<table><caption>**TABLE 1** Efficacy in Pts With CLL/SLL Who Had Received ≥2 Prior Therapies</caption><thead><tr><th>Endpoint</th><th>DUV N = 95</th><th>OFA N = 101</th></tr></thead><tbody><tr><td>PFS, median, months</td><td>16.4<sup>a</sup></td><td>9.1</td></tr><tr><td>95% CI</td><td>12.0-20.5</td><td>7.9-10.7</td></tr><tr><td>Hazard ratio (95% CI)</td><td>0.4 (0.27-0.59)</td><td></td></tr><tr><td>ORR, %</td><td>78.9<sup>a,b</sup></td><td>38.6</td></tr><tr><td>95% CI</td><td>70.7-87.1</td><td>29.1-48.1</td></tr><tr><td>Odds ratio (95% CI)</td><td>7.28 (3.61-14.67)</td><td></td></tr><tr><td>CR</td><td>0</td><td>0</td></tr><tr><td>PR</td><td>77.9</td><td>38.6</td></tr><tr><td>PRwL</td><td>1.1</td><td>0</td></tr><tr><td>LNRR, %</td><td>88.4<sup>a</sup></td><td>13.9</td></tr><tr><td>95% CI</td><td>82.0-94.9</td><td>7.1-20.6</td></tr></tbody></table>

**Conclusions:** DUV monotherapy had a manageable safety profile and demonstrated significantly improved clinical outcomes over OFA in CLL/SLL pts who had received ≥2 prior therapies, a population in need of additional targeted therapies.

**Keywords:** chronic lymphocytic leukemia (CLL); Duvelisib; PI3K/AKT/mTOR.

**Disclosures:** Flinn, I: Consultant Advisory Role: Abbvie, Seattle Genetics, TG Therapeutics, Verastem Oncology; Research Funding: Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals, Roche, TG Therapeutics, Trillium Therapeutics, Abbvie, ArQuile, BeiGene, Curis, Forma Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem Oncology, Gilead Sciences, AstraZeneca, Juno Therapeutics, Unum Therapeutics, MorphoSys, AG. Davids, M: Consultant Advisory Role: AbbVie, Acerta Pharma, Adaptive Biotechnologies, Astra-Zeneca, Celgene, Genentech, Gilead Sciences, Janssen, MEI Pharma, Merck, Pharmacyclics, Roche, Syros Pharmaceuticals, TG Therapeutics, Verastem; Research Funding: Acerta Pharma, Bristol-Myers Squibb, Genentech, MEI Pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem. Hillmen, P: Consultant Advisory Role: Verastem Oncology; Honoraria: AbbVie, Gilead, Janssen, Roche; Research Funding: AbbVie, Gilead, Janssen, Roche. Montillo, M: Consultant Advisory Role: ABBVIE, JANSSEN; GILEAD, ASTRA ZENECA; Honoraria: ABBVIE, JANSSEN, GILEAD. Kuss, B: Consultant Advisory Role: Roche, AbbVie, Janssen, Mundipharma, Takeda, Gilead, Merck; Honoraria: Roche, AbbVie, Janssen, Mundipharma, Takeda, Gilead, Merck; Other Remuneration: Gilead, Janssen, Roche, AbbVie, Gilead, Janssen. Tam, C: Honoraria: Janssen-Cilag, Abbvie, Novartis, Beigene, Pharmacyclics; Research Funding: Janssen-Cilag, Abbvie. Jäger, U: Consultant Advisory Role: Amgen, Celgene, Abbvie, Roche, Novartis, Gilead Sciences; Honoraria: Amgen, Celgene, Abbvie, Roche, Novartis, Gilead Sciences, AOP Orphan Pharmaceuticals, Bioverativ, Emergent

BioSolutions, Janssen-Cilag, Mundipharma, Sandoz, Takeda, Bristol-Myers Squibb; Research Funding: Novartis, Gilead Sciences, Roche, Abbvie, Bioverativ, Celgene, Infinity Pharmaceuticals, Janssen-Cilag, Takeda, MSD. Ghia, P: Consultant Advisory Role: AbbVie, AstraZeneca, BeiGene, Celgene, Janssen, Gilead, Sunesis; Honoraria: AbbVie, AstraZeneca, BeiGene, Celgene, Janssen, Gilead; Research Funding: AbbVie, Janssen, Gilead, Sunesis, Novartis; Other Remuneration: Gilead. Stilgenbauer, S: Consultant Advisory Role: AbbVie; Amgen; Boehringer Ingelheim; Celgene; Genentech; Genzyme; Gilead Sciences; GlaxoSmithKline; Janssen; Mundipharma; Novartis; Pharmacyclics; Roche; Sanofi; Research Funding: Abbvie; Amgen; Boehringer Ingelheim; Celgene; Genentech; Genzyme; Gilead Sciences; GlaxoSmithKline; Janssen; Mundipharma; Novartis; Pharmacyclics; Roche; Sanofi; Other Remuneration: Abbvie; Amgen; Boehringer Ingelheim; Celgene; Genentech; Genzyme; Gilead Sciences; GlaxoSmithKline; Janssen; Mundipharma; Novartis; Pharmacyclics; Roche; Sanofi. Lustgarten, S: Employment Leadership Position: Verastem Oncology; Stock Ownership: Verastem Oncology. Weaver, D: Employment Leadership Position: Verastem Oncology; Consultant Advisory Role: FemtoDx, Nanogen Therapeutics; Stock Ownership: Verastem Oncology, FemtoDx, Nanogen Therapeutics. Youssoufian, H: Employment Leadership Position: Verastem Oncology; Stock Ownership: Verastem Oncology. Cymbalista, F: Consultant Advisory Role: Abbvie; Honoraria: Abbvie, Gilead, Roche, Janssen, Sunesis; Research Funding: Sunesis; Other Remuneration: Roche, Janssen, Abbvie Gilead.

## 166 EFFECT OF DOSE MODIFICATIONS ON RESPONSE TO DUVELISIB IN PATIENTS WITH RELAPSED/REFRACTORY CLL/SLL IN THE DUO TRIAL

P. Ghia<fnref n="1" /> | I.W. Flinn² | N. Lamanna<fnref n="3" /> |

M. Montillo⁴ | Á. Illés⁵ | G. Etienne<fnref n="6" /> | J. Delgado<fnref n="7" /> |

B.J. Kuss<fnref n="8" /> | C.S. Tam⁹ | F. Offner¹⁰ | F. Bosch¹¹ |

M.S. Davids¹² | U. Jäger¹³ | F. Cymbalista¹⁴ |

D.T. Weaver¹⁵ | S. Lustgarten¹⁵ | H. Youssoufian¹⁵ |

S. Stilgenbauer¹⁶

<footnote><sup>a</sup>Statistically significant (P<.0001).</footnote>

<footnote><sup>b</sup>Includes CR, CRi, PR, and PRwL per iwCLL/revised IWG criteria.</footnote>

<footnote n="1">¹Division of Experimental Oncology, Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy; ²Lymphoma Research, Sarah Cannon Research Institute, Nashville, TN, United States;</footnote>

<footnote n="3">³Department of Medicine Division of Hematology/Oncology, New York Presbyterian, Columbia University Medical Center, New York, NY, United States; ⁴Department of Haematology and Oncology, Niguarda Cancer Center, Niguarda Hospital, Milan, Italy; ⁵Department of Hematology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;</footnote>

<footnote n="6">⁶Hematology Department, Institut Bergonie, Bordeaux, France;</footnote>

<footnote n="7">⁷Department of Hematology, Hospital Clinic, Barcelona, Spain;</footnote>

<footnote n="8">⁸Molecular Medicine and Pathology, Flinders Medical Centre-Flinders University, Bedford Park, Australia; ⁹Division of Hematology and Oncology, Peter MacCallum Cancer Centre, St Vincent's Hospital and</footnote>
University of Melbourne, Melbourne, Australia; ¹⁰Hematology, University Hospital Ghent, Gent, Belgium; ¹¹Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain; ¹²Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; ¹³Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Wien, Austria; ¹⁴Laboratoire d'hématologie, Hôpital Avicenne, Paris, France; ¹⁵Medical Affairs, Verastem Oncology, Needham, MA, United States; ¹⁶Department III of Internal Medicine, University Hospital Ulm, Ulm, Germany

**Introduction:** Duvelisib (DUV), a first-in-class oral dual PI3K-δ,γ inhibitor, is approved for treatment of relapsed/refractory (R/R) CLL/SLL after ≥ 2 prior therapies. In the phase 3 DUO trial, DUV 25 mg BID significantly improved efficacy vs ofatumumab (OFA; mPFS, 13.3 vs 9.9 mo; HR, 0.52 [P < .0001]; ORR, 74% vs 45% [P < .0001]) in pts with R/R CLL/SLL (Flinn et al. *Blood* 2018). Treatment-emergent AEs (TEAEs) of special interest (AESIs) such as infections, diarrhea, colitis, neutropenia, rash, ALT/AST elevation, and pneumonitis, were moderate and manageable with early intervention and dose modification. We examined dose-modification patterns and their impact on response to DUV in the DUO trial.

