 patient with premature end of treatment was not evaluable and considered not responding). 13 of 14 patients commenced HCT-ASCT; 30 days after HCT-ASCT 12/13 patients achieved CR and 1/13 PR. No treatment related deaths were recorded. After a median follow-up of 30 months, one patient developed progressive disease 9 months after HCT-ASCT and died due to lymphoma progression later on. All other patients are in complete remission. Respective 2-year PFS and OS rates were 92% (95% CI 79% to 100%) and 89% (95% CI 71% - 100%).

**Conclusions:** In selected elderly PCNSL patients age-adapted induction treatment followed by HCT-ASCT with thiotepa and busulfan is safe and effective. Further details will be presented at the meeting. A phase II study in Germany (MARTA trial, DRKS 00011932) is currently investigating this approach in a multicenter setting.

**Keywords:** autologous stem cell transplantation (ASCT); elderly; primary CNS lymphoma (PCNSL).

**Disclosures:** Schorb, E: Honoraria: Riemser GmbH; Research Funding: Riemser GmbH. Finke, J: Honoraria: Riemser GmbH; Research Funding: Riemser GmbH. Illerhaus, G: Honoraria: Riemser GmbH; Research Funding: Riemser GmbH.

## PTCL AND NK/T CELL LYMPHOMAS

## 218
MEMBRANE EXPRESSION OF NK RECEPTOR KIR3DL2 CONTRIBUTES TO DELINEATE THE ACUTE-TYPE AND IS A THERAPEUTIC TARGET IN ADULT T-CELL LEUKEMIA/LYMPHOMA

M. Cheminant<fnref n="1" /> | L. Lhermitte<fnref n="2" /> | J. Bruneau<fnref n="3" /> |

H. Sicard⁴ | C. Bonnafous⁴ | N. Ortonne⁵ |

L. Genestier⁶ | P. Gaulard⁵ | P. Palmic<fnref n="3" /> |

M. Dussiot⁷ | L. Waast⁸ | V. Avettand-Fenoel⁹ |

C. Brouzes<fnref n="2" /> | Y. Lepelletier⁷ | V. Asnafi<fnref n="2" /> |

A. Marçais<fnref n="1" /> | O. Hermine<fnref n="1" />

<footnote n="1">¹Department of Hematology and Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; ²Department of Hematology, Oncology and Palliative Care, Klinikum Stuttgart, Stuttgart, Germany;</footnote>

<footnote n="3">³Clinical Trials Unit, Faculty of Medicine, University of Freiburg, Freiburg, Germany</footnote>

<footnote n="1">¹Clinical Hematology, Necker University Hospital, AP-HP, Paris, France;</footnote>

<footnote n="2">²Biological Hematology, Necker University Hospital, AP-HP, Paris, France; ³Pathology Department, Necker University Hospital, AP-HP, Paris, France; ⁴Innate Pharma, Marseille, France; ⁵Pathology, Groupe Hospitalier Henri Mondor, AP-HP, Créteil, France; ⁶Centre Léon Bérard, Université Claude Bernard Lyon I, Lyon, France, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Lyon, France; ⁷INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Imagine Institute, Paris, France; ⁸INSERM U1016, CNRS UMR 8104,</footnote>
Université Paris Descartes, Sorbonne Paris Cité, Institut Cochin, Paris,
France; ⁹Virology, Necker University Hospital, AP-HP, Paris, France

**Introduction:** Adult T-cell leukemia/lymphoma (ATL) is a lymphoid neoplasm of CD4+ T lymphocytes caused by the human T-cell leukaemia virus type I (HTLV-1), which is classified into 4 clinical subtypes (ie, smoldering, chronic, acute, and lymphoma). Natural killer receptors (NKRs) were previously identified on T-cell lymphoma.

**Methods:** NKRs expression was assessed by flow-cytometry and immunohistochemistry on peripheral blood samples (n = 55) and biopsies (n = 21) obtained from 50 ATL patients. Array-based analysis of genomic DNA methylation patterns of KIR3DL2 promoter was assessed. To explore the role of HTLV-1 on KIR3DL2 expression, KIR3DL2 and TAX mRNA expressions were assessed on primary ATL cells and on activated CD4+ T cells that were infected with HTLV-1 in-vitro. Ex-vivo autologous antibody dependent cell cytotoxicity (ADCC) was performed on sorted primary ATL cells with IPH4102, a monoclonal anti-KIR3DL2 antibody that has shown robust clinical activity in Phase I in patients with relapsed Sézary Syndrome (NCT02593045).

**Results:** KIR3DL2 was the only detected NKR, mainly expressed on acute- compared to lymphoma- and chronic-types ATL (28/30 vs. 2/8 and 2/12 respectively; p = 0.001). KIR3DL2 expression correlated with the demethylation status in its promoter, and treatment by 5-Aza increased its expression from a positive basal state. TAX mRNA and KIR3DL2 expressions were correlated on primary ATL cells. HTLV-1 infection triggered KIR3DL2 protein expression by CD4+ cells. However, Tax alone is not sufficient to induce KIR3DL2 mRNA expression. Treatment with IPH4102 can selectively kill human KIR3DL2+ primary ATL cells ex-vivo through ADCC with autologous NK cells.

**Conclusion:** KIR3DL2 expression is mainly associated with acute-type ATL, the most frequent subtype with the poorest prognosis. Induction of KIR3DL2 gene transcription may be triggered by HTLV-1 infection followed by transcription maintenance due to DNA hypomethylation of the gene promoter. The benefit of targeting KIR3DL2 by IPH4102 should be further investigated in ATL patients.

**Keywords:** human T-lymphotropic virus (HTLV); monoclonal antibodies (MoAb); peripheral T-cell lymphomas (PTCL).

**Disclosures:** Cheminant, M: Research Funding: yes. Bruneau, J: Research Funding: yes. Sicard, H: Employment Leadership Position: yes; Stock Ownership: yes. Bonnafous, C: Employment Leadership Position: yes; Stock Ownership: yes. Hermine, O: Research Funding: yes.

¹U1163, Imagine Institute, Paris, France; ²Hematology Department, CHU Limoges, Limoges, France; ³Pathology Department, Necker Hospital, AP-HP, Paris, France; ⁴Bioinformatics department, CALYM-LYSARC, Paris, France; ⁵Hematology Department, Necker Hospital, AP-HP, Paris, France; ⁶Hematology Department, CHU Rennes, Rennes, France; ⁷Hematology Department, CHU Angers, Angers, France; ⁸Hematology Department, Saint Antoine Hospital, AP-HP, Paris, France; ⁹Hematology Department, CHR Orléans, Orléans, France; ¹⁰Hematology Department, Henri-Mondor Hospital, AP-HP, Créteil, France; ¹¹Hematology Department, Paoli Calmettes Institute, Marseille, France; ¹²Hematology Department, Centre Hospitalier Annecy Genevois, Metz, France; ¹³U955, Pathology Department, Henri-Mondor Hospital, AP-HP, Créteil, France; ¹⁴Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan; ¹⁵Hematology Department, CHU Lyon Sud, Pierre-Bénite, France

**Introduction:** Extranodal Natural killer/T-cell lymphoma, nasal type (ENKTCL) is a rare and aggressive subtype of peripheral T cell lymphoma strongly associated with Epstein-Barr virus. The use of Asparaginase in the last ten years has significantly improved the prognosis of this lymphoma. Although 60% of these patients are now cured with this regimen even while relapsing, some are however primary refractory or relapse early. NK/T lymphomagenesis is characterized by immune resistance with inefficient immune response directed against EBV-positive tumor cells. The PD-1 (programmed cell death protein 1) / PD-L1 (programmed cell death protein ligand 1) axis is thought to play a role in this process by averting effector T-cell targeting. PD-1/PD-L1 blockade represents therefore a relevant therapeutic strategy in relapsed/ refractory ENKTCL patients and has already demonstrated efficacy in very few cases.

**Methods:** We report here the outcome of 13 ENKTCL patients treated with PD-1 inhibitors between March 2017 and August 2018. All patients presented with relapsed or refractory lymphoma failing Asparaginase regimens. Four out of these patients have been treated in the frame of the AcSé Pembrolizumab UNICANCER Immunotherapy Group protocol.

**Results:** Median age was 44 years (range, 20-73) and sex ratio (M/F) was 1.6. Five patients presented at diagnosis with localized disease and 8 had advanced-stage disease. PINK score was low in 2, intermediate in 7 and high in 4 patients. All patients have been previously treated by at least one line of chemotherapy containing Asparaginase. In most cases (12/13), patients have received pembrolizumab as PD-1 inhibitor and a median of 5 (range, 1-14) cycles were administered. Four patients (31%) have responded to pembrolizumab durably (3 complete response and one partial response) with a median follow
up of 12.5 months (range, 7.7-19). One patient achieved partial response but relapsed, 7 patients (53%) progressed and one was unevaluable. Progression-free survival and overall survival at 12 months were 39% and 46% respectively. Treatment-related adverse events of grade ≥3 were observed in 3 patients (cytopenia in 2 cases and cytokine release syndrome in one case).

PD-L1 immunohistochemical data are currently available in 4 patients (1 complete response, 1 partial response and 2 progressions). In all patients, no PD-L1 expression was detected in ENKCTL cells, suggesting that response to anti-PD1 antibodies is not correlated to PD-L1 expression in the tumor.

**Conclusions:** To our knowledge, this is the largest reported series of ENKCTL patients treated with PD-1 inhibitors. Our findings indicate that PD-1 blockade represents a potent strategy for a subset of relapsed/refractory ENKCTL patients failing Asparaginase regimens. However, further immunohistochemical and molecular studies are warranted to identify predictive biomarkers of response to immune checkpoints inhibitors in order to improve patient selection.

**Keywords:** non-Hodgkin lymphoma (NHL); PD-1; Pembrolizumab.

**Disclosures:** Salles, G: Honoraria: from BMS and Merck to participate to advisory boards and symposiums.

## 220
A PROSPECTIVE PHASE II STUDY OF PEGASPARGASE-COEPL PLUS RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED EXTRA-NODAL NK/T-CELL LYMPHOMA

S. Hu<fnref n="1" /> | J. Liu<fnref n="1" /> | N. Lin<fnref n="1" /> | Y. Sun<fnref n="2" /> | W. Liu<fnref n="1" /> | X. Wang<fnref n="1" /> | Y. Xie<fnref n="1" /> | Y. Song<fnref n="1" /> | J. Zhu<fnref n="1" /> | Y. Wen<fnref n="3" />

**Introduction:** The optimal first-line treatment for extra-nodal NK/T-cell lymphoma (ENKTL) has not been well-defined. This study aimed to evaluate the efficacy and safety of pegaspargase, cyclophosphamide, vincristine, etoposide and prednisone (COEPL) regimens combined with radiotherapy for patients with newly diagnosed ENKTL.

**Methods:** Our study is a prospective, open-label clinical trial. Patients with newly diagnosed ENKTL and an ECOG performance status of 0 to 2 were eligible for enrollment. For patients with stage I/II nasal type ENKTL, treatment included 2-3 cycles of induction COEPL (cyclophosphamide 750mg/m<fnref n="2" /> day 1; vincristine

1.4mg/m<fnref n="2" /> day 1; etoposide 60mg/m<fnref n="2" /> days 1-3; prednisone 100mg days 1-5; pegaspargase 2500IU/mg/m<fnref n="2" /> day 2, every 21 days) followed by concurrent chemoradiotherapy (e.g. RT ≥50Gy with concurrent 1-2 cycles of LOP regimen: pegaspargase, vincristine and prednisone every 14-21 days, with the same doses as described above), then by 1-2 cycles of COEPL regimen as consolidation. For patients with stage III/IV or extra-nasal ENKTL, treatment included 6 cycles of COEPL regimen with or without radiotherapy to local sites, and autologous stem cell transplantation was given in selected patients.

**Results:** A total of 80 patients were enrolled. The median age was 41 years (range, 15-76 years). Sixteen patients (20%) had stage III/IV disease, 6 (8%) presented with extra-nasal ENKTL, and 10 (12.5%) had a PINK score ≥2. Complete response and overall response rates were 75.0% and 87.0%, respectively. With a median follow-up of 41.4 months (range 2.7-76.2 months), the 3-year progression-free survival (PFS) and overall survival (OS) rates were 71.3% (95%CI 61.1-81.5%) and 73.3% (95%CI 63.1-83.5%), respectively. For patients with stage I/II nasal type ENKTL (n = 62), the 3-year PFS and OS were 78.1% and 81.2%, respectively. For patients with stage III/IV or extra-nasal ENKTL (n = 18), 3-year PFS and OS were 48.1% and 45.7%, respectively. Major grade 3-4 adverse events were anemia (21.3%), leucopenia (18.8%), neutropenia (13.8%), thrombocytopenia (7.6%) and transaminase elevation (3.8%). No treatment-related death was observed.

**Conclusions:** Pegaspargase-COEPL chemotherapy in combination with radiotherapy is highly effective and safe for patients with newly diagnosed ENKTL.

**Keywords:** chemotherapy; T-cell lymphoma (TCL).

## 221
A PROSPECTIVE STUDY OF MRI AND PET/CT-GUIDED THERAPY FOR IMPROVING SURVIVAL IN UPPER AERODIGESTIVE TRACT NATURAL KILLER/T-CELL LYMPHOMA, NASAL TYPE

T. Lin<fnref n="1" /> | Q. Ren<fnref n="1" /> | H. Huang<fnref n="1" /> | X. Li<fnref n="2" /> | H. Hong<fnref n="3" /> | Z. Wang<fnref n="1" /> | X. Fang<fnref n="1" /> | C. Guo<fnref n="1" /> | F. Li<fnref n="1" /> | L. Zhang<fnref n="1" /> | Y. Yao<fnref n="1" /> | Z. Chen<fnref n="1" /> | Y. Huang<fnref n="1" /> | Z. Li<fnref n="1" /> | Q. Cai<fnref n="1" /> | Y. Tian<fnref n="1" /> | H. Wang<fnref n="1" /> | X. Lin<fnref n="1" /> | W. Fan<fnref n="1" /> | L. Zheng<fnref n="1" /> | S. Lin<fnref n="1" /> | Q. Liu<fnref n="1" />

<footnote n="1">¹Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China; ²Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, China; ³Medical Department, Medpison (Beijing) Medical Technology Co., Ltd, Beijing, China</footnote>

<footnote n="1">¹Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China;</footnote>

<footnote n="2">²Department of Medical Oncology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China, Guangzhou, China;</footnote>

<footnote n="3">³Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Guangzhou, China</footnote>
<table><caption>**TABLE 1** HN-MRI could revise the initial clinical stages in patients undergoing PET/CT According to the Ann Arbor and TNM Staging Systems</caption><thead><tr><th rowspan="2">PET/CT<sup>a</sup></th><th colspan="4">PET/CT-MRI<sup>b</sup></th><th rowspan="2">P value</th></tr><tr><th>I</th><th>II</th><th>III</th><th>IV</th></tr></thead><tbody><tr><td colspan="6">AA Staging<sup>c</sup></td></tr><tr><td>I</td><td>14</td><td>8</td><td>0</td><td>0</td><td rowspan="4">0.011</td></tr><tr><td>II</td><td>0</td><td>46</td><td>0</td><td>1</td></tr><tr><td>III</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>IV</td><td>0</td><td>0</td><td>0</td><td>2</td></tr><tr><td colspan="6">TNM Staging<sup>d</sup></td></tr><tr><td>I</td><td>25</td><td>2</td><td>5</td><td>0</td><td rowspan="4">0.019</td></tr><tr><td>II</td><td>0</td><td>2</td><td>3</td><td>0</td></tr><tr><td>III</td><td>0</td><td>0</td><td>26</td><td>0</td></tr><tr><td>IV</td><td>0</td><td>0</td><td>0</td><td>8</td></tr></tbody></table>

a, PET/CT, [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography; b, PET/CT-MRI, [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography combined with magnetic resonance imaging; c, AA Stage, Ann Arbor staging; d, TNM Staging (American Joint Committee on Cancer for Nasopharyngeal Carcinoma, 8th edition, 2017). Survival of patients undergoing HN-MRI with PET/CT were significantly better than that of patients undergoing PET/CT alone

**Introduction:** Radiotherapy is extremely important in extranodal natural killer/T-cell lymphoma (ENKTL). [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is a routine pretreatment imaging technique used in ENKTL, while magnetic resonance imaging (MRI) plays a key role in head and neck (HN) cancer. The purpose of this study was to investigate the value of pretreatment HN-MRI and PET/CT-guided therapy in improving survival in upper aerodigestive tract ENKTL (UADT-ENKTL).