**Methods:** TEAEs were assessed according to the NCI CTCAE v4.03. Dose interruptions (DI) or reductions (DR) to 15, 10, or 5 mg BID were permitted per study protocol to manage TEAEs. Responses were assessed by an independent review committee before and after dose modifications and were analyzed using descriptive statistics.

**Results:** Among 158 DUV-treated pts, median duration of DUV exposure was 11.6 mo (vs 5.3 mo, OFA). DI and DR occurred in 80% (126/158) and 27% (43/158) of pts, respectively. The most common cause of DI was diarrhea (23%), followed by neutropenia (12%) and pneumonia or colitis (11% each). Among responders (n = 118), median time to first response on DUV was 1.9 mo and estimated median duration of response was 11.1 mo. Median time to first DI was 3.9 mo and median duration of DI was 15 d (range, 1-133 d). Response to DUV was improved or maintained in most pts evaluated for response who had ≥ 1 DI for > 1 wk (84% [42/50]) or > 2 wk (82% [31/38]) followed by ≥ 3 wk on DUV. In a landmark analysis, median PFS was similar in pts with DI and those without DI for > 1 wk (17.8 vs 16.3 mo) or > 2 wk (17.8 vs 16.3 mo) within the first 3 mo. The median time to DR after CR/PR was 5.6 mo (n = 25) and median duration was 3.4 mo. Median time to onset across AESIs after starting DUV ranged from 2.2 to 4.3 mo; median time to resolution was within 4 wk across AESIs. Proportions of pts experiencing AESIs were stable or decreased over time after 3-6 mo: 0-3 mo, 64% (101/158); > 3-6 mo, 63% (86/137); > 6-9 mo, 47% (54/114); > 9-12 mo, 52% (52/100), and seldom led to discontinuation of DUV (≤ 10%).

**Conclusions:** DI/DR can contribute to the effective management of TEAEs with DUV. These findings suggest that DI of > 1-2 weeks or more do not appear to significantly impact response to DUV or PFS.

**Keywords:** chronic lymphocytic leukemia (CLL); PI3K/AKT/mTOR; small lymphocytic lymphoma (SLL).

**Disclosures:** Ghia, P: Consultant Advisory Role: Abbvie, AstraZeneca, BeiGene, Celgene, Janssen, Gilead Sciences, Sunesis Pharmaceuticals; Honoraria: Abbvie, AstraZeneca, BeiGene, Celgene, Janssen, Gilead Sciences; Research Funding: Abbvie, Janssen, Gilead Sciences, Sunesis Pharmaceuticals, Novartis; Other Remuneration: Gilead Sciences. 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, Pharmacyclics, Pfizer, Portola Pharmaceuticals, Roche, Takeda, Teva, TG Therapeutics, Trilium Therapeutics, Unum Therapeutics, Verastem. Lamanna, N: Consultant Advisory Role: Celgene, Genentech, Abbvie, ProNAi, Pharmacyclics, Juno Therapeutics, Roche; Research Funding: Genentech/Abbvie, Abbvie, Infinity Pharmaceuticals, Gilead Sciences, ProNAi. Montillo, M: Consultant Advisory Role: Abbvie, Janssen, Gilead Sciences, AstraZeneca; Honoraria: Abbvie, Janssen, Gilead Sciences. Illés, Á: Research Funding: Novartis, Roche, Abbvie. Etienne, G: Consultant Advisory Role: Bristol-Myers Squibb, Pfizer, Incyte, Novartis; Other Remuneration: Pfizer, Novartis, Incyte, Bristol-Myers Squibb. Kuss, B: Consultant Advisory Role: Roche, Abbvie, Janssen, Mundipharma, Takeda, Gilead Sciences, Merck; Honoraria: Roche, Abbvie, Janssen, Mundipharma, Takeda, Gilead Sciences, Merck; Other Remuneration: Gilead Sciences, Janssen, Roche, Abbvie. Tam, C: Honoraria: Janssen-Cilag, Abbvie, Novartis, Beigene, Pharmacyclics; Research Funding: Janssen-Cilag, Abbvie. Bosch, F: Consultant Advisory Role: Roche, Abbvie, Janssen, Novartis, Gilead Sciences, AstraZeneca; Honoraria: Roche, Abbvie, Janssen, Novartis, Gilead Sciences; Research Funding: Roche, Abbvie, Janssen, Novartis, Gilead Sciences, AstraZeneca; Other Remuneration: Roche, Abbvie, Janssen, Novartis, Gilead, AstraZeneca. Davids, M: Consultant Advisory Role: Genentech, Janssen, Pharmacyclics, TG Therapeutics, Abbvie, Merck, AstraZeneca, Celgene, MEI Pharma, Acerta Pharma, Adaptive Biotechnologies, Gilead Sciences, Roche, Syros Pharmaceuticals, Verastem; Research Funding: Genentech, TG Therapeutics, Pharmacyclics, Bristol-Myers Squibb, Surface Oncology, MEI Pharma, Acerta Pharma, Verastem; Other Remuneration: TG Therapeutics. Jäger, U: Consultant Advisory Role: Amgen, Celgene, Abbvie, Roche, Novartis, Gilead Sciences; Honoraria: Amgen, Celgene, Abbvie, Roche, Novartis, Gilead Sciences, AOP Orphan Pharmaceuticals, Bioverativ, Emergent BioSolutions, Janssen-Cilag, Mundipharma, Sandoz, Takeda, Bristol-Myers Squibb; Research Funding: Novartis, Gilead Sciences, Roche, Abbvie, Bioverativ, Celgene, Infinity Pharmaceuticals, Janssen-Cilag, Takeda, MSD. Cymbalista, F: Consultant Advisory Role: Abbvie; Honoraria: Abbvie, Gilead Sciences, Roche, Janssen, Sunesis Pharmaceuticals; Research Funding: Sunesis Pharmaceuticals; Other Remuneration: Roche, Janssen, Abbvie, Gilead Sciences. Weaver, D: Employment Leadership Position: Verastem Oncology, Agios; Consultant Advisory Role: FemtoDX, Nanogen; Stock Ownership: Verastem Oncology, Agios, FemtoDX, Nanogen; Other Remuneration: Patent Verastem, Patent Ovascience, Patent Agios. Lustgarten, S: Employment Leadership Position: Verastem Oncology, ARIAD/Takeda; Stock Ownership: Verastem Oncology, ARIAD/Takeda. Youssoufian, H: Employment Leadership Position: Verastem Oncology, BIND Therapeutics;
Consultant Advisory Role: Verastem Oncology; Stock Ownership: Verastem Oncology; Other Remuneration: Verastem Oncology. Stilgenbauer, S: Consultant Advisory Role: Abbvie, AstraZeneca, Celgene, Gilead Sciences, GSK, Hoffmann La-Roche, Janssen; Honoraria: Abbvie, AstraZeneca, Celgene, Gilead Sciences, GSK, Hoffmann La-Roche, Janssen; Research Funding: Abbvie, AstraZeneca, Celgene, Gilead Sciences, GSK, Hoffmann La-Roche, Janssen; Other Remuneration: Abbvie, AstraZeneca, Celgene, Gilead Sciences, GSK, Hoffmann La-Roche, Janssen.