**Methods:** We prospectively conducted a single center study on untreated patients with pathologically diagnosed UADT-ENKTL. Patients undergoing PET/CT with/without HN-MRI were decided by clinicians for staging and restaging. The patients were treated with L-asparaginase/Pegaspargase and non-anthra-cycline-based chemotherapy with intensity-modulated radiation therapy (IMRT).

**Results:** We enrolled 171 patients (median age, 44 years; range, 18-75 years; 118 (69%) males) from April 2011 to March 2018. Overall, 71 patients underwent PET/CT and HN-MRI (PET/CT-MRI) and 100 patients underwent PET/CT alone. HN-MRI upgraded the clinical stages in 8 patients (8/71) undergoing PET/CT based on the Ann Arbor staging system and in 10 patients (10/71) based on the TNM staging system by detecting additional local lesions (P = 0.011 and P = 0.019, respectively). With a median follow-up of 54 months, the 5-year overall survival (OS), local recurrence-free survival (LRFS) and progression-free survival (PFS) rates were 72.7%, 68.6% and 68.2%, respectively, for all patients. The 5-year LRFS rate was 100% in the PET/CT-MRI group and

<figure><img src="image_151.png" /></figure>

64.3% in the PET/CT group (P<0.001). Similarly, the 5-year OS and PFS were longer in the PET/CT-MRI group than in the PET/CT group (84.5% vs. 67.8% and 78.3% vs. 65.6%; P = 0.04 and P = 0.03, respectively).

**Conclusions:** HN-MRI and PET/CT-guided therapy could assist in decreasing local recurrence, which improved prognosis in UADT-ENKTL patients. Therefore, HN-MRI and PET/CT should be incorporated into routine pretreatment imaging examinations in patients with UADT-ENKTL.

**Keywords:** magnetic resonance imaging (MRI); non-Hodgkin lymphoma (NHL); positron emission tomography (PET).

## 222
CLINICAL OUTCOMES AND DIAGNOSIS-TO-TREATMENT INTERVAL IN PATIENTS WITH NK/T-CELL LYMPHOMA: 7-YEAR FOLLOW-UP OF THE NKEA STUDY

M. Yamaguchi¹ | R. Suzuki² | M. Oguchi³ |
K. Miyazaki¹ | S. Taguchi³ | J. Amaki⁴ | T. Maeda⁵ |
N. Kubota⁶ | D. Maruyama⁷ | Y. Terui⁸ |
N. Sekiguchi⁹ | J. Takizawa¹⁰ | H. Tsukamoto¹¹ |
T. Murayama¹² | T. Ando¹³ | H. Matsuoka¹⁴ |
M. Hasegawa¹⁵ | H. Wada¹⁶ | R. Sakai¹⁷ |
Y. Kameoka¹⁸ | N. Tsukamoto¹⁹ | I. Choi²⁰ |
Y. Masaki²¹ | K. Shimada²² | N. Fukuhara²³ |

T. Utsumi²⁴ | N. Uoshima²⁵ | Y. Kagami²⁶ |

N. Asano²⁷ | N. Katayama¹

¹Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan; ²Oncology and Hematology, Shimane University Hospital, Izumo, Japan; ³Radiation Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; ⁴Hematology and Oncology, Tokai University School of Medicine, Kanagawa, Japan; ⁵Hematology, Kurashiki Central Hospital, Kurashiki, Japan; ⁶Hematology, Saitama Cancer Center, Ina, Japan; ⁷Hematology, National Cancer Center Hospital, Tokyo, Japan; ⁸Hematology Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; ⁹Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan; ¹⁰Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Niigata, Japan; ¹¹Hematology, Showa University School of Medicine, Tokyo, Japan; ¹²Hematology, Hyogo Cancer Center, Akashi, Japan; ¹³Hematology, Respiratory Medicine and Oncology, Saga University, Saga, Japan; ¹⁴Medical Oncology/Hematology, Kobe University, Kobe, Japan; ¹⁵Radiation Oncology, Nara Medical University, Kashihara, Japan; ¹⁶Hematology, Kawasaki Medical School, Kurashiki, Japan; ¹⁷Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan

**Introduction:** Our recent retrospective study (NKEA Part A) revealed the treatments and outcomes of 358 patients (pts) with extranodal NK/T-cell lymphoma, nasal type (ENKL) diagnosed between 2000 and 2013 at 31 institutes in Japan (Yamaguchi M, et al. JCO 2017). The study also demonstrated that the baseline clinical features, efficacy, and toxicity of pts who received RT-DeVIC in clinical practice were comparable to those of pts enrolled in a clinical trial of RT-DeVIC (JCOG0211) and that the incidence of 2nd malignancies was 5% at a median (med.) follow-up (f/u) of 5.6 years (yrs). A recent study demonstrated that the diagnosis-to-treatment interval (DTI) was shorter in pts in clinical practice (med., 15 days) than in those enrolled in clinical trials (med., 23 days) and was strongly associated with clinical factors and outcomes in diffuse large B-cell lymphoma (DLBCL) (Maurer MJ, et al. JCO 2018). The aim of the present analysis was to update data on the efficacy and toxicity of RT-DeVIC

and to determine the relationship between DTI and survival in ENKL.

**Methods:** Data on survival, late toxicity, and DTI of our NKEA Part A dataset were collected as of Feb 20, 2019. According to the original report for DTI, the date of diagnosis used to calculate DTI was defined as the biopsy date from the first biopsy specimen containing lymphoma.

**Results:** Data on the survival of 313 pts were updated and included in the analysis. The med. f/u period was 7.9 yrs. The 5-yr OS and PFS were respectively 56% and 48% in the whole cohort and 66% and 58% in pts with localized disease. In pts with localized ENKL who received RT-DeVIC in clinical practice (n = 140), the 5-yr OS and PFS were 71% and 64%, respectively. OS events after 5 yrs from diagnosis included 2 events of ENKL, 4 events of 2nd malignancy, and 6 events of other diseases. Late toxicity was manageable in most pts. Ten (7.1%) pts experienced 2nd malignancies. Of those, 7 were men and were > 60 yrs of age. The remaining 3 pts were women and had been heavily treated for relapsed ENKL. Data on DTI were obtained from 298 pts. The med. DTI was 25 days (0-163) in the whole cohort, 27 days (0-163) in pts with localized disease, and 19 days (0-79) in pts with advanced disease. In pts with localized ENKL who received RT-DeVIC, the DTI was 27 days in 130 pts in clinical practice and 30 days in 10 pts who were enrolled in the clinical trial. Shorter DTI grouped by week was not associated with shorter OS and PFS in pts with localized ENKL (P = 0.23 and 0.30, respectively) in contrast to those with advanced ENKL (P = 0.001 and 0.072, respectively).

**Conclusions:** Our 7-yr f/u analysis provided an update on survival in pts with ENKL and confirmed the efficacy and safety of RT-DeVIC. The incidence of 2nd malignancies (7.1% at 7.9 yrs) did not increase compared to the results of our previous analysis. DTI in pts with localized ENKL was long and its impact on survival was relatively small, supporting the feasibility of future clinical trials for localized ENKL.

**Keywords:** extranodal lymphomas.

**Disclosures:** Yamaguchi, M: Consultant Advisory Role: Sorrento; Honoraria: Chugai Pharma, Eisai, Kyowa Hakko Kirin, Janssen, Meiji Seika Kaisha, MSD, Teijin Pharma, Celgene, Takeda. Suzuki, R: Honoraria: Kyowa Hakko Kirin, Chugai Pharma, Bristol-Myers-Squibb, Eisai, MSD, Celgene, Janssen, AbbVie, Takeda, Meiji Seika Kaisha, Ono Pharmaceutical, Novartis. Miyazaki, K: Honoraria: Chugai Pharma, Kyowa Hakko Kirin, Celgene. Katayama, N: Honoraria: Bristol-Myers Squibb, Takeda, Astellas Pharma, Novartis, Shire, Shionogi Pharmaceutical, Novo Nordisk, Taisho Toyama Pharma, Sysmex, Celgene, Pfizer, Alexion Pharmaceuticals, Kyowa Hakko Kirin, Chugai Pharma, Nippon Shinyaku, Sumitomo Group; Research Funding: Teijin Pharma, Mochida Pharmaceutical Co. Ltd., Toyama Chemical Co, Ono Pharmaceutical, Takeda, Janssen, Astellas Pharma, Novartis, Shionogi Pharmaceutical, Novo Nordisk, Daiichi Sankyo, Eisai, Pfizer, Kyowa Hakko Kirin, Chugai Pharma, Nippon Shinyaku, Sumitomo Group.
223
CLINICOPATHOLOGICAL DIFFERENCES OF
NODAL PTCL WITH TFH PHENOTYPE
FROM AITL AND PTCL, NOS, AND
DETECTION OF PROGNOSTIC MARKER OF
NODAL PTCL WITH TFH PHENOTYPE

T. Suzuki<fnref n="1" /> | H. Miyoshi<fnref n="1" /> | E. Yanagida<fnref n="1" /> |
K. Kawamoto<fnref n="2" /> | K. Yamada<fnref n="1" /> | M. Takeuchi<fnref n="1" /> |
K. Ohshima<fnref n="1" />

**Introduction:** In the revised 4th edition of WHO classification (2017), nodal peripheral T-cell lymphoma with Tfh phenotype (PTCL with Tfh-phenotype) has been listed as lymphoma derived from T follicular helper (Tfh) cells as well as angioimmunoblastic T-cell lymphoma (AITL) apart from peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). Few researches have investigated the clinicopathological

differences among these diseases, and prognostic marker of PTCL
with Tfh.

**Methods:** We reviewed 166 cases of peripheral T-cell lymphoma diagnosed at Kurume University. Cases with FDC meshwork and high endothelial venules in the stroma were classified as AITL (n = 45). PTCL with Tfh-phenotype (n = 63) were CD4-positive and exhibited two or more positive TFH markers including CD10, PD-1, bcl6, CXCL13, ICOS, SAP, CXCR5, c-Maf and CD200. Remaining cases were classified as PTCL, NOS (n = 58). Chi-squared test, Fisher's two-sided exact test, and Mann-Whitney Test were performed to determine the statistical association of clinicopathological features. Overall survival curves are shown by Kaplan-Meier method, and Log-lank test is used for comparison.

**Results:** There are no significant differences in clinical findings of PTCL with Tfh-phenotype comparison with AITL and PTCL, NOS including age, sex, Ann Arbor stage, B-symptom, splenomegaly, hepatoomegaly, PS, IPI, extra nodal involvement, bone marrow infiltration, hemolytic anemia, circulating tumor cells in blood, white blood cell counts, neutrophil counts, lymphocyte counts, hemoglobin, platelets, elevated LDH, hypergammaglobulinemia, hypercalcemia, elevated CRP, and OS curves. In morphological features, PTCL with Tfh-phenotype had lower value of infiltration of plasma cells (P = 0.018)

<table><caption>TABLE 1 Pathological findings of AITL, PTCL with Tfh-phenotype, and PTCL, NOS</caption><thead><tr><th>Pathological features</th><th>AITL(n=45)</th><th>AITL vs PTCL with Tfh-phenotype (p-value)</th><th>PTCL with Tfh-phenotype(n=63)</th><th>PTCL with Tfh-phenotype vs PTCL, NOS (p-value)</th><th>PTCL, NOS (n=58)</th></tr></thead><tbody><tr><td>Polymorphic infiltrate neutro (count/10HPF), average/median [range]</td><td>0.3/0 [0-1]</td><td>0.054</td><td>6.0/3.0 [0-25]</td><td>0.111</td><td>30.0/0.5 [0-464]</td></tr><tr><td>Polymorphic infiltrate eosino (count/10HPF), average/median [range]</td><td>261.0/267.0 [8-508]</td><td>0.140</td><td>132.0/7.0 [0-1200]</td><td><strong>0.037</strong></td><td>42.2/0 [0-907]</td></tr><tr><td>Polymorphic infiltrate plasma (count/10HPF), average/median [range]</td><td>109.6/40.0 [14-275]</td><td><strong>0.018</strong></td><td>19.3/5.5 [0-205]</td><td>0.651</td><td>55.8/1.5 [0-456]</td></tr><tr><td>High endothelial venules (count/10HPF), average/median [range]</td><td>58.6/57.0 [57-62]</td><td>0.093</td><td>38.5/35.5 [6-116]</td><td>0.496</td><td>31.2/21.5 [7-82]</td></tr><tr><td>Clear cell (%,) average/median [range]</td><td>53.3/60.0 [30-70]</td><td>0.574</td><td>40.6/40.0 [0-90]</td><td>0.370</td><td>30.9/25 [0-90]</td></tr><tr><td>EBER potive cells in surrounding cells</td><td>48.9 (%)</td><td>0.535</td><td>42.9 (%)</td><td>0.431</td><td>50.0 (%)</td></tr><tr><td>Tumor cell size, Large</td><td>66.7 (%)</td><td>0.252</td><td>31.3 (%)</td><td>0.735</td><td>40.9 (%)</td></tr><tr><td><strong>Tfh markers</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>PD-1</td><td>71.1 (%)</td><td><strong>0.003</strong></td><td>42.9 (%)</td><td><strong>&lt;0.0001</strong></td><td>8.6 (%)</td></tr><tr><td>CXCL13</td><td>15.6 (%)</td><td><strong>0.026</strong></td><td>3.2 (%)</td><td>1.000</td><td>1.7 (%)</td></tr><tr><td>CD10</td><td>15.6 (%)</td><td><strong>0.032</strong></td><td>3.2 (%)</td><td>0.497</td><td>0 (%)</td></tr><tr><td>Bcl-6</td><td>75.6 (%)</td><td>0.316</td><td>66.7 (%)</td><td><strong>&lt;0.0001</strong></td><td>12.1 (%)</td></tr><tr><td>ICOS</td><td>75.6 (%)</td><td><strong>0.001</strong></td><td>44.4 (%)</td><td><strong>&lt;0.0001</strong></td><td>10.3 (%)</td></tr><tr><td>SAP</td><td>31.1 (%)</td><td>0.808</td><td>33.3 (%)</td><td>0.002</td><td>8.6 (%)</td></tr><tr><td>CXCR5</td><td>6.7 (%)</td><td>0.424</td><td>11.1 (%)</td><td>0.063</td><td>1.7 (%)</td></tr><tr><td>c-Maf</td><td>60.0 (%)</td><td>0.108</td><td>74.6 (%)</td><td><strong>&lt;0.0001</strong></td><td>29.3 (%)</td></tr><tr><td>CD200</td><td>42.2 (%)</td><td>0.428</td><td>49.2 (%)</td><td>0.066</td><td>32.8 (%)</td></tr></tbody></table>

<footnote n="1">¹Pathology, Kurume University, School of Medicine, Kurume, Japan;</footnote>

<footnote n="2">²Hematology, Endocrinology and Metabolism, Faculty of Medicine,
Niigata University, Niigata, Japan</footnote>
than AITL, and higher value of that of eosinophils (P = 0.037). In analysis of Tfh markers, many kinds of Tfh markers in PTCL with Tfh-phenotype are less observed than AITL and more than PTCL, NOS.