# 167 PATTERN OF DUVELISIB-INDUCED LYMPHOCYTOSIS IN PATIENTS WITH R/R CLL OR SLL INCLUDING THOSE WITH HIGH-RISK FACTORS TREATED IN THE DUO TRIAL

J. Barrientos¹ | I. Flinn² | M.S. Davids³ |

A. Cashen⁴ | N. Chiorazzi⁵ | S. Chen⁵ | S. Hidy⁶ |

J. Pachter⁶ | S. Lustgarten⁶ | D.T. Weaver⁶ | J. Brown³

¹Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY, United States; ²Lymphoma Research, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, United States; ³Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; ⁴Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States; ⁵Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Manhasset, NY, United States; ⁶Medical Affairs, Verastem Oncology, Needham, MA, United States

**Background:** Although lymphocytosis is a defining feature of chronic lymphocytic leukemia (CLL), it is also recognized as a class effect of treatment with B-cell receptor pathway inhibitors. Duvelisib (DUV) is a first-in-class, oral, dual PI3K-δ,γ inhibitor approved for the treatment of pts with relapsed/refractory (R/R) CLL or small lymphocytic lymphoma (SLL) who have received ≥2 prior therapies (Flinn et al. ICHM 2019). In the phase 3 multicenter DUO trial, DUV 25 mg twice daily (BID) showed a significant improvement in efficacy vs ofatumumab (mPFS, 13.3 vs 9.9 mo; HR, 0.5 [P<.0001]; ORR, 74% vs 45% [P<.0001]) with a manageable safety profile (Flinn et al. Blood. 2018). In preclinical studies using CLL cells from pts transferred into mice, dual PI3K-δ,γ inhibition was more effective than PI3K-δ inhibition alone in reducing CLL cell burden (Chen et al. ASH 2018). Herein we aim to characterize the pattern of DUV-related lymphocytosis in the DUO trial.

**Methods:** Lymphocytosis was defined as an absolute lymphocyte count (ALC) of ≥5×10⁹/L and a ≥50% increase of ALC from baseline (BL). ALC measured by local laboratories to determine peak ALC, median time to 50% reduction from BL ALC, and median time to onset (TTO) and resolution (TTR) of lymphocytosis. Median TTR was defined as ALC at or below the BL value or ALC of <5×10⁹/L, whichever occurred first. Data were summarized using descriptive statistics,

including medians for continuous variables and proportions for discrete variables.

**Results:** Of 158 pts treated with DUV, 78% experienced lymphocytosis. Median ALC at BL was 41.1×10⁹/L (range, 0.2-381.7). Median TTO of lymphocytosis was 1 wk across all pts, including high-risk pts. Median TTR of lymphocytosis (<5×10⁹/L or BL) was 14 wk (Figure; solid arrow), with a 50% reduction from BL ALC at 21 wk (Figure; dashed arrow). Similar results were observed regardless of high-risk status: del(17p)/TP53 (n = 48 [30%]), 14 wk; del(11q) (n = 38 [24%]), 18 wk; bulky disease (n = 74 [47%]), 11 wk; unmutated IGHV (n = 110 [70%]), 13 wk. Rapid shrinkage of lymph nodes was noted, with 86% of pts achieving lymph node response. Among pts who achieved a response with DUV at first or second assessment, 78% and 86%, respectively, experienced lymphocytosis; median TTR of lymphocytosis in these pts was 12 and 18 wk, respectively. Prolonged lymphocytosis (for >12 mo) occurred in 12 pts (8%). The ORR in pts with prolonged lymphocytosis was 83%. Of note, the median PFS was similar among pts with and those without prolonged lymphocytosis (22.1 mo [95% CI, 12.9-27.6]) vs [24 mo [95% CI, 20.5-NE], respectively].

**Conclusion:** DUV monotherapy induces rapid and transient lymphocytosis temporally associated with a reduction in lymphadenopathy in pts with R/R CLL/SLL. Notably, DUV resulted in a deep and prolonged resolution of lymphocytosis to >50% below BL. The pattern of lymphocytosis in high-risk pts was similar to that in the general pt population.

**Keywords:** chronic lymphocytic leukemia (CLL); Duvelisib; PI3K/AKT/mTOR.

**Disclosures:** Barrientos, J: Consultant Advisory Role: Pharmacyclics/Abbvie, Genentech, Gilead; Honoraria: Janssen. Flinn, I: Consultant Advisory Role: Abbvie, Seattle Genetics, TG Therapeutics, Verastem Oncology; Research Funding: Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals, Roche, TG Therapeutics, Trillium Therapeutics, Abbvie, ArQule, BeiGene, Curis, Forma Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem Oncology, Gilead Sciences, AstraZeneca, Juno Therapeutics, Unum Therapeutics, MorphoSys, AG. Davids, M: Consultant Advisory Role: AbbVie, Acerta Pharma, Adaptive Biotechnologies, AstraZeneca, Celgene, Genentech, Gilead Sciences, Janssen, MEI Pharma, Merck, Pharmacyclics, Roche, Syros Pharmaceuticals, TG Therapeutics, Verastem; Research Funding: Acerta Pharma, Bristol-Myers Squibb, Genentech, MEI Pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem. Cashen, A: Consultant Advisory Role: Verastem Oncology. Chiorazzi, N: Other Remuneration: Verastem Oncology. Chen, S: Research Funding: Verastem Oncology. Hidy, S: Employment Leadership Position: Verastem Oncology. Pachter, J: Employment Leadership Position: Verastem Oncology; Stock Ownership: Verastem Oncology. Lustgarten, S: Employment Leadership Position: Verastem Oncology; Stock Ownership: Verastem Oncology. Weaver, D: Employment Leadership Position: Verastem Oncology; Consultant Advisory Role: FemtoDx, Nanogen Therapeutics; Stock Ownership: Verastem, FemtoDx, Nanogen Therapeutics. Brown, J: Consultant Advisory Role:
<figure><img src="image_122.png" /></figure>

Note: The upper CI for ALC at 24 months exceeds 125%

Abbvie, Acerta, Beigene, Genentech/Roche, Gilead, Juno/Celgene, Kite, Loxo, Novartis, Pfizer, Pharmacyclics, Sunesis, TG Therapeutics, Verastem Oncology; Honoraria: Janssen, Teva; Research Funding: Gilead, Loxo, Sun, Verastem Oncology; Other Remuneration: Morphosys, Invectys.

168
BRIEF CO-ADMINISTRATION OF
IDELALISIB MAY IMPROVE THE LONG-
TERM EFFICACY OF FRONTLINE
CHEMOIMMUNOTHERAPY IN CHRONIC
LYMPHOCYTIC LEUKAEMIA: 3-YEAR
FOLLOW-UP FROM THE RIALTO TRIAL

A. Pettitt<fnref n="1" /> | N. Kalakonda<fnref n="1" /> | S. Cicconi² |
C. Murphy² | G. Menon³ | S.E. Coupland<fnref n="1" /> |
M. Oates<fnref n="1" /> | K. Lin⁴ | C. Pocock⁵ | S. Jenkins⁶ |
A. Schuh⁷ | F. Wandroo⁸ | S. Rassam⁹ |
A.S. Duncombe¹⁰ | P. Cervi¹¹ | S. Paneesha¹² |
M. Aldouri¹³ | C. Fox¹⁴ | C. Knechtli¹⁵ |
M. Hamblin¹⁶ | D. Turner¹⁷ | P. Hillmen¹⁸

Hospital, Haematology Unit, Dudley, United Kingdom; ⁷Department of
Oncology, University of Oxford, Oxford, United Kingdom; ⁸Department of
Haematology, Sandwell Hospital, Birmingham, United Kingdom;
⁹Department of Haematology, Maidstone Hospital, Maidstone, United
Kingdom; ¹⁰Department of Haematology, University Hospital
Southampton, Southampton, United Kingdom; ¹¹Department of
Haematology & Blood Transfusion, Southend Hospital, Southend, United
Kingdom; ¹²Department of Haematology, Heartlands Hospital,
Birmingham, United Kingdom; ¹³Department of Haematology, Medway
Maritime Hospital, Gillingham, United Kingdom; ¹⁴Department of Clinical
Haematology, Nottingham University Hospitals NHS Trust, Nottingham,
United Kingdom; ¹⁵Department of Clinical Haematology, Royal United
Hospital, Bath, United Kingdom; ¹⁶Department of Haematology,
Colchester General Hospital, Colchester, United Kingdom; ¹⁷Oncology
Unit, Torbay Hospital, Torquay, United Kingdom; ¹⁸Faculty of Medicine
and Health, University of Leeds, Leeds, United Kingdom

**Introduction:** The Phase 3 RIALTO trial opened in December 2011 to compare ofatumumab plus chlorambucil (O+C) with ofatumumab plus bendamustine (O+B) in patients with previously untreated chronic lymphocytic leukaemia (CLL) considered unfit for FCR (fludarabine, cyclophosphamide, rituximab). The protocol was amended in September 2014 to investigate the addition of idelalisib (first-in-class inhibitor of the p110δ isoform of phosphoinositol-3 kinase) or placebo. However, all idelalisib/placebo treatment was withdrawn from the trial in March 2016 following safety analysis of idelalisib registration studies and recommendations from Gilead Sciences Ltd and regulatory authorities. Here, we present an updated ad-hoc analysis of the cohort of patients in RIALTO who received idelalisib or placebo.

<footnote n="1">¹Molecular and Clinical Cancer Medicine, University of Liverpool,
Liverpool, United Kingdom; ²CR-UK Liverpool Cancer Trials Unit,
University of Liverpool, Liverpool, United Kingdom; ³Liverpool Clinical
Laboratories, Haemato-Oncology Diagnostic Service, Liverpool, United
Kingdom; ⁴Liverpool Clinical Laboratories, Department of Blood Sciences,
Liverpool, United Kingdom; ⁵Department of Haematology, Kent &
Canterbury Hospital, Canterbury, United Kingdom; ⁶Russells Hall</footnote>
<figure><img src="image_123.png" /></figure>

**Methods:** Patients were eligible for inclusion if they had previously untreated CLL requiring treatment by NCI/IWCLL criteria, were considered unfit for FCR and did not have any contraindications to the study drugs. Consenting patients underwent an unblinded 1:1 randomisation to ofatumumab (300mg iv day 1 and 1000mg iv day 8 of cycle 1; 1000mg iv day 1 of cycle 2 onwards) plus either chlorambucil (10mg/m² day 1-7, repeated every 28 days for 3-12 cycles) or bendamustine (70mg/m² iv day 1-2 for 3-6 cycles) and a double-blinded 1:1 randomisation to concurrently administered placebo or idelalisib (150mg bd for up to 3 years). Co-trimoxazole prophylaxis was recommended. Study drugs were discontinued in the event of disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). The mandatory post-treatment reporting period for serious adverse events (SAEs) was 6 months for grade ≥3 infections and 28 days for other events.

**Results:** 145 patients received idelalisib (73) or placebo (72), the two arms being well balanced for age, gender, stage, co-morbidity, performance status and chemotherapy allocation. The median idelalisib exposure time was 3.3 months (IQR 1.2-7.3 months). As of January 2019, SAEs were reported in 79% of idelalisib-treated patients (87 grade 3-4 and 9 grade 5) compared to 50% of the placebo arm (38 grade 3-4 and 6 grade 5). The frequency of SAEs in the idelalisib arm was similar in both chemotherapy groups. After a median follow-up of 41.7 months (IQR 36.2-45.4 months), 28 PFS events have been reported in the idelalisib arm compared with 39 in the placebo arm (P = 0.070, log-rank test), while 10 and 16 deaths have been observed in the idelalisib and placebo arms, respectively (P = 0.218, log-rank test). Although 6-month mortality in the idelalisib arm was twice that of the placebo arm, only 2 deaths have been reported beyond 6 months in the idelalisib arm compared with 12 in the placebo arm.

**Conclusions:** The early toxicity associated with the addition of idelalisib to frontline chemoimmunotherapy in CLL appears to be offset by improved long-term efficacy.

**Keywords:** chronic lymphocytic leukemia (CLL); idelalisib; ofatumumab.

**Disclosures:** Pettitt, A: Research Funding: Celgene, Chugai, Gilead, GSK/Novartis, Roche, Verastem; Other Remuneration: Celgene, Gilead.

**Kalakonda, N:** Research Funding: Celgene. Schuh, A: Consultant Advisory Role: Gilead, Abbvie, Janssen, Roche; Honoraria: Gilead, Abbvie, Janssen, Roche; Research Funding: Gilead and Janssen. Duncombe, A:

Honoraria: Abbvie, Novartis, Gilead, Janssen. Paneesha, S: Honoraria: Speaker Fee Janssen, Gilead, Abbvie. Fox, C: Consultant Advisory Role:

Abbvie, Adienne, Celgene, Gilead, Janssen, Roche, Takeda, Sunesis, Atarabio; Honoraria: Abbvie, Adienne, Celgene, Gilead, Janssen, Roche, Takeda, Sunesis, Atarabio; Research Funding: Abbvie, Adienne, Gilead,

Roche. Hamblin, M: Honoraria: Roche. Hillmen, P: Honoraria: Janssen, Abbvie, Roche; Research Funding: Janssen, Pharmacyclics, Abbvie,

Roche, Gilead.

<footnote n="1">¹3rd Medical Department, Paracelsus Medical University, Salzburg, Austria; ²Dept. Internal Medicine I, Medical University Vienna, Vienna, Austria; ³Dept. Hematology, University Hospital Essen, Essen, Germany; ⁴3rd Medical Department for Hematology and Oncology, Hanusch</footnote>
Hospital Vienna, Vienna, Austria; ⁵Dept. Internal Medicine V, Medical University Innsbruck, Innsbruck, Austria; ⁶Department of Haematology, University of Cambridge, Cambridge, United Kingdom; ⁷Service d'Hématologie, IUCT-Oncopole, Toulouse, France

**Introduction:** Kinase inhibitors (KI) rapidly changed treatment paradigms in CLL and ibrutinib currently enters clinical standards in previously untreated patients. Thus, the prevailing “treat-until-progression” concept will lead to very long treatment durations or a need for drug cessation. However, explored stopping rules largely rely on MRD negativity, rarely achieved with KI. Outcomes in lineages after KI are reported mostly on patients that received immediate salvage treatment. However, in real-life experiences a large proportion of discontinuations of KI in CLL treatment happen due to toxicity and patient decisions rather than progression and often happen in meaningful clinical remission due to the KI, but without achieving MRD negativity. Their fate in a treatment-free observation setting is unknown.

**Methods:** We here report a first real-world cohort of CLL patients that had received ibrutinib or idelalisib in different lines of treatment, that had achieved measurable response, suffered toxicities or made decisions to stop therapy and remained in unmaintained (i.e. untreated) observation after discontinuing the kinase inhibitor. Retrospective analyses from chart review in 7 academic centres were performed.

**Results:** We report on 54 patients, treated with either ibrutinib (n = 29) or idelalisib (n = 25). Median age was 74 years at the start of the novel drug and the median number of treatments prior to KI was 1 (range 0 to 6). The median duration on KI was 8 months before stopping due to toxicity (n = 49) or patient's decision (n = 5). Expectedly, the most important toxicities leading to drug cessation were cardiac events, infection and bleeding for ibrutinib and gastrointestinal events, as well as skin and hepatic toxicity for idelalisib. FISH cytogenetics were available in 51 and mutation states in 42 patients. Twenty patients had del17p and 13 had del11q. Eleven patients stopped treatment in CR and 43 achieved PR. Median PFS after treatment cessation was 9.4 months, median TTNT was 12 months and OS was 62% at a median observation time of 27 months. PFS and TTNT at 2a were 19 and 27%, respectively. No differences were observed between the two drugs in PFS and TTNT, but the idelalisib cohort had a significantly better OS (median n.r. vs 20 mo, p = .002) in our cohort. PFS, TTNT and OS were not significantly different by FISH risk, while unmutated IgVH predicted earlier progression, but not OS. Despite low numbers in some groups, the type of toxicity had no apparent large effect on outcome. While the line of treatment did not affect PFS or OS, achievement of CR showed better PFS, but not OS.