Among clinicopathological features of PTCL with Tfh-phenotype, cases with PS≥2 (P = 0.001), elevated CRP (P = 0.020), and bcl6-negative (P = 0.008) showed significantly poorer OS curve, respectively.

**Conclusions:** PTCL with Tfh-phenotype should be considered clinicopathologically as disease entity distributed between AITL and PTCL, NOS. Prognostic markers might be useful for stratification of clinical strategy. More investigation including genomic abnormalities and mRNA expression would be desired to confirm the results of this study.

**Keywords:** angioimmunoblastic T-cell lymphoma (AITL); peripheral T-cell lymphomas (PTCL); prognostic indices.

224

EVENT FREE SURVIVAL AT 12 MONTHS AND 24 MONTHS AS PREDICTORS FOR OUTCOME OF SYSTEMIC PERIPHERAL T CELL LYMPHOMA: ANALYSIS OF NATIONWIDE THAI LYMPHOMA STUDY GROUP

K. Wudhikarn¹

U. Bunworasate¹

J. Julamanee²

A. Lekhakula²

S. Ekwattanakit³

A. Khuhapinant³

L. Norasetthada⁴

W. Nawarawong⁴

C. Laoruangroj⁵

T. Numbenjapon⁵

P. Niparuck⁶

S. Chancharunee⁶

N. Kanitsap⁷

S. Wongkhantee⁸

N. Makruasi⁹

P. Wong¹⁰

C. Sirijerachai¹¹

K. Chansung¹¹

T. Suwanban¹²

P. Praditsuktavorn¹³

T. Intragumtornchai¹

¹Medicine, Faculty of Medicine Chulalongkorn University, Bangkok, Thailand; ²Medicine, Faculty of Medicine Prince of Songkla University, Songkhla, Thailand; ³Medicine, Faculty of Medicine Siriraj Hospital Mahidol University, Bangkok, Thailand; ⁴Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; ⁵Medicine, Faculty of Medicine, Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand; ⁶Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; ⁷Medicine, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand; ⁸Medicine, Khon Kaen Regional Hospital, Khon Kaen, Thailand; ⁹Medicine, Faculty of Medicine, Srinakharinwirot University, Nakhon Nayok, Thailand; ¹⁰Medicine, Faculty of Medicine, Naresuan University, Phitsanulok,

<figure><img src="image_152.png" /><figcaption>**Figure 1:** Kaplan Meier Survival Curve A) EFS and OS of entire cohort B) OS from treatment initiation stratified by EFS12 C) OS from landmark 12 months timepoint stratified by EFS12 D) OS from landmark 24 months timepoint stratified by EFS24</figcaption></figure>
Thailand; ¹¹Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; ¹²Medicine, Rajavithi Hospital, Bangkok, Thailand; ¹³Medicine, Faculty of Medicine, HRH Princess Chulabhorn College of Medical Science, Bangkok, Thailand

**Background:** Peripheral T cell lymphoma (PTCL) is relatively uncommon compared to B cell lymphoma, however, it generally carries worse prognosis. Treatment failure and early relapse are major dilemma of PTCL. Identification of high-risk patients using various tools may better refine long-term prognosis of PTCL patients. There were data indicating event free survival (EFS) at 12 months (EFS12) and 24 months (EFS24) as strong surrogate predictors for disease-related outcomes in many B-cell lymphoma. However, the implication of such surrogate end-points has been limited in PTCL. Herein, we explored EFS12 and EFS24 as tools to stratify survival outcome in PTCL patients.

**Methods:** Thai Lymphoma Study Group is the nationwide collaborative effort composing of 13 major medical centers in Thailand. The registry prospectively enrolled newly diagnosed lymphoma patients between 2006 and 2014. Here, we focused on systemic PTCL treated with chemotherapy and had adequate follow-up data. EFS was defined as time between primary treatment to relapse, re-treatment, or death from any causes. EFS12 and EFS24 were binary endpoints defined as whether developing events at 12 and 24 months after treatment initiation. Overall survival (OS) was defined as time from a specific timepoints either diagnosis or EFS12 to death. Logistic regression model was used to evaluate associations between clinical characteristics and EFS12/EFS24. Cox regression with EFS12/EFS24 as a time-dependent covariate was applied to evaluate the association between EFS12 and OS.

**Results:** Of 353 PTCL, 292 (83%) received multiagent chemotherapy. Median age at diagnosis was 49 years (IQR 36-60 years). Median EFS and OS of patients who received treatment were 16.3 and 27.7 months (CI 95% 12.6-28.3 and 18.8-50.4 months respectively). A total of 138 patients (47.1%) developed an event within 12 months after treatment initiation (failed to achieve EFS12). Patients who failed to achieve EFS12 had higher proportion of impaired performance status, high CPI, and presence of B symptoms. After a median follow-up of 53.7 months, Patients who achieved EFS12 had superior OS compared to patients who failed to achieve EFS12 (5-years OS after treatment initiation 70.5% vs 12%, HR 7.0, p<0.001). Landmark analysis confirmed the association between EFS12 and OS after 12 months timepoint (5-years OS after EFS12 67.5% vs 11.5%, HR 6.45, p<0.001). Similar results were seen with patients who achieved EFS24 for both survival after treatment initiation and after 24 months timepoint (Figure 1).

**Conclusion:** EFS12 and EFS24 are strong surrogate endpoints for treatment outcomes in PTCLs.

**Keywords:** peripheral T-cell lymphomas (PTCL); prognostic indices; T-cell lymphoma (TCL).

BONE MARROW INVOLVEMENT, BUT NO BLOOD INVOLVEMENT, IMPAIRS SURVIVAL IN ANGIOIMMUNOBLASTIC T CELL LYMPHOMA: AN ANCILLARY STUDY OF THE REVAIL TRIAL

F. Lemonnier¹ | V. Safar² | A. Ferchiou³ |
A. Cottereau⁴ | E. Bachy² | G. Cartron⁵ |
M. Moles-Moreau⁶ | A. Delmer⁷ | R. Bouabdallah⁸ |
L. Voillat⁹ | M. Parrens¹⁰ | O. Casasnovas¹¹ |
V. Cacheux¹² | C. Réguy¹³ | H. Tilly¹⁴ |
M. Meignan¹⁵ | P. Gaulard¹⁶ | L. de Leval¹⁷ |
M. Delfau-Larrue³ | C. Haioun¹

¹Unité Hémopathies Lymphoïdes, INSERMU955, Université Paris Est, Hôpitaux Universitaires Henri Mondor, Créteil, France; ²Hématologie, Hôpital Lyon Sud, Pierre Bénite, France; ³Laboratoire d'immunologie, Université Paris Est, Hôpitaux Universitaires Henri Mondor, Créteil, France; ⁴Département de Médecine Nucléaire, Hopital Cochin, Paris, France; ⁵Département d'Hématologie Clinique, CHU Montpellier, Montpellier, France; ⁶Service d'Hématologie, CHU Angers, Angers, France; ⁷Service d'Hématologie Clinique, CHU Reims, Reims, France; ⁸Service d'Hématologie, Institut Paoli Calmette, Marseille, France; ⁹Service d'Hématologie, CH Chalon sur Saône, Chalon-sur-Saône, France; ¹⁰Service de Pathologie, CHU Bordeaux Haut Levèque, Pessac, France; ¹¹Service d'Hématologie, CHU de Dijon, Dijon, France; ¹²Service d'Hématologie, CHU de Clermont-Ferrand, Clermont Ferrand, France; ¹³Service d'Hématologie, CHU Grenoble, La Tronche, France; ¹⁴Service d'Hématologie, Centre Henri Becquerel, Rouen, France; ¹⁵LYSA IM, Henri Mondor, Créteil, France; ¹⁶Département de Pathologie, Hôpital Henri Mondor, Créteil, France; ¹⁷Département de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

**Introduction:** Angioimmunoblastic T-cell lymphoma (AITL) is the most frequent peripheral T-cell lymphoma. Treatment with CHOP has limited efficacy. In the recent analysis of the REVAIL study, a phase 2 trial assessing the combination of Lenalidomide and CHOP in previously untreated patients with AITL, the mutational landscape (i.e TET2, DNMT3A, IDH2 or RHOA) has limited impact on survival (Lemonnier, Safar et al. ASH 2018), making important to find alternative methods to predict the prognosis of AITL patients.

**Methods:** The 72 patients included in REVAIL study with a centrally confirmed diagnosis of AITL are analyzed. Bone marrow involvement (BMI) was determined locally on BM trephine biopsy. Fresh blood samples were centrally collected for flow cytometry and DGGE PCR analyses aiming at detecting circulating neoplastic T cells by aberrant immunophenotype or a monoclonal TCR rearrangement. Total metabolic tumor volume (TMTV) was measured on baseline PET CT as previously reported (PMID: 28864629).
<figure><img src="image_153.png" /></figure>

**Results:** At inclusion, 33/67 (49%) patients had a BMI. No difference in median age, performance status or presence of B symptoms was observed between patients with or without BMI. However, IPI was higher in patients with BMI (60% of patients with BMI vs 30% of patients without BMI had IPI 4-5, p = 0.02). Although the complete metabolic response rate was similar in patients with or without BMI [13/33 (39%) vs 18/34 (53%)] (p = 0.33), BMI was associated to poorer outcome, as the median progression-free survival (PFS) was 9 months versus 36 months (p = 0.029) and the median overall survival (OS) was 17 vs 54 months (p = 0.006) in patients with or without BMI, respectively. We thus compared the relevance of three prognostic models [International prognosis index, Prognostic Index for Peripheral T-Cell Lymphoma (PIT), and Prognostic Index for AITL] used in T-cell lymphomas. As shown in the figure, PIT, which includes BMI as a prognostic factor, gave the best discrimination between high-risk and low-risk patients with a 2yr OS of 38% for PIT 3-4 and 79% for PIT 0-2. Flow cytometry identified abnormal circulating cells in 30/51 (59%) patients, and DGGE PCR identified a circulating clonal population in 39/59 (66%) patients. However, the presence of circulating cells identified by flow cytometry or PCR had no impact on survival and was not correlated with the presence of BMI. We also observed that lymphomas with BMI had a higher percentage of neoplastic T cells in the tumor and higher TMTV. Mutational analysis revealed that BMI was present in 12/13 (92%) IDH2-mutated samples and in 19/47 (40%) IDH2 unmutated samples (p = 0.001).

**Conclusion:** In this prospective series of homogeneously treated AITL patients, BMI had a pejorative impact on survival. In contrary to B-cell lymphomas, detection of circulating lymphoma cells does not correlate with BMI and had no prognostic impact. BMI is associated with specific features, such as the presence of IDH2 mutations.

**Keywords:** angioimmunoblastic T-cell lymphoma (AITL); prognostic indices.

**Disclosures:** Bachy, E: Consultant Advisory Role: Beigene, Celgene; Honoraria: Amgen, Roche; Research Funding: Takeda. Cartron, G: Consultant Advisory Role: Celgene; Honoraria: Celgene. Casasnovas, O: Consultant Advisory Role: Celgene, Roche, Takeda, BMS, MSD, Gilead, Janssen; Research Funding: Takeda, Gilead, Roche. Meignan, M: Honoraria: Roche. Gaulard, P: Consultant Advisory Role: Takeda; Honoraria: Takeda; Research Funding: Takeda.

226
COMBINATION OF CHIDAMIDE WITH
CHOEP REGIMEN IN PREVIOUSLY
UNTREATED PATIENTS WITH PERIPHERAL
T-CELL LYMPHOMA: A PROSPECTIVE,
MULTICENTER, SINGLE-ARM, PHASE 1B/2
TRIAL

D. Zhou<fnref n="1" /> | W. Zhang<fnref n="1" /> | L. Su² | L. Liu³ |
Y. Gao³ | Q. Wang⁴ | H. Su⁵ | Y. Song⁶ |
H. Zhang⁷ | J. Shen⁸ | H. Jing⁹ | S. Wang¹⁰ |
X. Cen¹¹ | H. Liu¹² | A. Liu¹³ | Z. Li¹⁴ |
J. Luo¹⁵ | J. He¹⁶ | J. Wang¹⁷

<footnote n="1">¹Department of Hematology, Peking Union Medical College Hospital, Beijing, China; ²Department of Hematology, Shanxi Provincial Cancer Hospital, Taiyuan, China; ³Department of Hematology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China; ⁴Department of Hematology, Chinese PLA General Hospital, Beijing, China; ⁵Department of Lymphoma, The 307 Hospital of PLA, Beijing, China; ⁶Department of Lymphoma, Peking University Cancer Hospital and Institute, Beijing, China; ⁷Department of Lymphoma, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China; ⁸Department of Hematology, Beijing</footnote>
A

PFS: intent-to-treat analysis

<figure><img src="image_154.png" /></figure>

OS: intent-to-treat analysis

<figure><img src="image_155.png" /></figure>

B

PFS: PTCL subtypes

<figure><img src="image_156.png" /></figure>

OS: PTCL subtypes

<figure><img src="image_157.png" /></figure>

Friendship Hospital, Beijing, China; ⁹Department of Hematology, Peking University Third Hospital, Beijing, China; ¹⁰Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, China; ¹¹Department of Hematology, Peking University First Hospital, Beijing, China; ¹²Department of Hematology, Beijing Hospital, Beijing, China; ¹³Department of Lymphoma, Harbin Medical University Cancer Hospital, Harbin, China; ¹⁴Lymphoma diagnosis and treatment center, Institute of Hematology and Blood Diseases Hospital, Tianjin, China; ¹⁵Department of Hematology, Second Hospital of Hebei Medical University, Shijiazhuang, China; ¹⁶Department of Hematology, Shanxi Provincial People's Hospital, Taiyuan, China; ¹⁷Department of Hematology, Beijing Tongren Hospital, Beijing, China

**Introduction:** The aim of this study was to assess the safety and efficacy of the histone deacetylase (HDAC) inhibitor chidamide together with the cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP) regimen (Chi-CHOEP) in previously untreated peripheral T-cell lymphoma (PTCL) patients.