**Conclusion:** Treatment cessation in CR or PR after kinase inhibitor treatment is associated with limited median PFS, but some patients experience prolonged treatment free intervals. Exploratory analyses point to clinical response quality and mutational state as predictors of PFS. OS from stop of kinase inhibitor was respectable for this elderly cohort, suggesting available salvage options.

**Keywords:** chronic lymphocytic leukemia (CLL); ibrutinib; idelalisib.

**Disclosures:** **Egle, A:** Consultant Advisory Role: Janssen, Gilead; Honoraria: Janssen, Gilead. **Jäger, U:** Consultant Advisory Role: Janssen and Gilead; Honoraria: Janssen and Gilead; Research Funding: Janssen and Gilead. **Nösslinger, T:** Consultant Advisory Role: Janssen and Gilead; Honoraria: Janssen and Gilead.

## INDOLENT LYMPHOMAS

# 170 LONG TERM FOLLOW-UP OF FoRT: A PHASE 3 MULTI-CENTER PROSPECTIVE RANDOMIZED TRIAL OF RADIATION THERAPY FOR FOLLICULAR AND MARGINAL ZONE LYMPHOMA

P. Hoskin¹ | A. Kirkwood² | B. Popova² |

O. Schofield² | C. Brammer³ | M. Robinson⁴ |

M. Brunt⁵ | M. Krishnaswamy⁶ | T. Illidge⁷ |

E. Gallop-Evans⁸ | I. Syndikus³ | L. Clifton-Hadley²

¹Cancer Centre, Mount Vernon Cancer Centre and University of Manchester, Northwood, United Kingdom; ²Cancer Research UK & UCL Cancer Trials Centre, University College London, London, United Kingdom; ³Cancer Centre, Clatterbridge Cancer Centre, Wirral, United Kingdom; ⁴Radiotherapy, Weston Park Hospital, Sheffield, United Kingdom; ⁵Cancer Centre, Royal Stoke University Hospital & Keele University, Stoke-on-Trent, Staffordshire, United Kingdom; ⁶Oncology, Southend University Hospital, Westcliff-on-Sea, United Kingdom; ⁷Manchester Cancer Research Institute, University of Manchester, Manchester, United Kingdom; ⁸Velindre Hospital, Velindre Cancer Centre, Cardiff, United Kingdom

**Introduction:** The FoRT trial was a prospective multi-center non-inferiority study designed to compare 24 Gy in 12 fractions with 4 Gy in 2 fractions. The initial analysis with a median follow-up of 26 months, showed that 24Gy resulted in significantly better local progression free survival than 4Gy. This data has now been updated with a median follow up of 73.8 months.

**Methods:** Patients requiring local radiation therapy for FL with either palliative or radical intent were eligible, and patients with marginal zone lymphoma (MZL) were also included later in the study. The primary endpoint was time to local progression, with overall survival, quality of life and toxicity as secondary endpoints.

**Results:** A total of 614 treatment sites in 548 patients were randomized. 299 were randomized to receive 24 Gy and 315 to 4 Gy. Median age was 66 years (25-95); 86.3% were diagnosed with FL and the remainder MZL. Treatment intent was curative in 40% and palliative in 60%. Stage at randomisation was: stage I (42.6%), stage II (17.6%), stage III (18.1%), stage IV (10.4%), stage unknown (10.9%). FLIPI index was: low (49.5%), intermediate (24.9%), high (15.6%), missing (9.9%).
<figure><img src="image_124.png" /></figure>

24.6% had received previous radiation therapy and 33.7% previous chemotherapy.

With a median follow up of 73.8 months the local progression free survival at 3 years was 90.9% after 24Gy and 74.6% after 4Gy; the corresponding rates at 5 years are 89.9% after 24Gy and 74.4% after 4Gy; at the median follow up of 73.8 months the rates are 89.3% and 68% (Hazard ratio (HR): 3.46 (95% CI: 2.25 – 5.33, p<0.001)- see figure below.

There remains no difference in overall survival (HR: 1.03 (0.74 – 1.43, p = 0.86). Median time to local progression has not been reached but for patients who had local progression these occurred at a median time of 19.3 months (range: 1.3 – 65.0) for sites treated with 24 Gy and 11.7 months (range: 0.9 – 88.3) for sites treated with 4Gy. In the subgroup treated with curative intent there were 5/119 relapses after 24Gy and 29/129 after 4Gy: HR: 5.80 (2.25 – 14.99) p<0.0001.

**Conclusions:** Whilst 4 Gy in 2 fractions can be effective in the palliative setting, it is significantly inferior to 24 Gy in 12 fractions. This difference is maintained with long term follow up and is greatest in patients treated with radical intent. 24Gy in 12 fractions should remain the schedule of choice for curative radiation therapy in follicular or marginal zone lymphoma.

**Keywords:** follicular lymphoma (FL); indolent lymphoma; marginal zone lymphoma (MZL).

# 171
## SYSTEMIC THERAPY AFTER RADIATION THERAPY IN STAGE I-II FOLLICULAR LYMPHOMA: FINAL RESULTS OF AN INTERNATIONAL RANDOMIZED TRIAL TROG 99.03

M.P. MacManus<fnref n="1" /> | R. Fisher<fnref n="1" /> | D. Roos² |

P. O'Brien³ | A. Macann⁴ | R. Tsang⁵ | S. Davis⁶ |

D. Christie⁷ | B. McClure<fnref n="1" /> | D. Joseph⁸ | J. Seymour⁹

Australia; ³Radiation Oncology, GenesisCare Lake Macquarie Private Hospital, Gateshead, Australia; ⁴Radiation Oncology, Auckland City Hospital, Auckland, New Zealand; ⁵Radiation Oncology, Princess Margaret Hospital, Toronto, Canada; ⁶Radiation Oncology, Alfred Hospital, Melbourne, Australia; ⁷Radiation Oncology, Genesis Care Premion, Southport, Australia; ⁸Radiation Oncology, Sir Charles Gairdner Hospital, Perth, Australia; ⁹Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia

**Aim:** The first analysis of the TROG 99.03 randomized controlled trial of curative-intent involved-field radiotherapy (IFRT) with or without systemic therapy reported improved progression-free survival (PFS) by the addition of systemic therapy, especially with rituximab. We present the final analysis of that study.

**Patients and Methods:** Patients from Australia, New Zealand and Canada with stage I-II FL of grade 1, 2 or 3a were enrolled after CT scans and bone marrow biopsies. Patients were randomized to either; Arm A: 30Gy IFRT alone or Arm B: IFRT followed by 6 cycles of cyclophosphamide 1000 mg/m² IV D1, vincristine 1.4 mg/m² D1 and prednisolone 50mg/m² D1-5 (CVP), stratified by center, stage, age and use of PET staging (which was not mandatory). A protocol amendment in 2006 added Rituximab 375 mg/m² D1 to arm B (R-CVP).

**Results:** Between February 2000 and July 2012, 150 patients were recruited: 75 per arm: 44 arm B patients were allocated CVP and 31 R-CVP. Median age was 57 (range 30-79) years, 52% were male, 75% had stage 1 and 48% were PET-staged. Only 8% had an extranodal site (ENS). Median potential follow-up was 11.3 years for this analysis. PFS remained significantly superior for arm B (IFRT + systemic therapy) compared to arm A [HR 0.60 (0.37-0.98); p = 0.043]. At 10 years PFS was 60% for arm B and 43% for arm A. Patients who received R-CVP had substantially superior PFS compared to those who received IFRT alone or with CVP (no rituximab) (83.1% (se = 6.9%) vs 50.4% (se = 4.8%) at 8 years, P = 0.013). In univariable analysis, patients with ENS (p = 0.041), fewer involved nodal regions (p = 0.018) and PET staging (p = 0.086) had improved PFS. When analysis of PFS was confined to 72 PET-staged patients the difference between arms A and B increased (HR 0.38 P = 0.027), whereas analysis confined to 78 non-PET staged patients showed weak evidence of a difference between arms (HR 0.78, P = 0.42). More deaths (Figure) occurred in arm A (13 versus 6), with 10-year overall survival rates of 95.3% (se = 2.7%) and 84.4% (se = 4.9%) for arms B and A respectively (HR 0.45, p = 0.11). One possible and 5 definite transformations to aggressive lymphoma occurred in arm B versus 11 in arm A.

**Conclusion:** Treatment with 6 cycles of CVP or R-CVP after IFRT significantly improved PFS compared to IFRT alone, especially for rituximab-treated patients. Improved PFS was most evident in PET staged patients. More deaths and transformations to high grade lymphoma were observed with IFRT alone and, with more than 10-years of follow-up, OS favors combined modality therapy (P = 0.11).

**Keywords:** follicular lymphoma (FL); positron emission tomography (PET); rituximab.

<footnote n="1">¹Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; ²Radiation Oncology, Royal Adelaide Hospital, Adelaide,</footnote>
<figure><img src="image_125.png" /></figure>

172

RESULTS OF A MULTICENTER PHASE2

TRIAL OF INVOLVED FIELD

RADIOTHERAPY ALONE FOR LOCALIZED

NON-GASTRIC MARGINAL ZONE

LYMPHOMA: TROG 05.02

M.P. MacManus<fnref n="1" />

D. Roos²

P. O'Brien³

R. Tsang⁴

A. Wirth<fnref n="1" />

A. Capp⁵

M. Bressel<fnref n="1" />

J. Seymour⁶

Waratah, Australia; ⁶Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia

**Introduction:** We conducted the first prospective phase 2 multicenter clinical trial to assess the long term efficacy and safety of radiotherapy for localized non-gastric marginal zone lymphoma (MZL) and documented the prevalence of autoantibodies, autoimmune events and *Helicobacter Pylori* (HP) infection in this population.

**Methods:** Eligible patients had untreated stage I or II, or paired-organ confined, non-gastric marginal zone lymphoma. Mandatory investigations included CT and bone marrow aspirate and trephine, autoantibody panel and HP evaluation. FDG-PET was optional. Involved-field or site, conventionally-fractionated radiotherapy was delivered to 30-30.6 Gy, except for orbital MZL which received 24-25 Gy.

**Results:** Six centres enrolled 70 patients. Two patients were ineligible after registration: 68 patients commenced protocol treatment. Median

<footnote n="1">¹Radiation Oncology, Peter MacCallum cancer Centre, Melbourne, Australia; ²Radiation Oncology, Royal Adelaide Hospital, Adelaide, Australia; ³Radiation Oncology, Genesis Care Lake Macquarie Private Hospital, Gateshead, Australia; ⁴Radiation Oncology, Princess Margaret Hospital, Totonto, Canada; ⁵Radiation Oncology, Calvary Mater Hospital,</footnote>
<figure><img src="image_126.png" /></figure>

K.W. Chau¹ | B.S. Imber¹ | E. Joffe² | J.C. Yang³ |
M.R. Chelius⁴ | C.J. Doyle¹ | C. Hajj¹ | J. Yahalom¹

¹Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, United States; ²Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States; ³Department of Radiation Oncology, University of California San Francisco, San Francisco, United States; ⁴Geisel School of Medicine, Dartmouth College, Hanover, United States

**Introduction:** Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are highly radiosensitive and often respond to very low dose radiation therapy (VLDRT). We investigated the outcomes of patients treated with 4 Gy from a large, contemporary, real world cohort, and a subset of potentially curable (PC) patients with early stage disease and no prior therapy before VLDRT.

**Methods:** We analyzed 221 treated sites from 180 consecutive adult patients (Table 1) with FL or MZL who were treated with VLDRT of 2 Gy x 2 fractions between 2006 and 2019 at our center. Initial overall response rate (ORR) was defined as complete response (CR) or partial response (PR) using Lugano radiographic or clinical criteria at 2 months post-RT. Stable disease (SD) or progressive disease (PD) at 2 months post-RT were considered local failure (LF). Freedom from local failure (FFLF) was defined as time from VLDRT to LF. Patients were censored at the start of a subsequent line of therapy if the VLDRT-treated site had not progressed. Event-free survival (EFS) was calculated per patient from VLDRT to LF or distant PD. FFLF and EFS were estimated using Kaplan-Meier and compared using log-rank.

**Results:** Initial ORR for all sites was 90% (CR: 66%, PR: 24%); 10% (n = 23) were initially nonresponding (SD: 6%, PD: 4%). Ten sites with initial PR/SD/PD received additional RT (median: 30 Gy) within 6 months of VLDRT and had subsequent CR (n = 5), PR (n = 4), and PD (n = 1). With median follow-up of 21 months, 2-year FFLF was 73%. Initial response to VLDRT was prognostic since the 2-year FFLF for sites with CR (n = 146) was significantly better than those with PR (n = 52) (90% vs. 66%, p<0.001). There was improved 2-year FFLF for nodal vs. extranodal disease (63% vs. 82%, p = 0.02) but not for previously untreated vs. relapsed/refractory (76% vs. 72%, p = 0.4) or early vs. advanced stage sites (73% vs. 73%, p = 0.4).

In the subset of PC patients (n = 48), median follow-up was 11 months with a 1-year EFS of 78%. The majority of PD (n = 11) were distant (73%). Diffuse large B cell lymphoma transformation after VLDRT was rare in the PC (n = 0) and overall (n = 7, 4%) cohort; all were diagnosed out of the VLDRT field.

**Conclusions:** Overall, patients with FL and MZL treated with only 4 Gy have excellent initial ORR. Early evaluation following VLDRT identifies nonresponders who may benefit from additional RT and spares many patients from higher doses of RT with durable local control. Our analysis of PC patients suggests that VLDRT does not compromise the standard RT curative approach.

**Keywords:** follicular lymphoma (FL); indolent lymphoma; marginal zone lymphoma (MZL).

age was 59 (range: 23-84) and 31 (46%) were male. Stage was I n = 55, II n = 9 and IV n = 4. Sites were orbital n = 18, conjunctiva n = 13, lacrimal n = 8, skin n = 8, primary nodal n = 8, salivary n = 7, muscle n = 3 and 15 other extranodal sites with single cases of each. Four patients (6%) had paired organ (salivary or orbital) MZL. Fourteen (21%) were PET-staged. Median follow-up was 5 years (range 0.7 – 9.4). At 7 years, freedom from progression and overall survival were 79% (95% CI: 67-93) (Figure) and 95% (95% CI: 89-100) respectively. One transformation to diffuse large B cell lymphoma occurred. There was one lymphoma-related death and 2 in-field failures (after 25 and 30 Gy respectively). Out-of-field relapse sites were skin (n = 2) duodenum, stomach, paravertebral muscle and conjunctiva. No patient with paired organ disease relapsed. Acute toxicity ≥ grade 3 occurred in 7 cases. Apart from cataracts (n = 18), there were 6 late grade 3 adverse events. Two grade 4 late events (nephrotic syndrome and catheter thrombosis) and two second malignancies were not treatment-related. Autoantibodies or auto-immune events were detected in 26 of 68 (38%) patients. HP infection was detected (and treated) in 15 of 63 patients tested (24%). Neither autoimmunity or HP was detected in 27/68 (40%) patients.

**Conclusions:** Most patients with localized non-gastric MZL had either evidence of autoimmunity or HP infection or both and RT was a highly effective treatment associated with low toxicity and excellent survival.