**Methods:** This was a prospective, multicenter, single-arm, open-label, phase 1b/2 clinical trial. The sample comprised patients with untreated PTCL. The study consisted of dose-escalation (phase 1b) and expansion (phase 2) phases. Patients received up to six cycles of CHOEP with chidamide. In the phase 1b study, a dose-escalation scheme was evaluated, and three dose levels of chidamide were tested. In the phase 2 study, the cohort of patients who received the recommended dose of chidamide plus CHOEP was extended. The primary endpoint was the recommended dose of chidamide plus CHOEP. Secondary endpoints included progression-free survival (PFS), overall

survival (OS), overall response rate (ORR), complete response (CR) rate, and the incidence of adverse events (AEs).

**Results:** A total of 82 patients from across China were enrolled in the study between Mar 2016 and Dec 2017. A chidamide dose of 20 mg biw was recommended for phase 2. In the intent-to-treat analysis of response to Chi-CHOEP, the ORR was 68.3% with a CR rate of 43.9% for chidamide across all dose levels (N = 82). After the median follow-up time of 12.7 months (range 0.3-30.8 months), 1-year PFS was 52.9% and 1-year OS was 74.5%. For PTCL not otherwise specified (PTCL-NOS) patients (N = 16), 1-year PFS was 77.9% and 1-year OS was 87.1%. Chi-CHOEP was generally well tolerated. The most common toxicities were leucopenia (84.1%), anemia (80.5%), neutropenia (75.6%), and nausea/vomiting (59.8%). No reactivation of Epstein-Barr virus (EBV) or Hepatitis B virus (HBV) was observed.

**Conclusion:** Chi-CHOEP is an effective novel regimen for untreated PTCL. It exhibits superiority in survival and among a subpopulation of PTCL-NOS patients compared with historical control data. This regimen requires further investigation in a phase 3 randomized trial.

**Keywords:** epigenetics; histone deacetylase inhibitors; peripheral T-cell lymphomas (PTCL).
M. Lunning¹ | S. Horwitz² | R. Advani³ | J. Vose¹ |

H. Lee⁴ | N. Mehta-Shah⁵ | J. Zain⁶ |

B. Haverkos⁷ | M. Lechowicz⁸ | A. Moskowitz² |

P. Heires¹ | L. Lyden¹ | S. Ansell⁹

¹Hematology/Oncology, University of Nebraska Medical Center, Omaha, United States; ²Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, United States; ³Lymphoma Program, Stanford University, Palo Alto, United States; ⁴Lymphoma & Myeloma, MD Anderson Cancer Center, Houston, United States; ⁵Oncology, Washington University, St. Louis, United States; ⁶Hematology & Hematopoetic Cell Transplantation, City of Hope, Duarte, United States; ⁷Oncology, University of Colorado, Aurora, United States; ⁸Hematology/Oncology, Emory, Atlanta, United States; ⁹Lymphoma, Mayo Clinic, Rochester, United States

**Introduction:** CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) is a common upfront regimen for peripheral T-cell lymphoma (PTCL). Lenalidomide (len) is an immunomodulatory agent with 22% single agent response rate in relapsed and refractory PTCL. Here we report the phase II results of len-CHOEP including consolidation outcomes of those proceeding to len maintenance or autologous stem cell transplantation (ASCT).

**Methods:** Eligible patients (pts) had newly diagnosed PTCL with adequate hematologic and organ function. Based on phase I results 10 mg of len was deemed the recommended phase II dose. CHOEP was administered at standard doses with len given on days 1-10 of 21-day cycle for 6 planned cycles. Pts received thromboprophylaxis and growth factor support. The primary endpoint was complete response (CR) by PET/CT after 6 cycles. Secondary endpoints included toxicity, overall response rate (ORR), progression free survival (PFS), 2-year PFS, and overall survival (OS). Pts who had CR or partial response (PR) at the end of therapy had the option of len maintenance (10 mg/day for 21 out of 28 days) for 1-year or consolidative ASCT without len maintenance.

**Results:** 39 pts with PTCL-NOS (n = 19), ALK negative ALCL (n = 4) and AITL (n = 16) enrolled into the phase II portion. Median age was 63 years (range 24-79) and 20 were male. Stage III/IV was seen in 89%. Prognosis by international prognostic index was 0-1 (15%), 2 (41%), and 3-5 (44%). 29 (75%) pts completed all 6 cycles. One pt was re-classified as Hodgkin lymphoma post completion of len-CHOEP and is included in toxicity analysis. Reasons for discontinuing len-CHOEP early were toxicity (n = 7) and progressive disease (PD; n = 5). The primary endpoint of CR by an intent to treat (ITT) analysis was 48% (19/40; 95CI-33-64%) with an ORR of 69%. Responding pts (CR/PR; n = 30) proceeded either to an ASCT (n = 16), len maintenance (n = 10) or neither (investigator/pts preference; n = 1). At a median follow up of 18 months (range: 2-30 months), the 1-year estimated PFS and OS is 67% [95% CI: 50-79%] and 90% [95%CI: 73-96%] respectively. There is no difference in 1-year PFS by PTCL subtype or between the len maintenance or ASCT. There were 5 grade (G) 5 events including PD (n = 1), secondary malignancy (n = 1; AML),

sepsis (n = 2), and cardiac arrest (n = 1). Serious or recurrent adverse events (SAEs or AEs; G 3-4) of interest occurring during any cycle included 38% febrile neutropenia despite mandated GCSF use, 43% anemia, 45% thrombocytopenia (without report of G 3-4 bleeding or bruising despite ASA use), and 8% diarrhea.

**Conclusions:** The phase II portion of the study in an ITT population noted a modest 48% CR rate and a high discontinuation rate due to AEs or SAEs. The utility of post initial therapy strategy (len maintenance vs ASCT) continue to be monitored for PFS and OS in this limited cohort. Improving frontline outcomes for pts with PTCL remains an unmet need.

**Keywords:** peripheral T-cell lymphomas (PTCL).

**Disclosures:** Lunning, M: Consultant Advisory Role: AbbVie, Bayer, Celgene, DAVA, Gilead Sciences, Inc Janssen, Juno Therapeutics, Kite, Novartis, OncLive, Portola, Seattle Genetics, Spectrum, TG Therapeutics, VANIUM, Verastem; Research Funding: Celgene, Curis, Janssen Scientific Affairs, LLC Juno Therapeutics, MiRagen, TG Therapeutics. Horwitz, S: Consultant Advisory Role: Millennium/Takeda; Trillium; Mundipharma; Kyowa-Hakka-Kirin; Portola; Aileron Therapeutics; Innate Pharma; Corvus; Spectrum; Seattle Genetics; Verastem; ADC Therapeutics; Research Funding: Millennium/Takeda, Kyowa Hakka Kiron; Aleron; Spectrum; Seattle Genetics; Verastem. Advani, R: Consultant Advisory Role: Janssen Pharmaceutical; Cell Medica; Bayer Healthcare Pharmaceutical; Merck; Forty Seven, Inc; Millenium; Roche/Genentech; Pharmacyclics; Celgene; Regeneron Pharmaceuticals, Inc; Kura; Infinity; Autolus; Kyowa; Takeda; Bristol Myers Squibb; Agensys; Gilead/Kite; Seattle Genetics; AstraZeneca; Research Funding: Forty Seven; Genentech; Seattle Genetics. Vose, J: Honoraria: Epizyme; Roche; Novartis; Legend; Abbvie; Research Funding: Novartis; Celgene; Incyte; Bristol Myers Squibb; Seattle Genetics; Acerta Pharma; Kite Pharma; Merck. Mehta-Shah, N: Consultant Advisory Role: Kyowa Hakka Kirin; Research Funding: Verastem; Celgene; Astra Zeneca; Roche/Genentech; Bristol Myers Squibb. Moskowitz, A: Consultant Advisory Role: Bristol Myers-Squibb; Seattle Genetics; Honoraria: Takeda; Seattle Genetics; Research Funding: Bristol Myers-Squibb; Incyte Seattle Genetics; ADC Therapeutics; Merck. Ansell, S: Research Funding: Regeneron; Trillium; Bristol-Myers Squibb; Celldex; LAM Therapeutics; Takeda; Seattle Genetics; Merck & Co; Pfizer; Affimed.

T. Illidge¹ | S. Horwitz² | S. Iyer³ | N. Bartlett⁴ |

W. Kim⁵ | H. Tilly⁶ | D. Belada⁷ | T. Feldman⁸ |

Á. Illés⁹ | E. Jacobsen¹⁰ | A. Hüttmann¹¹ |

P. Zinzani¹² | O.A. O'Connor¹³ | W. Trepicchio¹⁴ |

H. Miao¹⁴ | S. Rao¹⁵ | M. Onsum¹⁵ | T. Manley¹⁵ |

R. Advani¹⁶
<table><caption>TABLE 1 Response by CD30 expression</caption><thead><tr><th></th><th>CD30</th><th>Pts, n</th><th>CR, n (%)</th><th>PR, n (%)</th></tr></thead><tbody><tr><td rowspan="3">AITL</td><td>CD30 &gt;median</td><td>14</td><td>8 (57)</td><td>1 (7)</td></tr><tr><td>CD30 ≤ median</td><td>15</td><td>8 (53)</td><td>3 (20)</td></tr><tr><td>CD30=10%</td><td>8</td><td>5 (63)</td><td>0</td></tr><tr><td rowspan="3">PTCL-NOS</td><td>CD30 &gt;median</td><td>14</td><td>8 (57)</td><td>2 (14)</td></tr><tr><td>CD30 ≤median</td><td>14</td><td>10 (71)</td><td>2 (14)</td></tr><tr><td>CD30=10%</td><td>6</td><td>4 (67)</td><td>2 (33)</td></tr></tbody></table>

Biomedical Research Centre, Manchester Academic Health Sciences Centre, Christie Hospital National Health Service Foundation Trust, Manchester, United Kingdom; ²Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, United States; ³Department of Lymphoma and Myeloma, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, United States; ⁴Department of Medicine, Oncology Division, Washington University School of Medicine, Siteman Cancer Center, Saint Louis, United States; ⁵Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Seoul, Republic of Korea; ⁶Department of Hematology, Centre Henri Becquerel, Université of Rouen Normandie, Rouen, France; ⁷⁴th Department of Internal Medicine - Haematology, Charles University, Hospital and Faculty of Medicine, Hradec Králové, Czech Republic; ⁸Hematology Division, Hackensack University Medical Center, Hackensack, United States; ⁹Department of Hematology, University of Debrecen, Faculty of Medicine, Debrecen, Hungary; ¹⁰Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, United States; ¹¹Department of Haematology, Universitatsklinikum Essen, Essen, Germany; ¹²Institute of Hematology, "Serágnoli" University of Bologna, Bologna, France; ¹³Department of Medicine, Columbia University Medical Center, New York, United States; ¹⁴Clinical Development, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceuticals Limited, Cambridge, United States; ¹⁵Development, Seattle Genetics, Inc., Bothell, United States; ¹⁶Medicine - Med/Oncology, Stanford Cancer Institute, Stanford, United States

**Introduction:** Brentuximab vedotin (BV) is an antibody-drug conjugate that targets CD30. The ECHELON-2 (E-2) study demonstrated significantly longer progression-free (P = 0.0110) and overall survival (P = 0.0244) with BV plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus CHOP in frontline treatment of patients (pts) with CD30+ peripheral T-cell lymphoma (PTCL). Complete remission (CR) rate (A+CHP 68%; CHOP 56%; P = 0.0066) and objective response rate (ORR) (A+CHP 83%; CHOP 72%; P = 0.0032) were also significantly increased. Expression of CD30 is universal in systemic anaplastic large-cell lymphoma (sALCL) but variable among non-sALCL subtypes. As ORR is a direct measure of antitumor activity, we examined response to A+CHP by CD30 expression.

**Methods:** Pts with CD30+ (≥10% by local review) PTCL were included in E-2. Eligible histologies included ALK+ sALCL (IPI ≥2), ALK- sALCL,

PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), adult T-cell leukemia/lymphoma, enteropathy-associated T-cell lymphoma, and hepatosplenic T-cell lymphoma. We analyzed the relationship between CD30 expression (IHC Ber H2 antibody) above and below the median (median CD30 = 18% PTCL-NOS; 25% AITL) and CR rate, ORR, and duration of CR (DOCR) in pts with AITL and PTCL-NOS treated with A+CHP.

**Results:** Most (26/29, 90%) AITL pts had CD30 expression between 10% and 30%. PTCL-NOS pts were more evenly distributed across levels of CD30 expression ranging from 10% to 100%. CD30 levels were neither predictive of response (Table) nor significantly associated with DOCR in pts with AITL (P = 0.30) or PTCL-NOS (P = 0.90) (log-rank test).

**Conclusions:** CD30 expression above vs below median (or at 10%) did not predict response to A+CHP in E-2 non-ALCL subtypes, as responses were seen across CD30 levels. This may be due to intra- and inter-tumoral heterogeneity of CD30 expression, limitations of IHC, the nature of CD30 on the cell surface, and multiple mechanisms of action of BV. Further evaluation of the expression-response relationship in PTCL pts with CD30 <10% is warranted.

**Keywords:** brentuximab vedotin; CD30; peripheral T-cell lymphomas (PTCL).

**Disclosures:** Illidge, T: Consultant Advisory Role: Takeda. Horwitz, S: Consultant Advisory Role: Celgene, Millennium, Kyowa Hakki Kirin, Seattle Genetics, ADC Therapeutics, Corvus Pharmaceuticals, Innate Pharma, miRagen, Portola Pharmaceuticals, Verastem, Takeda; Research Funding: Celgene, Seattle Genetics, Takeda, Kyowa Hakko Kirin, Aileron Therapeutics, ADC Therapeutics, Verastem, Forty Seven. Iyer, S: Research Funding: Bristol-Myers Squibb, Takeda, Novartis, Genentech/Roche, Incyte, Arog. Bartlett, N: Consultant Advisory Role: Pfizer, Kite Pharma, Seattle Genetics; Research Funding: Seattle Genetics, Pfizer, Genentech, Kite Pharma, Merck, Bristol-Myers Squibb, Celgene, Immune Design, Forty Seven, Affimed Therapeutics, Janssen, Pharmacyclics, Millennium, Gilead Sciences, Novartis, MedImmune, Dynavax. Kim, W: Research Funding: Roche, Pfizer, Takeda, Mundipharma, Johnson & Johnson, Kyowa-Kirin, Celltrion. Tilly, H: Consultant Advisory Role: Karyopharm Therapeutics, Roche, Janssen; Honoraria: Bristol-Myers Squibb, SERVIER; Other Remuneration: Roche. Belada, D: Consultant Advisory Role: Roche, Gilead Sciences, Janssen-Cilag, Takeda; Research Funding: Roche, Gilead Sciences, Janssen-Cilag, Takeda; Other Remuneration: Gilead Sciences, Takeda, Roche. Feldman, T: Consultant Advisory Role: Seattle Genetics, Bayer, Bristol-Myers Squibb, Kite Pharma, Pharmacyclics, Abbvie, Janssen, Celgene; Honoraria: Seattle Genetics, Pharmacyclics/Janssen, Abbvie, Bristol-Myers Squibb, Kite Pharma, Bayer, Takeda; Research Funding: Bristol-Myers Squibb, Seattle Genetics, Portola Pharmaceuticals, Eisai, Kyowo Hakko Kirin, Amgen. Biracta Therapeutics, Cell Medical, Kyowa Hakko Kirin, Roche, Trillium Therapeutics, Pfizer, Viracta Therapeutics; Other Remuneration: Seattle Genetics, Kite Pharma, Pharmacyclics, Abbvie, Takeda.

**Illés, Á:** Consultant Advisory Role: Novartis, Roche, Janssen, Takeda, Celgene; Research Funding: Takeda, Seattle Genetics; Other Remuneration: Roche, Takeda. Jacobsen, E: Consultant Advisory Role: Merck,
Janssen, Seattle Genetics; Research Funding: Celgene; Other Remuneration: Merck. Hüttmann, A: Consultant Advisory Role: Pfizer, Gildead Sciences; Honoraria: Takeda; Other Remuneration: Celgene, Roche. Zinzani, P: Consultant Advisory Role: MSD, BMS, Servier, Janssen, Gilead; Honoraria: MSD, BMS, Servier, Janssen, Gilead. O'Connor, O: Consultant Advisory Role: Mundipharma, Seattle Genetics, Novartis, Millennium, Spectrum Pharmaceuticals, Allos Therapeutics; Honoraria: Mundipharma, Millennium, Seattle Genetics, Novartis; Research Funding: Millennium, Seattle Genetics, Acetylon Pharmaceuticals, Celgene, Roche Spectrum Pharmaceuticals; Other Remuneration: Millennium, Mundipharma, Acetylon Pharmaceuticals, Seattle Genetics, Spectrum Pharmaceuticals. Trepicchio, W: Employment Leadership Position: Takeda. Miao, H: Employment Leadership Position: Takeda; Stock Ownership: Takeda. Rao, S: Employment Leadership Position: Seattle Genetics, Bristol-Myers Squibb; Stock Ownership: Seattle Genetics. Onsum, M: Employment Leadership Position: Seattle Genetics; Stock Ownership: Seattle Genetics. Manley, T: Employment Leadership Position: Seattle Genetics; Stock Ownership: Seattle Genetics. Advani, R: Consultant Advisory Role: Astra Zeneca, Autolus, Bayer Healthcare Pharmaceuticals, Bristol Myers Squibb, Cell Medica, Gilead/Kite, Kyowa, Pharmacyclics, Roche/Genentech, Seattle Genetics, Takeda; Research Funding: Agensys, Bristol Myers Squibb, Celgene, Forty Seven, Inc., Genentech/Roche, Infinity, Janssen Pharmaceutical, Kura, Merck, Millennium, Pharmacyclics, Regeneron, Seattle Genetics.

229

ANAPLASTIC LARGE CELL LYMPHOMA, ALK-NEGATIVE: ANALYSIS OF 235 CASES COLLECTED BY THE T-CELL PROJECT

A. Shustov<fnref n="1" /> | M. Cabrera² | M. Bellei³ |
M. Civallero³ | Y.H. Ko⁴ | M. Manni³ |
S.M. Horwitz⁵ | C. Antonio De Souza⁶ | J. Radford⁷ |
S.B. Varela⁸ | M.V. Prates⁹ | A. Ferreri¹⁰ |
C. Chiattone¹¹ | M. Spina¹² | J.M. Vose¹³ |
A. Chiappella¹⁴ | D. Laszlo¹⁵ | D. Marino¹⁶ |
C. Stelitano¹⁷ | T. Skrypets³ | M. Federico³

Oncology & Hematology, University of Nebraska Medical Center, Omaha, NE, United States; ¹⁴Hematology Division, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; ¹⁵Division of Haemato-Oncology, Istituto Europeo di Oncologia, Milan, Italy; ¹⁶Department of Clinical and Experimental Oncology, Veneto Institute of Oncology IOV-IRCCS Padova, Padua, Italy; ¹⁷Department of Haematology, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy

**Introduction:** Anaplastic Large Cell Lymphoma, ALK-Negative(ALCL, ALK-) is an aggressive lymphoid neoplasm of T/null-cell lineage with strong expression of CD30, which represent 5.5% of all PTCL and NKTCL, with a unique ethnic and geographical distribution. ALCL, ALK- displays a poorer outcome compared to ALK-positive, with a 5-year OS of 49% and 70%, respectively. This study aims to provide accurate and update information on prognostic factors, therapy, and outcomes of ALK- ALCL registered in the T-Cell Project.

**Methods:** Eligible patients (pts) with the first diagnosis of aggressive, mature PTCLs were prospectively registered at a dedicated website and baseline demographic, clinical and laboratory data, as well as therapy details and outcome data were collected.

**Results:** From Sept 2006 to Feb 2018, a diagnosis of ALCL, ALK- was reported in 235 cases out of 1553 validated cases registered by 77 sites from 14 countries worldwide. The median age at diagnosis was 54 (range, 18-89) years with male predominance (61%). Stage III-IV disease was identified in 71% pts, bulky and bone marrow involvement were uncommon. Therapy was administered according to treating physician's standard practice. Out of 205 patients for which we have available data about treatment, in 9% were addressed to consolidating post-transplant chemotherapy.

The overall response rate was 77% with 57% of patients achieving complete remission. After a median follow-up of 55 (95% CI, 36-75) months, the PFS was 41 (95% CI, 17-62) months, the 3-year and 5-year PFS rates were 47% and 39%, respectively. The median OS was 55 (95% CI, 36-75) months, 3-year and 5-year OS rates were 60% (95CI 48-72) and 49% (95CI35-59), respectively. International Prognostic Index (IPI) and the Prognostic Index for T-cell Lymphomas (PIT) were both predictive of clinical outcomes. Treatment with anthracycline and etoposide vs. anthracycline-only containing regimens was associated with a better OS( 3 and 5-year OS 56% and 44% vs 76% and 69%, respectively, (P = 0.05), but not PFS 3 and 5 year PFS 47% (95CI 32-59) and 39 % (95CI 29-48) vs. 65% (95CI 32-87) and 50% (95CI 36-89) respectively (P = 0.186).

In the multivariate analysis the presence of B symptoms (P = 0.008), elevated LDH rate (P = 0.001), ECOG-PS >2 (P = 0.001) and PTL<150x10⁹(P = 0.05), were significant for OS. The presence of B symptoms (p = 0.02), elevated LDH (P = 0.001) and ECOG-PS>2 (P = 0.001) maintained their adverse prognostic value for PFS.

**Conclusions:** ALCL, ALK- remains a difficult T cell lymphoma to be cured. Combinations regimens that include both etoposide and anthracycline might improve outcomes. In this large prospective

<footnote n="1">¹Division of Hematology, University of Washington Medical Center, Seattle, United States; ²Seccion Hematologia, Hospital del Salvador, Universidad de Chile, Santiago, Chile; ³Department of Diagnostic, Clinical, and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy; ⁴Department of Pathology, Sungkyunkwan University, Seoul, Republic of Korea; ⁵Department of Medical Oncology, Memorial Sloan-Kettering Cancer Ctr, New York, United States; ⁶Centro de Hematologia e Hemoterapia, University of Campinas, Campinas, Brazil; ⁷Manchester Academic Health Science Centre, University of Manchester and the Christie NHS Foundation Trust, Manchester, United Kingdom; ⁸Hospital Vall D'Hebron, University Hospital Vall D'Hebron, Barcelona, Spain; ⁹Gatla, Laboratorio Varifarma sa, Buenos Aires, Argentina; ¹⁰Unit of Lymphoid Malignancies, IRCCS San Raffaele Scientific Institute, Milan, Italy; ¹¹Hematology Division, Santa Casa Medical School, São Paulo, Brazil; ¹²Centro Di Riferimento Oncologico, Aviano, Italy; ¹³Division of</footnote>
cohort study, we observed an outcome comparable with a previous
report from the retrospective International Lymphoma Project. The
study underscores the urgent need for designing new treatment plat-
forms for ALCL, ALK-, and establishes a benchmark for future pro-
spective clinical trials.

**Keywords:** anaplastic large cell lymphoma (ALCL); prognostic indices; T-cell lymphoma (TCL).

**Disclosures:** Horwitz, S: Consultant Advisory Role: Affimed, Angimmune, Beigene, Corvus, Innate Pharma, Kura, Merck, Miragen, Mundipharma, Portola, Syros Pharmaceutical, ADCT Therapeutics, Aileron, Forty-Seven Infinity/Verastem Kyowa-Hakka-Kirin, Millennium / Takeda, Seattle Genetics; Research Funding: Celgene, Trillium, ADCT Therapeutics, Aileron, Forty-Seven Infinity/Verastem Kyowa-Hakka-Kirin, Millennium / Takeda, Seattle Genetics. Spina, M: Consultant Advisory Role: Menarini, Mundipharma, Teva, GILEAD, Janssen-Cilag, CTI, Servier, Sandoz, Novartis, Pfizer; Honoraria: Mundipharma, Teva, GILEAD, Janssen-Cilag, CTI, Servier, Celgene.

230
INCREASED RISK OF SECOND PRIMARY
HEMATOLOGIC AND SOLID
MALIGNANCIES IN PATIENTS WITH
MYCOSIS FUNGOIDES: IMPACT ON
OVERALL SURVIVAL IN SEER REGISTRY

A. Lazaryan<fnref n="1" /> | N. Rubin² | A. Goyal²

**Background:** Mycosis fungoides (MF) is a rare, generally indolent non-Hodgkin T-cell lymphoma of the skin. It has previously been associated with increased risk of second hematologic malignancies but association with second solid malignancies has not been well characterized.

**Methods:** We studied a large population of patients diagnosed with MF from 2000-2015 in the 18 population-based United States cancer registries of the Surveillance, Epidemiology, and End Results Program (SEER-18) to assess the risk of developing a second primary hematologic or solid malignancy. Relative risks were estimated using the standardized incidence ratios (SIR). Overall survival (OS) was assessed by Cox proportional hazards analysis.

**Results:** In the SEER-18 cohort, of 6742 patients, there were 511 (7.5%) second cancer events (SIR 10.15, 95% confidence interval [CI], 9.29-11.07). These included 184 (36.0%) hematologic malignancies (SIR 39.71, 95% CI, 34.05-46.05) and 327 (64.0%) solid tumor malignancies (SIR 7.33, 95% CI, 6.56-8.17). Patients with MF were at substantially increased risk for non-Hodgkin (SIR 66.65, 95% CI, 56.06-78.65) and Hodgkin lymphoma (SIR 105.26, 95% CI, 54.39-183.87). MF patients were also at higher risk of melanoma (SIR 9.00, 95% CI, 5.5-13.9), lung (SIR 8.34, 95% CI, 6.4-10.6), female breast (SIR 11.28, 95% CI, 8.29-15.00), prostate (SIR 5.65, 95% CI, 4.3-7.28), bladder (SIR 4.35, CI 2.38-7.3), colon (SIR 6.99, CI 4.9-9.68) and renal (SIR 3.26 CI, 1.33-8.87) cancers. Females with MF were at higher risk (SIR 13.95, 95% CI 12.09-16.02) than males (SIR 8.62, 95% CI, 7.69-12.09) of being diagnosed with second malignancies (p<0.05). All ethnic groups showed a statistically significant elevation in SIR with Non-Hispanic white patients having the lowest SIR (9.13, 95% CI, 8.22-10.11). There was no significant difference in the incidence of second malignancy based on MF stage

<figure><img src="image_158.png" /></figure>

<footnote n="1">¹BMT-Cellular Immunotherapy, Moffitt Cancer Center, Tampa, United States; ²Dermatology, University of Minnesota, Minneapolis, United States</footnote>
(p = 0.17 for stage IA-IIA vs. stage IIB+). Second malignancy was associated with worse overall survival (Figure) in the Cox proportionate hazards ratio model, the hazard ratio (HR) for patients with vs. those without second malignancy was 2.72 (95% CI, 2.37-3.12, p<0.001) after adjustment for age (p<0.001), ethnicity (p<0.001), and stage (p<0.001) of disease.

**Conclusions:** Patients with MF are at increased risk of developing second hematologic and solid malignancies which in turn leads to poor survival. These findings warrant careful screening for signs and symptoms of second malignancies in patients with MF.

**Keywords:** cutaneous T-cell lymphoma (CTCL); mycosis fungoides (MF).

## 231 TIME TO NEXT TREATMENT IN PATIENTS WITH PREVIOUSLY TREATED CUTANEOUS T-CELL LYMPHOMA (CTCL) RECEIVING MOGAMULIZUMAB OR VORINOSTAT: A POST-HOC ANALYSIS OF THE MAVORIC STUDY

Y.H. Kim<fnref n="1" /> | P.L. Ortiz-Romero² | B. Pro³ |

L. Sokol<fnref n="4" /> | J. Scarisbrick⁵ | A. Musiek⁶ |

M. Vermeer⁷ | R. Dummer⁸ | A. Halwani⁹ |

M. Fierro¹⁰ | J. Moriya<fnref n="11" /> | M. Leoni¹² | M. Bagot¹³

**Introduction:** CTCL is a rare group of NHL of T-cell origin, characterized by relapsing/remitting behavior and progressive resistance to treatments, with a reported median time to next treatment (TTNT; mostly systemic therapies, total skin radiation, excludes localized treatments, topical steroids) in mycosis fungoides (MF) and Sézary syndrome (SS) of 5.4 months (mo) (Hughes CF, et al. Blood, 2015). The phase 3 MAVORIC study demonstrated mogamulizumab (MOGA; Poteligeo®), a novel anti-CCR4 monoclonal antibody, was superior to vorinostat (VORI) in progression-free survival (median 7.7 vs 3.1 mo, P<0.0001) and confirmed overall response rates (28% vs 4.8%, P<0.0001) in previously treated patients with MF/SS (Kim YH, et al. Lancet Oncol 2018). In MF/SS-CTCL with a chronic course where patients suffer life-quality issues, the duration of clinical benefit of treatments, as reflected by TTNT, is an important clinically meaningful endpoint. This post-hoc analysis examines TTNT to further explore the patient clinical experience.

**Methods:** Patients with MF/SS (n = 372) who were treated with ≥1 prior systemic therapy were randomized 1:1 to receive MOGA (1.0 mg/kg, administered once weekly for the first 28-day cycle, then on Days 1 and 15 of subsequent cycles) or oral VORI (400 mg daily). Patients on VORI were permitted to crossover to MOGA upon approval (e.g., disease progression or intolerable toxicity). TTNT was defined as time to any significant therapy (systemic treatment, total skin radiation, or psoralen-UVA therapy). The length of TTNT was assessed overall and by disease stage grouping (IB/II and III/IV) and disease type (MF and SS).

**Results:** Median TTNT for the full ITT population was longer with MOGA at 11 mo (95% CI, 8.8-12.6) compared to VORI at 3.5 mo and consistently longer for MOGA vs VORI across disease stage grouping or by disease type (Table). In subjects who crossed over to MOGA, median TTNT was 10 months (95% CI: 8.0-12.6).

**Conclusions:** TTNT in MF/SS represents an additional measure of clinical benefit and disease control in patients who may have progressed based on strict protocol definitions of progression. This post hoc analysis showing a prolonged TTNT across disease stages and types supports a clinical benefit for MF and SS patients who receive MOGA.