**Keywords:** extranodal marginal zone lymphoma of MALT type; Helicobacter pylori; marginal zone lymphoma (MZL).
<table><caption>TABLE 1 Characteristics of patients and sites treated with 4 Gy</caption><thead><tr><th>Per patient (n = 180)</th><th>Characteristics</th><th>n</th><th>(%)</th></tr></thead><tbody><tr><td></td><td>Sex</td><td></td><td></td></tr><tr><td></td><td>Female</td><td>86</td><td>(48)</td></tr><tr><td></td><td>Age at VLDRT (years)</td><td></td><td></td></tr><tr><td></td><td>Median</td><td>67</td><td></td></tr><tr><td></td><td>Range</td><td>27-92</td><td></td></tr><tr><th>Per lesion (n = 221)</th><th>Characteristics</th><th>n</th><th>(%)</th></tr><tr><td></td><td>Histology</td><td></td><td></td></tr><tr><td></td><td>FL</td><td>137</td><td>(62)</td></tr><tr><td></td><td>MZL</td><td>65</td><td>(29)</td></tr><tr><td></td><td>Mixed FL and MZL</td><td>19</td><td>(9)</td></tr><tr><td></td><td>Type</td><td></td><td></td></tr><tr><td></td><td>Extranodal</td><td>133</td><td>(60)</td></tr><tr><td></td><td>Nodal</td><td>79</td><td>(36)</td></tr><tr><td></td><td>Mixed</td><td>9</td><td>(4)</td></tr><tr><td></td><td>Stage at VLDRT</td><td></td><td></td></tr><tr><td></td><td>I-II</td><td>145</td><td>(66)</td></tr><tr><td></td><td>Prior treatment</td><td></td><td></td></tr><tr><td></td><td>No</td><td>71</td><td>(32)</td></tr></tbody></table>

Abbreviations: VLDRT, very low dose radiation therapy; FL, follicular lymphoma; MZL, marginal zone lymphoma.

<figure><img src="image_127.png" /><figcaption>Figure 1. Freedom from local failure estimates for sites treated with 4 Gy, stratified by early stage (I-II) vs. advanced stage (III-IV) (A), and initial complete response (CR) vs. partial response (PR) at 2 months follow-up (B).</figcaption></figure>

174
CLONAL B-CELL LYMPHOCYTOSIS OF
MARGINAL ZONE ORIGIN (CBL-MZ):
DESCRIPTION OF MAIN CLINICAL

FEATURES, DISEASE EVOLUTION AND
OUTCOME IN A SERIES OF 100 PATIENTS

C. Kalpadakis¹ | G.A. Pangalis² | E. Konstantinou³ |
T.P. Vassilakopoulos³ | V. Telonis³ | S. Sachanas² |
P. Tsirkinidis² | M. Moschogiannis² | X. Yiakoumis² |
M. Siakantaris³ | P. Tsaftaridis³ | T. Iliakis³ |
M. Befani³ | M. Kyrtsonis⁴ | A. Dimitrakopoulou⁵ |
G. Boutsikas³ | P. Korkolopoulou⁶ | F. Kontopidou⁷ |
E. Koulieris² | C. Pontikoglou¹ | M. Ximeri¹ |
M. Psylaki¹ | M. Roumelioti⁴ | D. Rontogiannis⁸ |
H. Papadaki¹ | P. Panagiotidis⁴ | M.K. Angelopoulou³

¹Department of Haematology, University Hospital, University of Crete, Heraklion, Crete, Greece; ²Department of Haematology, Athens Medical Center, Athens, Greece; ³Department of Haematology, University of Athens, Laikon General Hospital, Athens, Greece; ⁴1st Department of Propedeutics, University of Athens, Laikon General Hospital, Athens, Greece; ⁵Immunology Laboratory, University of Athens, Laikon General Hospital, Athens, Greece; ⁶Department of Pathology, University of Athens, Laikon General Hospital, Athens, Greece; ⁷Second Department of Internal Medicine, Hippokrateio General Hospital, University of Athens, Athens, Greece; ⁸Department of Anatomic Pathology, Evangelismos General Hospital, Athens, Greece

**Introduction:** CBL-MZ has been recognized in WHO classification as a provisional entity. In the present analysis we describe CBL-MZ patients' (pts) characteristics, disease evolution and prognostic factors for outcome after a long follow-up.

**Methods:** Pts were selected based on the presence of circulating CD5-clonal B-cells with MZ features, without B-symptoms, no evidence of disease elsewhere than the bone marrow (BM), and no cytopenias.

**Results:** 100 consecutive pts were analyzed. The median age was 70y (33-90). Referral reasons: incidental lymphocytosis (77%) or paraproteinemia (13%) or inverted differential (10%). Median # of absolute lymphocyte counts (ALCs) and circulating CBL were 6780/µL (1000-150.000) and 3447/µl (185-145.000), respectively. Elevated LDH and paraproteinemia were found in 10% and 38%, respectively. All but one pts presented BM infiltration by small lymphoid cells (median 30%) with an intrasinusoidal pattern in 1/3 of pts. Immunophenotyping revealed positivity for CD23, CD11c and CD38 in 31%, 43% and 11%, respectively. MYD-88 was positive in 9/84 (11%). The presence of paraprotein was significantly associated with MYD-88 positivity (p<0.0001), lower ALCs (p = 0.002) and CBL (p = 0.001) counts, higher frequency of CD38 expression (p = 0.03) and lymphoplasmacytic differentiation in the BM (p = 0.001). The degree of BM infiltration was associated with the level of ALCs (p = 0.003). At a median follow-up time of 42.3 mos, 30 pts progressed but only 10 required treatment. Progression included: worsening lymphocytosis (17%), cytopenias (4%), splenomegaly (5%), nodal MZL (1%) and increase in paraprotein levels (3%). Therefore, five patterns of disease evolution were recognized (Figure).
<figure><img src="image_128.png" /><figcaption>*Primary bone marrow marginal zone lymphoma

Figure. Pattern of progression - clinical evolution of MBL-MZ patients</figcaption></figure>

Treatment was delivered due to cytopenias in 7 pts, symptomatic paraprotein in 1 and bulky splenomegaly in 2. Seven deaths were recorded, one disease related. The median OS was not reached; 5-y time to treatment (TTT) was 91%, and the median time to progression (TTP) 95.6 mos. By univariate analysis ALC ≥median (6780/µL), p = 0.014, CD38+, p = 0.006 and elevated LDH, p<0.0001 were significantly associated with TTP. These factors remained significant at multivariate analysis. We constructed a prognostic model for TTP stratifying pts into 3 risk groups: low-risk - 0 risk factors; intermediate - ALC≥median; high-risk – any of the 2 remaining risk factors or ≥2 factors. Median TTP was 159, 96 and 49 months, for the low-, intermediate and high-risk groups, respectively (p<0.0001). This model was prognostic of TTT, as well, though at a lower level of significance (p = 0.03).

**Summary/Conclusion:** CBL-MZ remain stable in the majority of pts. Progressive disease requiring treatment occurs rarely and it is usually associated with worsening cytopenias. Progression to SMZL was evident in 5%. A prognostic model for TTP using 3 factors was developed: ALCs, LDH and CD38 expression, needing further validation.