**Sponsor:** Kyowa Kirin.

**Keywords:** cutaneous T-cell lymphoma (CTCL); mycosis fungoides (MF); Sézary syndrome.

**Disclosures:** Kim, Y: Consultant Advisory Role: Kyowa Kirin; Research Funding: Kyowa Kirin. Ortiz-Romero, P: Consultant

<table><caption>TABLE 1 TTNT, Overall and By Disease Stage and Type</caption><thead><tr><td>Median TTNT (mo), 95% CI</td><td>N</td><td>MOGA</td><td>N</td><td>VORI</td><td>P-value (stratified log-rank)</td></tr></thead><tbody><tr><td>Intent-to-treat population</td><td>186</td><td>11.0 (8.8-12.6)</td><td>186</td><td>3.5 (3.1-4.3)</td><td>&lt;0.0001</td></tr><tr><td>Stage IB/II</td><td>68</td><td>7.0 (4.9-10.1)</td><td>72</td><td>3.3 (2.8-4.9)</td><td>0.0664</td></tr><tr><td>Stage III/IV</td><td>118</td><td>12.9 (10.6-16.7)</td><td>114</td><td>3.5 (2.8-4.7)</td><td>&lt;0.0001</td></tr><tr><td>MF</td><td>105</td><td>8.8 (6.1-11.5)</td><td>99</td><td>4.1 (3.1-5.2)</td><td>0.0038</td></tr><tr><td>SS</td><td>81</td><td>12.9 (10.7-16.7)</td><td>87</td><td>3.3 (2.6-3.8)</td><td>&lt;0.0001</td></tr></tbody></table>

<footnote n="1">¹Dermatology, Stanford University School of Medicine, Stanford, United States; ²Dermatología, Instituto i+12, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid, Spain; ³Oncology, Northwestern University, Chicago, United States;</footnote>

<footnote n="4">⁴Hematology/Oncology, H. Lee Moffitt Cancer Center, Tampa, United States; ⁵Lymphoma Service, University Hospitals Birmingham, Birmingham, United Kingdom; ⁶Dermatology, Washington University, St. Louis, United States; ⁷Dermatology, Leiden University Medical Center, Leiden, Netherlands; ⁸Dermatology, UniversitätsSpital Zurich, Zurich, Switzerland; ⁹Hematology, University of Utah, Salt Lake City, United States; ¹⁰Scienze Mediche, Università di Torino, Torino, Italy;</footnote>

<footnote n="11">¹¹Biostatistics, Kyowa Kirin Pharmaceutical Development, Inc., Princeton, United States; ¹²Medical Sciences, Kyowa Kirin Pharmaceutical Development, Inc., Princeton, United States; ¹³Service de Dermatologie, Hôpital Saint Louis, APHP, Inserm U976, Université Paris 7, Paris, France</footnote>
Advisory Role: 4SC, Actelion, Innate, Kyowa Kirin, miRagen, Takeda; Other Remuneration: Patent, PLCG1 mutation; Travel, Almirall, Janssen, Leo, Novartis. Pro, B: Honoraria: Celgene, Kyowa Kirin, Seattle Genetics, Takeda; Research Funding: Celgene, Takeda; Other Remuneration: Travel, Seattle Genetics, Takeda. Sokol, L: Consultant Advisory Role: Celgene, Seattle Genetics, Spectrum. Scarisbrick, J: Consultant Advisory Role: 4SC, Innate, Kyowa, Mallinckrodt, Takeda; Honoraria: 4SC, Kyowa, Mallinckrodt, Takeda; Research Funding: Kyowa, Takeda. Musiek, A: Consultant Advisory Role: Actelion, Kyowa Hakko Kirin, Seattle Genetics; Other Remuneration: Investigator, Actelion, Elorac, Helsinn, Kyowa Hakko Kirin, miRagen, Pfizer, Soligenix. Vermeer, M: Consultant Advisory Role: Innate, Kyowa Kirin; Research Funding: Teva. Dummer, R: Consultant Advisory Role: Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma, Takeda; Honoraria: Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma, Takeda; Research Funding: Amgen, Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Roche. Halwani, A: Research Funding: AbbVie, AbbVie/Genentech, Amgen, Bristol-Myers Squibb, Genentech, Immune Design, Kyowa Kirin, miRagen, Pharmacyclics, Roche/Genentech, Takeda; Other Remuneration: Travel, AbbVie, Immune Design, Pharmacyclics, Seattle Genetics. Fierro, M: Other Remuneration: Travel, Bristol-Myers Squibb. Moriya, J: Employment Leadership Position: Kyowa Kirin. Leoni, M: Employment Leadership Position: Kyowa Kirin. Bagot, M: Consultant Advisory Role: Innate, Kyowa Kirin, miRagen, Takeda; Stock Ownership: Innate; Other Remuneration: Patent, Innate.

232

FINAL DATA FROM THE PHASE 3 ALCANZA STUDY: BRENTUXIMAB VEDOTIN (BV) VS PHYSICIAN'S CHOICE (PC) IN PATIENTS (PTS) WITH CD30-POSITIVE (CD30+) CUTANEOUS T-CELL LYMPHOMA (CTCL)

S.M. Horwitz<fnref n="1" /> | J. Scarisbrick² | H.M. Prince³ |
S. Whittaker⁴ | M. Duvic⁵ | Y.H. Kim⁶ |
P. Quaglino⁷ | P.L. Zinzani⁸ | O. Bechter⁹ |
H. Eradat¹⁰ | L. Pinter-Brown¹¹ | O. Akilov¹² |
L. Geskin¹³ | J. Sanches¹⁴ | P. Ortiz-Romero¹⁵ |
J. Lisano¹⁶ | L. Brown¹⁷ | M.C. Palanca-Wessels¹⁸ |
A. Gautam¹⁹ | V. Bunn²⁰ | M. Little²¹ | R. Dummer²²

Foundation Trust, London, United Kingdom; ⁵Department of Dermatology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States; ⁶Department of Dermatology, Stanford University School of Medicine and Stanford Cancer Institute, Stanford, United States; ⁷Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy; ⁸Institute of Haematology, University of Bologna, Bologna, Italy; ⁹Department of General Medical Oncology, University Hospitals Leuven, Leuven, KU, Belgium; ¹⁰Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States; ¹¹Division of Hematology Oncology, Chao Family Comprehensive Cancer Center, University of California, Irvine, United States; ¹²Department of Dermatology, University of Pittsburgh, Pittsburgh, United States; ¹³Department of Dermatology, Columbia University, New York, United States; ¹⁴Department of Dermatology, University of São Paulo Medical School, São Paulo, Brazil; ¹⁵Department of Dermatology, University Hospital 12 de Octubre, Institute i+12 Medical School, University Complutense, Madrid, Spain; ¹⁶Medical Affairs, Seattle Genetics, Inc., Bothell, United States; ¹⁷Biostatistics, Seattle Genetics, Inc., Bothell, United States; ¹⁸Clinical Development, Seattle Genetics, Inc., Bothell, United States;

<table><caption>TABLE 1 Subsequent anti-cancer therapy (intent-to-treat population)</caption><thead><tr><th></th><th>BV n=64</th><th>PC n=64</th></tr></thead><tbody><tr><td>Pts with ≥1 subsequent anti-cancer therapy, n (%)</td><td>50 (78)</td><td>48 (75)</td></tr><tr><td>Type of therapy, n (%)*</td><td></td><td></td></tr><tr><td>Skin-directed therapy</td><td>26 (52)</td><td>30 (63)</td></tr><tr><td>Radiotherapy</td><td>15 (30)</td><td>20 (42)</td></tr><tr><td>Phototherapy</td><td>13 (26)</td><td>13 (27)</td></tr><tr><td>Topical steroids</td><td>3 (6)</td><td>6 (13)</td></tr><tr><td>Other</td><td>0</td><td>0</td></tr><tr><td>Topical chemotherapy</td><td>0</td><td>0</td></tr><tr><td>Topical retinoids</td><td>0</td><td>0</td></tr><tr><td>Systemic therapy</td><td>44 (88)</td><td>45 (94)</td></tr><tr><td>Chemotherapy</td><td>34 (68)</td><td>27 (56)</td></tr><tr><td>Other</td><td>28 (56)</td><td>23 (48)</td></tr><tr><td>Methotrexate</td><td>14 (28)</td><td>10 (21)</td></tr><tr><td>BV</td><td>12 (24)</td><td>33 (69)</td></tr><tr><td>Immunotherapy</td><td>12 (24)</td><td>9 (19)</td></tr><tr><td>Other</td><td>9 (18)</td><td>5 (10)</td></tr><tr><td>Bexarotene</td><td>6 (12)</td><td>6 (13)</td></tr><tr><td>Histone deacetylase inhibitor</td><td>6 (12)</td><td>4 (8)</td></tr><tr><td>Non-topical retinoids</td><td>3 (6)</td><td>0</td></tr><tr><td>Photopheresis</td><td>1 (2)</td><td>1 (2)</td></tr><tr><td>Denileukin diftitox</td><td>0</td><td>0</td></tr><tr><td>Other/Unknown</td><td>1 (2)</td><td>4 (8)</td></tr></tbody></table>

<footnote n="1">¹Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States; ²Department of Dermatology, University Hospital Birmingham, Birmingham, United Kingdom; ³Division of Cancer Medicine, Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia; ⁴St John's Institute of Dermatology, Guys and St Thomas NHS</footnote>

<footnote>*Percentages are based on the number of patients with ≥1 subsequent anti-cancer therapy in the intent-to-treat population in each arm. Abbreviations: BV, brentuximab vedotin; PC, physician's choice; pts, patients.</footnote>
<figure><img src="image_159.png" /><figcaption>Figure. PFS per IRF (intent-to-treat population; median follow-up: 36.8 months)</figcaption></figure>

BV, brentuximab vedotin; CI, confidence interval; HR, hazard ratio; IRF, independent review facility; PC, physician's choice; PFS, progression-free survival

¹⁹Global Medical Affairs, Millennium Pharmaceuticals, Inc., a wholly
owned subsidiary of Takeda Pharmaceutical Company Limited,
Cambridge, United States; ²⁰Oncology Statistics, Millennium
Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda
Pharmaceutical Company Limited, Cambridge, United States; ²¹Oncology
Clinical Research, Millennium Pharmaceuticals Inc., a wholly owned
subsidiary of Takeda Pharmaceutical Company Limited, Cambridge,
United States; ²²Department of Dermatology, University Hospital Zürich,
Zürich, Switzerland

**Introduction:** The original ALCANZA analysis (median follow-up: 22.9 months; Prince et al, Lancet, 2017; NCT01578499) showed significant improvements in rate of objective response lasting ≥4 months (ORR4) and progression-free survival (PFS) with BV vs PC (methotrexate or bexarotene) for the treatment of CD30+ CTCL. We report final ALCANZA results (data cut-off: 28 Sep 2018; median follow-up for overall survival [OS]: 45.9 months).

**Methods:** Adults with previously treated CD30+ mycosis fungoides (MF; including transformed MF) or primary cutaneous anaplastic large cell lymphoma (pcALCL) were randomized 1:1 to BV or PC. Detailed methods have been published previously.

**Results:** The intent-to-treat population comprised 128 pts (MF = 97; pcALCL = 31). Final results demonstrate improved efficacy with BV vs PC: ORR4 per independent review facility (IRF), 54.7% vs 12.5% (P<0.001); ORR4 per investigator, 59.4% vs 7.8% (P<0.001); CR rate per IRF, 17.2% vs 1.6% (P = 0.002). Median PFS was 16.7 months in the BV arm vs 3.5 months with PC (P<0.001; **Figure**). In the BV and PC arms, 78% and 75% of pts had received subsequent antineoplastic therapy, respectively. Median time to next therapy (TTNT) was significantly longer with BV vs PC (14.2 vs 5.6 months;

HR, 0.269; 95% CI: 0.171, 0.424; p<0.001). In the BV arm, the probability of pts not requiring subsequent antineoplastic therapy was 65.5% at 1 year and 23.6% at 2 years. Types of subsequent anti-cancer therapy are shown in the **Table**; 24% of pts were retreated with BV, and 69% received BV after PC. There were 23 deaths in the BV arm and 25 in the PC arm (HR: 0.745; 95% CI: 0.421, 1.318; P = 0.310; ALCANZA was not powered to evaluate OS). Peripheral neuropathy (PN) is a known toxicity with BV. 44/66 pts (67%) treated with BV (safety population) experienced a PN event (standardised MedDRA query); most events were Grade (G) 1 (18/44) or 2 (20/44), and there were 6 G3 and no G4 events. Final results show that 86% (38/44) of pts with PN events in the BV arm had complete resolution (26/44) or improvement (by at least 1 grade; 12/44) of all PN events, compared with 82% (36/44) in the original analysis; ongoing PN was G1/2 in 15/3 pts (no pts had ongoing G3/4 PN), compared with G1/2 in 17/5 pts in the original analysis.

**Conclusions:** Final analyses from ALCANZA confirm improved, durable responses and longer PFS with BV vs PC in CD30+ CTCL. BV demonstrated extended TTNT vs PC, suggesting that durable BV responses were clinically meaningful. PN is ongoing in 27% (18/66) of pts treated with BV, but is all G1/2.

**Keywords:** brentuximab vedotin; CD30; cutaneous T-cell lymphoma (CTCL).

**Disclosures:** Horwitz, S: Consultant Advisory Role: ADCT Therapeutics, Aileron, Forty-Seven, Infinity/Verastem, Kyowa-Hakka-Kirin, Millennium Pharmaceuticals Inc, Seattle Genetics, Affimed, Angimmune, Beigene, Corvus, Innate Pharma, Kura, Merck, Miragen, Mundipharma, Portola, Syros Pharmaceutical; Research Funding: ADCT Therapeutics, Aileron, Forty-Seven, Infinity/Verastem, Kyowa-Hakka-Kirin, Millennium
Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Seattle Genetics, Celgene, Trillium. **Scarisbrick, J:** Consultant Advisory Role: Helsinn, Kyowa, Millennium Pharmaceuticals Inc, Innate Pharma, 4SC, Mallinckrodt. **Prince, H:** Consultant Advisory Role: Millennium Pharmaceuticals, Inc.; Honoraria: Millennium Pharmaceuticals, Inc.; Research Funding: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. **Duvic, M:** Employment Leadership Position: UT MD Anderson Cancer Center; Consultant Advisory Role: Huya Bioscience Int'l, Covance Laboratory Services (formerly MiRagen Therapeutics), Array Biopharma, Cell Medica Ltd, Celgene Corp, Kyowa Hakko Kirin, Seattle Genetics, Mallinckrodt Pharmaceuticals (formerly Therakos Inc), Millennium Pharmaceuticals Inc, Aclaris Therapeutics Int'l Ltd; Honoraria: Array Biopharma, Cell Medica Ltd, Celgene Corp, Kyowa Hakko Kirin, Seattle Genetics, Mallinckrodt Pharmaceuticals (formerly Therakos Inc), Millennium Pharmaceuticals Inc, Aclaris Therapeutics Int'l Ltd, Therakos, Jonathan Wood & Assoc; Research Funding: Eisai, Sharpe, Allos, Rhizen Pharma, Spatz Foundation, Oncoceuticals, Tetralogics, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Mallinckrodt Pharmaceuticals (formerly Therakos Inc), Kyowa Hakko Kirin, Seattle Genetics, Soligenetics. **Kim, Y:** Honoraria: Eisai, Kyowa Hakko Kirin, Millennium Pharmaceuticals Inc, Seattle Genetics, Medivir, Innate, Portola Pharma, Corvus; Research Funding: Eisai, Kyowa Hakko Kirin, Merck, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Seattle Genetics, Soligenix, miRagen, Forty Seven Inc, Neumedicine, Innate, Portola Pharma, Trillium. **Quaglino, P:** Consultant Advisory Role: Millennium Pharmaceuticals Inc, Kyowa Kirin, Therakos, 4SC. **Zinzani, P:** Consultant Advisory Role: Verastem, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Snadoz, MSD, Immune Design, Celgene, Portola, Roche, Eusapharma, Kyowa Kirin, Sanofi. **Eradat, H:** Consultant Advisory Role: Genentech, Roche, Abbvie, Pharmacyclics; Honoraria: Genentech, Roche, Abbvie, Pharmacyclics, Millennium Pharmaceuticals Inc; Research Funding: Genentech, Roche, Abbvie, Pharmacyclics, ATARA, Celgene. **Pinter-Brown, L:** Consultant Advisory Role: Millennium Pharmaceuticals, Inc.; Honoraria: Millennium Pharmaceuticals, Inc. **Akilov, O:** Consultant Advisory Role: Trillium Therapeutics, Actelion, Mallinckrodt, Medivir, Seattle Genetics, Kyowa Kirin; Honoraria: Soligenix; Research Funding: Trillium Therapeutics, Pfizer, Actelion. **Geskin, L:** Consultant Advisory Role: Kyowa Kirin, Therakos, Helsinn, BMS; Research Funding: Kyowa Kirin, Therakos, Helsinn, BMS. **Sanches, J:** Consultant Advisory Role: Millennium Pharmaceuticals, Inc. **Ortiz-Romero, P:** Consultant Advisory Role: Kyowa, Millennium Pharmaceuticals Inc, Actelion, 4SC, BMS; Research Funding: Meda. **Lisano, J:** Employment Leadership Position: Seattle Genetics, Inc. **Brown, L:** Employment Leadership Position: Seattle Genetics, Inc.; Stock Ownership: Seattle Genetics, Inc. **Palanca-Wessels, M:** Employment Leadership Position: Seattle Genetics, Inc.; Stock Ownership: Seattle Genetics, Inc. **Gautam, A:** Employment Leadership Position: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; Stock Ownership: Takeda Pharmaceutical Company Limited. **Bunn, V:** Employment Leadership Position: Millennium Pharmaceuticals, Inc.,

a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. **Little, M:** Employment Leadership Position: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; Stock Ownership: Takeda Pharmaceutical Company Limited. **Dummer, R:** Consultant Advisory Role: Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Pharmaceuticals Inc, Pierre Fabre, Sun Pharma.

## 233
CLINICAL AND BIOLOGICAL PREDICTORS OF OUTCOME IN LARGE GRANULAR LYMPHOCYTE LEUKEMIA: A SINGLE CENTER EXPERIENCE OF 205 PATIENTS

**R. Zambello** | **G. Barilà** | **A. Teramo** | **G. Calabretto** |

**C. Vicenzetto** | **V.R. Gasparini** | **L. Pavan** |

**M. Leoncin** | **M. Facco** | **G. Semenzato**

Department of Medicine (DIMED), Hematology and Clinical Immunology Section, Padua University School of Medicine, Padua, Italy

**Introduction:** Large Granular Lymphocyte Leukemia (LGLL) is a rare chronic lymphoproliferative disorder characterized by the expansion of LGLs. Among LGLL, according to the phenotype, a CD3+ T-LGLL and a CD3- Chronic Lymphoproliferative disorder of Natural Killer cells (CLPD-NK) are recognized. Moreover, according to the T cell receptor rearrangement, the Tαβ and Tγδ subsets can be identified. LGLL is a heterogeneous disease with some patients being asymptomatic and other developing cytopenias. The etiology is unknown but a constitutive activation of JAK/STAT pathway is involved in LGL proliferation, supported by the evidence of somatic STAT3 and STAT5b mutations in approximately 40% of patients.

The aim of this study is to analyse clinical and biological features of a large cohort of LGLL patients to identify prognostic markers affecting patients' outcome.

**Methods:** From 1992 to 2018, clinical and biological data of 205 patients affected by LGLL have been collected. STAT3 exon 21 mutation and STAT5b exon 16-18 mutation analyses were performed by Sanger sequencing.

**Results:** Median age at diagnosis was 58 years. By phenotype, 129/205 (62.9%) patients were affected by Tαβ LGLL, 23/205 (11.2%) by Tγδ LGLL, and 36/205 (17.6%) by CLPD-NK. Moreover, 17 patients (8.3%) were characterized by a bi-phenotypical variant, identified by a concomitant T/NK or Tαβ/Tγδ clone. According to CD4 and CD8 expression, Tαβ LGLL was further classified in CD4-/CD8+ LGLL (CD8+ T-LGLL, 84/205, 41%) and CD4+/CD8dim/neg LGLL (CD4+ T-LGLL, 45/205, 21.9%).

Neutropenia (Absolute Neutrophil's Count, ANC<1,500/mm³) was the most relevant feature (78/205, 38%), severe neutropenia (ANC<500/mm³) being present in 20.5% of patients. Anemia (Hb<120 g/L, 27/205, 13.2%), severe anemia (Hb<90g/L, 20/205, 9.8%) and thrombocytopenia (PLTs <100.000/mm³, 12/205, 4.8%) were less recurring.
DNA samples of 166 and 152 patients were available for STAT3 and STAT5b mutations analysis, respectively. STAT3 mutations were detected in 47 patients (28.3%), with a higher frequency in CD8+ Tαβ LGLL towards Tγδ LGLL (60% vs 25%, p = 0.0232) and CLPD-NK (60% vs 5.8%, p<0.0001). At variance, STAT5b mutations were found in 15 patients (9.8%), in 12 case were CD4+ Tαβ LGLL and in 3 cases were Tγδ LGLL.

With a median follow up of 8 years, median overall survival (OS) of our cohort was not reached. Major features associated to reduced OS were ANC<500/mm<fnref n="3" /> (267 months vs not reached, p = 0.0297), severe anemia (144 months vs not reached, p<0.0001), treatment requirement (214 vs not reached, p = 0.0011) and presence of STAT3 mutations (267 months vs not reached, p = 0.0113).

**Conclusion:** Our results confirmed the remarkable heterogeneity of LGLL. We identified clinical and biological features associated to reduced OS in LGLL patients and, for the first time, we demonstrated the dismal impact of STAT3 mutations in patients' survival, suggesting that this marker should be regarded as a potential target of therapy.

**Keywords:** immunophenotype; non-Hodgkin lymphoma (NHL).

## HODGKIN LYMPHOMA

### 234
CLINICAL CHARACTERISTICS AND
OUTCOME OF PATIENTS WITH
HODGKIN'S LYMPHOMA OLDER THAN
60 YEARS TREATED IN SWITZERLAND
OVER THE LAST 17 YEARS

S. Aeppli<fnref n="1" /> | A. Moccia² | M. Bargetzi<fnref n="3" /> |

D. Brülisauer<fnref n="4" /> | C. Caspar⁵ | M. Ebnöther⁶ |

M. Fehr<fnref n="1" /> | N. Fischer⁷ | G. Ghilardi<fnref n="8" /> | F. Krasniqi⁹ |

N. Lang¹⁰ | U. Mey¹¹ | W. Mingrone¹² |

U. Novak¹³ | P. Richter¹¹ | M. Rütti¹⁴ |

A. Schmidt¹⁵ | F. Stenner⁹ | M. Voegeli¹⁶ |

T. Zander¹⁷ | F. Hitz<fnref n="1" />

Switzerland; ¹³Klinik für Medizinische Onkologie, Inselspital, Universitätsspital Bern, Bern, Switzerland; ¹⁴Medizinische Klinik, Spital Wil, Wil, Switzerland; ¹⁵Klinik für Medizinische Onkologie und Hämatologie, Stadtspital Triemli, Zürich; ¹⁶Onkologie und Hämatologie, Kantonsspital Baselland, Liestal, Switzerland; ¹⁷medizinische Onkologie, Luzerner Kantonsspital, Luzern, Switzerland

**Introduction:** Approximately 20% of Hodgkin lymphoma (HL) patients (pts) are older than 60 years at diagnosis. Despite the fact that HL remains a highly curable disease, this particular group of pts tends to have a less favorable outcome than their younger counterparts. This is mainly related to the increased toxicity resulting in higher treatment-related mortality and insufficient dosing of the drugs applied.

**Methods:** We conducted a population-based, retrospective analysis which aimed to investigate patient characteristics, treatment strategies and outcome of pts with HL older than 60 years of age, treated between 2000 and 2017, in 15 Centers across Switzerland.

**Results:** We identified 249 pts with the following characteristics: Median age at diagnosis 71 years (range: 60-94), 123 pts 60-70 years, 89 pts 71 - 80 years, 37 pts > 80 years. 158 (63.5%) male, 191 (81.7%) Performance Status (PS) 0-1, Charlson Comorbidity Index (CCI) low (2-4 points) in 42 (16.9%) pts and high (> 4 points) in 205 (82.3%) pts. 121 (49%) pts with stage I/II; 126 (51%) with stage III/IV and the following histologies: 238 (96%) classical HL, 11 (4%) nodular lymphocyte predominant HL. Treatment was performed as follows: radiotherapy (RT) only in 11 (4%) pts; chemotherapy followed by RT in 79 (32%) pts, chemotherapy only 142 (57%) pts; 221 pts received systemic therapy with: ABVD 117 (53 %); BEACOPPesc. 8 (4.0 %), other chemotherapy combinations or single agent 57 (25 %), antibody drug conjugate one pt; 12 (5.0 %) pts received best supportive care, in 5 (2%) pts information was missing. Haematological

<figure><img src="image_160.png" /></figure>

<footnote n="1">¹Klinik für Medizinische Onkologie und Hämatologie, Kantonsspital St. Gallen, St.Gallen, Switzerland; ²Department of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;</footnote>

<footnote n="3">³Hämatologie, Kantonsspital Aarau, Aarau, Switzerland;</footnote>

<footnote n="4">⁴Universitätsklinik für medizinische Onkologie, Inselspital, Universitätsspital Bern, Bern, Switzerland; ⁵Onkologie und Hämatologie, Kantonsspital Baden, Baden, Switzerland; ⁶Onkologie/Hämatologie, Claraspital, Basel, Switzerland; ⁷Klinik für medizinische Onkologie und Hämatologie, Kantonsspital Winterthur, Winterthur, Switzerland;</footnote>

<footnote n="8">⁸Department of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; ⁹Onkologie, Universitätsspital Basel, Basel, Switzerland; ¹⁰Oncologie, Hôpitaux Universitaires Genève, Genève, Switzerland; ¹¹Onkologie/Hämatologie, Kantonsspital Graubünden, Chur, Switzerland; ¹²Onkologiezentrum, Kantonsspital Olten, Olten,</footnote>
toxicity ≥G2 was observed in 111 (42.7%) pts, 65 (25%) pts presented with infections and 44 (17%) pts with febrile neutropenia.

Bleomycin lung-toxicity (BLT) was documented in 25 (18%) pts: 6 (4%) pts had mild toxicity (radiologic changes only), 12 (9%) pts had severe toxicity (leading to hospitalization), in 7 (5%) pts severity was unknown.

In 58 (24%) pts treatment was discontinued prematurely due to toxicity. 171 (68.7%) pts achieved complete remission, 30 (12%) partial response. 58 (23%) pts relapsed/progressed after first line treatment. 25 (23%) pts died of HL and 15 (14%) of treatment toxicity. With a median follow-up of 4.1 years (range: 0.05 - 17.95) for the whole study population, progression-free survival (PFS) at 2 and 5 years was 81% and 72% respectively, cause-specific survival (CSS) at 2 and 5 years was 85% and 78%, respectively. CSS for pts 71-80 years vs 60-70 years; HR = 3.25, p<0.001 and > 80 years vs 60-70 years; HR 3.84, p = 0.001.

**Conclusion:** Cause-specific survival of unselected, elderly HL pts > 71 years decreased significantly in comparison to those 60 to 70 years. Toxicities appeared to be relevant, in particular infections and BLT. Bleomycin needs to be used with extreme caution in this particular group of patients. New treatment strategies with a low toxicity profile are clearly needed, in particular for frail pts and pts older than 70 years.

**Keywords:** elderly; Hodgkin lymphoma (HL).

**Disclosures:** Moccia, A: Other Remuneration: Advisory Roche, Janssen, Takeda.

235
# EXPLORATORY BIOMARKER ANALYSIS IN THE PH 3 ECHELON-1 STUDY: WORSE OUTCOME WITH ABVD IN PATIENTS WITH ELEVATED BASELINE LEVELS OF SCD30 AND TARC

J. Radford<fnref n="1" /> | J.M. Connors² | A. Younes³ |

A. Gallamini⁴ | S.M. Ansell<fnref n="5" /> | W.S. Kim<fnref n="6" /> |

J. Cheong⁷ | I. Flinn<fnref n="8" /> | N. Kalakonda⁹ |

M. Kaminski¹⁰ | R. Pettengell¹¹ | M. Onsum¹² |

N. Josephson¹³ | S. Kuroda¹⁴ | R. Liu¹⁵ |

H. Miao¹⁶ | A. Gautam¹⁷ | W.L. Trepicchio¹⁸ |

A. Sureda¹⁹

Yonsei University College of Medicine, Seoul, Republic of Korea;

**Introduction:** Soluble (s)CD30 and thymus and activation-regulated chemokine (TARC) are established prognostic biomarkers in Hodgkin lymphoma (HL): higher baseline serum levels are associated with poorer survival outcomes. Elevated sCD30 and TARC levels are also associated with established poor prognostic factors in HL, e.g. Stage IV disease, higher International Prognostic Score (IPS), and extranodal involvement (ENI). The phase 3 ECHELON-1 study compared front-line brentuximab vedotin (a CD30-directed antibody-drug conjugate) plus doxorubicin, vinblastine, and dacarbazine (A+AVD) vs ABVD in patients (pts) with advanced classical HL (cHL). A+AVD demonstrated superior modified progression-free survival (modified PFS) vs ABVD (HR = 0.77 [95% CI 0.60-0.98]; p = 0.035; 2-yr mPFS 82.1% vs 77.2%). An exploratory ad-hoc biomarker analysis evaluated mPFS according to baseline sCD30 and TARC levels.

**Methods:** Serum samples were collected from 1334 pts with Stage III (36%) or IV (64%) cHL during the screening period and analyzed using validated assays for sCD30 (Covance Labs) and TARC (ICON Labs). mPFS (defined as time to progression, death, or evidence of noncomplete response followed by subsequent anticancer therapy) per independent review facility (IRF) was analyzed according to baseline sCD30 and TARC levels; the association of biomarker levels with treatment outcomes along with other potential predictive factors was explored in a multivariate Cox model.

**Results:** For the ad-hoc sCD30 analysis, pts were dichotomized around the median sCD30 baseline level (207.9 ng/mL). Pts in the A +AVD arm performed similarly regardless of baseline sCD30 level, with a 2-yr mPFS of 80.7% (sCD30 >median) and 82.7% (sCD30 ≤median). However, a decrease in effectiveness of ABVD was observed in pts with sCD30 >median with a 2-yr mPFS of 68.9% [sCD30 >median] and 85.7% [sCD30 ≤median]). A mPFS benefit in

<footnote n="1">¹Department of Medical Oncology, University of Manchester and the
Christie NHS Foundation Trust, Manchester Academic Health Science
Centre, Manchester, United Kingdom; ²Centre for Lymphoid Cancer,
British Columbia Cancer Centre for Lymphoid Cancer, Vancouver,
Canada; ³Division of Hematologic Oncology, Memorial Sloan Kettering
Cancer Center, New York, United States; ⁴Research, Innovation and
Statistics Department, A Lacassagne Cancer Centre, Nice, France;</footnote>

<footnote n="5">⁵Department of Medicine, Mayo Clinic, Rochester, United States;</footnote>

<footnote n="6">⁶Hematology-Oncology, Samsung Medical Center, Seoul, Republic of
Korea; ⁷Division of Hematology, Department of Internal Medicine,</footnote>

<footnote n="8">⁸Department of Oncology, Sarah Cannon Research Institute, Nashville, United States; ⁹Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom; ¹⁰Internal Medicine, University of Michigan, Ann Arbor, United States; ¹¹Haematology, St George's Hospital, London, United Kingdom; ¹²Biomarkers, Seattle Genetics, Inc., Bothell, United States; ¹³Clinical Development, Seattle Genetics, Inc., Bothell, United States; ¹⁴Biostatistics, Takeda</footnote>

<footnote>Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan; ¹⁵Biostatistics, Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, United States; ¹⁶OTAU Clinical Research, Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda</footnote>

<footnote>Pharmaceutical Company Limited, Cambridge, United States; ¹⁷Global Medical Affairs, Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, United States; ¹⁸Translational and Biomarker Research, Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda</footnote>

<footnote>Pharmaceutical Company Limited, Cambridge, United States; ¹⁹Clinical Hematology, Institut Català d'Oncologia - Hospital Duran i Reynals, Barcelona, Spain</footnote>
favor of A+AVD vs ABVD was observed in pts with sCD30 >median (HR (95% CI) = 0.600 (0.428-0.841)). Multivariate Cox analysis with the interaction between treatment group and sCD30 level showed an increased risk of experiencing an mPFS event with ABVD and sCD30 >median (interaction p = 0.025) when adjusted by other prognostic factors (Ann Arbor stage, IPS and ENI). Similar trends were observed with the exploratory ad-hoc TARC analysis. No new safety signals were reported in subgroups with elevated sCD30 or TARC levels.

**Conclusions:** Preliminary adhoc analysis indicates that ABVD treated patients do not perform as well with elevated baseline sCD30 and TARC levels. A+AVD treated patients perform well regardless of levels of these poor prognostic markers. Prospective studies need to be conducted in order to further validate these findings. If validated, these biomarkers may help identify patient populations that could benefit from more effectively targeted therapy.

**Keywords:** ABVD; brentuximab vedotin; classical Hodgkin lymphoma (cHL).

**Disclosures:** Radford, J: Consultant Advisory Role: Millennium Pharmaceuticals Inc, ADC Therapeutics, BMS, Novartis; Stock Ownership: GSK, AstraZeneca (spouse); Honoraria: Millennium Pharmaceuticals Inc, Seattle Genetics, Novartis, BMS; Research Funding: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Connors, J: Consultant Advisory Role: Seattle Genetics, Millennium Pharmaceuticals Inc; Honoraria: Seattle Genetics, Millennium Pharmaceuticals Inc; Research Funding: Seattle Genetics. Younes, A: Consultant Advisory Role: BMS, Incyte, Janssen, Genentech, Merck; Honoraria: Genentech, Merck, Millennium Pharmaceuticals Inc, Incyte, BMS, AbbVie; Research Funding: Novartis, J&J, Curis, Roche, BMS. Ansell, S: Research Funding: BMS, Seattle Genetics, Trillium, Affimed, Pfizer, LAM Therapeutics, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Kim, W: Research Funding: Roche, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, J&J, Mundupharma, Kyowa-kirin, Celltrion, DongaN. Flinn, I: Consultant Advisory Role: Abbvie, Seattle Genetics, TG Therapeutics, Verastem; Research Funding: Abbvie, Acerta Pharma, Agios, ArQule, AstraZeneca, BeiGene, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Curis, FORMA Therapeutics, Forty Seven, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma, Merck, MorphoSys AG, Novartis, Pfizer, Pharmacyclics, Portola Pharmaceuticals, Roche, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Teva, TG Therapeutics, Trilium Therapeutics, Unum Therapeutics, Verastem. Pettengell, R: Consultant Advisory Role: CTI Life Sciences Ltd, Immune Design, Pfizer, Roche Ltd, Servier, Millennium Pharmaceuticals Inc, TEVA; Honoraria: CTI Life Sciences Ltd, Immune Design, Pfizer, Roche Ltd, Servier, Millennium Pharmaceuticals Inc, TEVA. Onsum, M: Employment Leadership Position: Seattle Genetics; Stock Ownership: Seattle Genetics. Josephson, N: Employment Leadership Position: Seattle Genetics, Inc.; Stock Ownership: Seattle Genetics, Inc.. Kuroda, S: Employment Leadership Position: Takeda Pharmaceutical Company Limited. Liu, R: Employment Leadership Position: Millennium

Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Miao, H: Employment Leadership Position: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Gautam, A: Employment Leadership Position: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; Stock Ownership: Takeda Pharmaceutical Company Limited. Trepicchio, W: Employment Leadership Position: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Sureda, A: Consultant Advisory Role: Millennium Pharmaceuticals Inc, BMS, Gilead, Novartis; Honoraria: Millennium Pharmaceuticals Inc, BMS, MSD, Gilead, Novartis, Jannssen, Celgene, Sanofi, Roche.

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DOSE DENSE ABVD (DD-ABVD) AS FIRST LINE THERAPY IN EARLY-STAGE UNFAVORABLE HODGKIN LYMPHOMA (HD): RESULTS OF A PHASE II, PROSPECTIVE STUDY BY FONDAZIONE ITALIANA LINFOMI

R. Mazza<fnref n="1" /> | M. Spina² | C. Califano³ | F. Gaudio⁴ |
M. Carella⁵ | U. Consoli⁶ | F. Palombi⁷ |
M. Musso⁸ | A. Pulsoni⁹ | S. Kovalchuk¹⁰ |
M. Bonfichi¹¹ | F. Ricci<fnref n="1" /> | A. Fabbri¹² |
A. Liberati¹³ | M. Rodari¹⁴ | L. Giordano¹⁵ |
M. Balzarotti<fnref n="1" /> | A. Gallamini¹⁶ | U. Ricardi¹⁷ |
S. Chauvie¹⁸ | F. Merli¹⁹ | C. Carlo-Stella²⁰ |
A. Santoro²⁰

<footnote n="1">¹Medical Oncology and Hematology Department, Humanitas Research Hospital, Rozzano-Milano, Italy; ²Medical Oncology Division, Centro Riferimento Oncologico, Aviano, Italy; ³Onco-Hematology Department, A. Tortora Hospital, Pagani, Italy; ⁴Emergency and Transplantation Department, Hematology section, University of Bari, Bari, Italy;
⁵Hematological Consultant, Casa di Cura La Madonnina, Milano, Italy;
⁶Garibaldi Nesima Hospital, Hematology Department, Catania, Italy;
⁷Hematology Department, Regina Elena National Cancer Institute, Roma, Italy; ⁸Onco-Hematology Unit, Casa di Cura "La Maddalena", Palermo, Italy; ⁹Cellular Biotechnologies and Hematology Department, Policlinico Umberto I, Sapienza University, Rome, Italy; ¹⁰Hematology Department, AOU Carreggi, Firenze, Italy; ¹¹Hematology Division, IRCCS Policlinico S. Matteo, Pavia, Italy; ¹²Hematology Unit, AOU Senese, Siena, Italy; ¹³Onco-Hematology Division, S. Maria Hospital, Terni, Italy; ¹⁴Humanitas Research Hospital, Nuclear Medicin Unit, Rozzano-Milano, Italy; ¹⁵Biostatistic Unit, Humanitas Research Hospital, Rozzano, Milano, Italy; ¹⁶Research, Innovation and Statistic Department, Centre Antoine-Lacassagne, Nice, France; ¹⁷Oncology Department, Radiation Oncology, University of Torino, Torino, Italy; ¹⁸Medical Physics Department, S Croce e Carle Hospital, Cuneo, Italy; ¹⁹Hematology Department, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy;</footnote>
²⁰Medical Oncology and Hematology Department, Humanitas University, Rozzano-Milano, Italy

Four cycles of ABVD followed by 30Gy involved site radiotherapy (ISRT) is the standard of care in unfavourable classical Hodgkin lymphoma (HL). Since dose-density might represent an important factor to achieve complete remission and longterm survival, we designed a trial to evaluate dose-dense ABVD (ddABVD) in ptinents (pts) with early unfavourable HL. This prospective, multicentric, phase 2 study enrolled pts aged 18-70 years with newly diagnosed cHL, unfavourable stage I or II (EORTC criteria). Stage IIB bulky were excluded.

Aims of the study were feasibility, safety and efficacy of ddABVD. DdABVD consists of Doxorubicin, Bleomycin, Vinblastine and Dacarbazine used at the same doses of conventional ABVD but is administered on days 1 and 8 every 3 weeks instead of days 1 and 15 every 4 weeks. In the absence of progressive disease (PD) or unacceptable toxicity, 4 cycles of ddABVD followed by ISRT were administered. Interim PET was mandatory after 2 courses (PET2). Pts experiencing PD were shifted to second-line therapy. Feasibility and activity of ddABVD were the primary endpoints of the study. By design, the study was considered feasible if ≤5 out of 52 pts required a dose reduction below 85% of the planned dose. The percentage of PET2 negativity was chosen as the parameter to evaluate its activity.

Between Feb 2012 and Jun 2015, 96 pts were enrolled and evaluated. The feasibility endpoint was achieved with only 4 out of 52 pts requiring a dose reduction greater than 15%. The mean dose intensity in the 96 pts who started ddABVD treatment was 93.7% with only 3 pts unable to complete ddABVD due to toxicity. The activity analysis was performed in all 96 pts. PET-2 was available for 92/96 (95.8%) pts: 79 were PET2 negative (85.9%) and 13 PET2 positive (14.1%). In 4 pts PET2 wasn't performed (3 logistic reasons, 1 switched to standard ABVD due to a SAE at cycle 1). Considering the global outcome of the 96 pts who received at least 1 ddABVD course: 90 pts achieved CR (93.8%), 1 PR (1%), 4 PD (4.2%) and 1 (1%) was without a known disease assessment. With a median followup of 39.9 months (2.1-57.6), median PFS and OS were not reached, at 24 months PFS and OS were 91.5% and 97.9%. No statistically significant differences were observed for PET2 negative and PET2 pts for both 2 years PFS (94.9% vs 84.6%, p:0.260) and OS (98.7% vs 100% a, p:0.560). Most frequent toxicities were haematological. The infection rate was low (infection 8.3% and febrile neutropenia 6.25%); no patient developed cardiac toxicity until now. There was 1 toxic death after cycle 4; 3 pts were discontinued due to toxicity and were switched to standard ABVD or AVD. The study demonstrates the feasibility of ddABVD in early unfavourable cHL which also allows a reduction in overall treatment duration without a significant increase in toxicity. The dose-dense strategy translated in excellent outcome in term of CR rate, PFS, OS with a low rate of PR at 2 years. DdABVD deserves further comparison with conventional ABVD.

**Keywords:** ABVD; chemotherapy; Hodgkin lymphoma (HL).

BRENTUXIMAB-VEDOTIN AND BENDAMUSTINE IS A FEASIBLE AND EFFECTIVE DRUG COMBINATION AS FIRST-LINE TREATMENT OF HODGKIN LYMPHOMA IN THE ELDERLY (HALO TRIAL)

A. Gallamini¹ | J. Schiano de Colella² | J. Viotti³ |

F. Bijou⁴ | A. Rambaldi⁵ | A. Perrot⁶ | C. Patti⁷ |

L. Gastaud⁸ | R. Sorasio⁹ | C. Debaigt¹ |

R. Schiappa³ | E. Chamorey³ | S. Viviani¹⁰ | A. Thyss⁸

¹Clinical Research and Innovation, A. Lacassagne Cancer Center, Nice, France; ²Unité de jour Médicale/Hématologie 4, Institut Paoli Calmettes, Marseille, France; ³Département d'Epidemiologie, de Biostatistiques et des Données de Santé, Centre Antoine Lacassagne, Nice, France;

⁴Oncologie Médicale, Institut Bergonié, Bordeaux, France; ⁵Ematologia, Ospedale Papa Giovanni XXII, Bergamo, Italy; ⁶Service Hématologie et Médecine Interne, CHU Nancy-Brabois, Vandoeuvre Les Nancy, France; ⁷Ematologia, Ospedali Riuniti Villa Sofia e Cervello, Palermo, Italy;

⁸Département d'Oncologie Médicale, Centre Antoine Lacassagne, Nice, France; ⁹Ematologia, Ospedale Sante Croce e Carle, Cuneo, Italy;

¹⁰Dipartimento di Oncologia Medica, Istituto Nazionale Dei Tumori, Milano, Italy

**Background:** Hodgkin Lymphoma (HL) in the elderly is a challenge as standard ABVD failed to achieve long-term disease control as in adults. Bendamustine (Be), and Brentuximab Vedotin (BV), are well-tolerated and effective drugs in relapsing HL, but only preliminary data exist with this combination in 1st line treatment of elderly HL (Evens AM 2018).

**Pts and methods:** A prospective multicenter phase I/II study (HALO study NCT n°02467946) was launched to assess the safety and efficacy of Be given at 90 mg/m2/D1D2 combined with BV at 1.2 mg/kg D1 repeated Q3W for 6 cycles, in 1st line therapy for advanced-stage (IIB-IV) HL patients (pts) aged 60-80 years. A non-decisional FDG-PET after the 2nd cycle (PET-2) was done and assessed using the Lugano criteria. Pts with Progressive Metabolic Disease (PMD) at any time underwent salvage therapy. The study was split up in a phase 1 (12 pts) for feasibility and a phase 2 (48 pts) for efficacy assessment. Secondary endpoint was the efficacy (3-Y PFS and OS) of the regimen

**Results:** The 60 pts required for the study design were enrolled, but only 42 with complete dataset are valuable for analysis. For this group, the mean age was 70 years (62-79), M/F ratio 28/14 and performance status 0 in 19 or 1-2 in 23. Histology was: HL classic NOS 8, nodular sclerosis 24, mixed cellularity 6, and lymphocyte rich 4. Mean Hb value was 12.2 g/dl, WBC 9.63 x 10³/µl, Albumin 36.8 g/l, LDH elevated in 14. The stage was II in 8, III in 13 and IV in 21 pts. B-symptoms were present in 29/42; 16 had no extranodal sites (ENS), 26 ≥1 ENS. IPS was 0-1 in 2, 2-3 in 22, > 3 in 18. Pts frailty was high, as geriatric ADL and IADL functional tests showed