**Keywords:** marginal zone lymphoma (MZL); monoclonal B-cell lymphocytosis (MBL).

175
FIRST APPLICATION OF MINIMAL
RESIDUAL DISEASE ANALYSIS IN SPLENIC
MARGINAL ZONE LYMPHOMA TRIALS:
PRELIMINARY RESULTS FROM
BRISMA/IELSG36 PHASE II STUDY

S. Ferrero¹ | M. Ladetto² | K. Beldjord³ |

D. Drandi¹ | C. Stelitano⁴ | S. Bernard³ |

B. Castagnari⁵ | K. Bouabdallah⁶ | M. Cesaretti⁷ |

I. Alvarez⁸ | R. Gressin⁹ | M. Ponzoni¹⁰ |

C. Tripodo¹¹ | A. Traverse-Glehen¹² | L. Baseggio¹³ |

A. Liberati¹⁴ | M. Merli¹⁵ | B. Tessoulin¹⁶ |

C. Patti¹⁷ | M. Cabras¹⁸ | P. Feugier¹⁹ | S. Pozzi²⁰ |

E. Zucca²¹ | E. Iannitto²² | C. Thieblemont³

¹Hematology Division, Università di Torino, Molecular Biotechnologies and Health Sciences, Torino, Italy; ²Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo, SC Ematologia, Alessandria, Italy; ³Hemato-Oncology, Hôpital Saint-Louis, Paris, France; ⁴U.O.C. Ematologia, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy; ⁵UOC of Hematology, Hospital Santa Maria delle Croci, Ravenna, Italy; ⁶CHU Bordeaux, Hematology, Bordeaux, France; ⁷University of Modena and Reggio Emilia, Department of Diagnostic, Clinical and Public Health Medicine, Modena, Italy; ⁸AUSL Reggio Emilia/IRCCS, Arcispedale Santa Maria Nuova, UOC of Hematology, Reggio Emilia, Italy; ⁹Grenoble Alpes University Hospital, Department of Hematology, Grenoble, France; ¹⁰Pathology Unit, Ateneo Vita-Salute and San Raffaele Scientific Institute, Milano, Italy; ¹¹Department of Health Science, Human Pathology Section, Tumor Immunology Unit, University of Palermo, Palermo, Italy; ¹²Pierre-Benite, Pathology CHU Lyon, Lyon, France; ¹³Pierre-Benite, Cytology, CHU Lyon, Lyon, France; ¹⁴University of Perugia, Oncology-Hematology, Santa Maria Hospital, Terni, Italy; ¹⁵ASST Settelaghi, University Hospital Ospedale di Circolo e Fondazione Macchi, Varese, Italy; ¹⁶CHU Nantes, Hematology, Nantes, France; ¹⁷Division of Hematology, Azienda Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy; ¹⁸Ospedale Businco, Division of Hematology, Cagliari, Italy; ¹⁹University Hospital of Nancy, Department of Haematology, Nancy, France; ²⁰Unit of Target Therapy in Onco-Hematology and Osteoncology, University of Modena and Reggio Emilia, Department of Oncology and Hematology, Modena Cancer Center, Modena, Italy; ²¹Institute of Oncology Research, Università della Svizzera Italiana (USI), IOSI, Oncology Institute of Southern Switzerland and IOR, Bellinzona, Switzerland; ²²Department of Oncology, "La Maddalena", Onco-Hematology and BMT Unit, Palermo, Italy

**Introduction:** Although often managed as an indolent disease, splenic marginal zone lymphoma (SMZL) can achieve complete clinical remission if treated with modern chemo-immunotherapy. It might be worthy to assess minimal residual disease (MRD) in SMZL, both to assess the prognosis and evaluate the efficacy of new compounds.

**Methods:** The BRISMA/IELSG36 trial is an international, phase II study (NCT02853370) designed by the Fondazione Italiana Linfomi (FIL) and the French LYmphoma Study Association (LYSA) to evaluate the efficacy of bendamustine and rituximab for six cycles (BR). [Iannitto, BJH 2018]. Between 2013-2014, 56 SMZL patients were enrolled. Bone marrow (BM) and peripheral blood (PB) samples were collected at baseline, after 3 BR (interim), after the last BR (EOT) cycle, respectively and during follow-up (1, 3 and 5 years) for MRD purposes. All patients provided written informed consent in accordance
# RITUXIMAB ALONE (R) VERSUS RITUXIMAB PLUS BENDAMUSTINE (BR) FOR SPLENIC (SMZL) AND NODAL MARGINAL ZONE LYMPHOMA (NMZL)

A.J. Olszewski

T. Ollila

J.L. Reagan

Hematology-Oncology, Brown University, Providence, United States

**Background:** SMZL and NMZL, rare lymphomas diagnosed at median age of 69, are increasingly treated with BR as 1st line therapy, despite limited histology-specific experience and uncertain risk/benefit ratio of BR over R monotherapy in these indolent subtypes. We compared outcomes of R and BR using causal inference methods in population-based data from Medicare beneficiaries.

**Methods:** Using Medicare claims linked to cancer registry (SEER) data from 19 areas of the United States covering about 34% of the population, we identified patients with SMZL/NMZL age ≥65 who received 1st line R or BR between 2009 and 2016. We used a propensity score to balance patient and disease characteristics (including histology, stage, B symptoms, prior splenectomy, anemia, transfusions, hospitalizations, comorbidities, and performance status) between treatment arms. In the resulting pseudo-randomized cohort we then compared time to treatment failure (TTF, defined 2nd line chemotherapy, splenectomy, hospice enrollment, or death), overall survival (OS), risk of major toxicities (hospitalization, transfusions), and Medicare spending.

**Results:** Among 958 eligible patients (median age 77 years, 54% women, 34% SMZL and 66% NMZL), proportion receiving BR (n = 235; 23%) increased from 8% in 2009 to 32% in 2016. BR was used less frequently among patients with age over 70 years, with SMZL, with stage IA lymphoma, and in those treated >3 months from diagnosis. Median TTF for the entire cohort was 4.5 years, and median OS was 5.7 years. In pseudo-randomized cohort balanced with regard to patient and disease characteristics, we did not observe any significant difference between BR and R for either TTF or OS, but toxicities were significantly higher with BR (Table). There was no evidence of a differential effect of the regimens between NMZL and SMZL (interaction P = 0.62 for TTF and 0.96 for OS). Adjusted costs of care were higher for BR than R ($84,003 vs. $53,048, P<.001). A sensitivity analysis for potential unobserved confounding showed that over 50% of BR patients would need to have an unrecorded risk factor doubling their mortality to explain the lack of survival benefit of BR over R.

**Conclusions:** Among older patients with SMZL and NMZL, BR offers no OS or TTF benefit over single-agent R, while it increases hospitalizations, need for transfusions, and costs. Without a formal randomized study (which has not been conducted), single-agent R may offer a

<figure><img src="image_129.png" /><figcaption>Figure 1. MRD analysis plot for BRISMA/IELSG 36 trial. R: relapse/refractory, Ø: out for patient withdraw</figcaption></figure>

with Helsinki's declaration. MRD was assessed both on BM and PB samples by droplet digital PCR, employing IGH-directed ASO primers. [Drandi, JMD 2015]

**Results:** 54/56 patients had at least 1 FU sample available for MRD analysis. A molecular marker was found in 43/54 (80%) cases: hereby, MRD results are reported for 39 patients. Median tumor burden at baseline was 1.45E-01 (range 1 - 2.67E-03) on BM and 4.04xE-01 (1 - 5.60E-03) on PB. MRD negativization rates were 47% at interim (BM: 13/32; PB: 21/36), 54% at EOT (BM: 10/23; PB: 18/22) and 61% after one year (BM: 14/22; PB: 19/29), Figure 1. Median tumor burden shrinkage was 4 logs both at interim and at EOT in BM (2.67E-05) and reached the negativity in PB (1.00xE-08). Three different trends of MRD kinetics were described: A) persistent MRD negativity (n = 16, 41%); B) persistent MRD positivity (n = 12, 31%); C) alternating MRD (n = 11, 28%). Only 6 relapses (based on Cheson 1999 criteria) were recorded so far, 5 of which being in the groups B and C. The median FU is currently 32 months: accordingly many relapses are expected. Three MRD recurrences were detected, so far, that might herald future clinical relapses.

**Conclusion:** This is the first application of MRD in a prospective trial for SMZL, with an overall good feasibility. The MRD trends highlighted the activity of BR in this disease and accurately described the response/relapse patterns. Moreover, MRD recurrences detected during FU might herald late relapse. Therefore, our preliminary results suggest that MRD analysis needs further development in SMZL.

**Keywords:** Bendamustine; minimal residual disease (MRD); splenic marginal zone lymphoma (SMZL).
<table><caption>TABLE 1</caption><thead><tr><th>Outcome</th><th>BR</th><th>R</th><th>Risk ratio</th><th>95% CI</th><th>P</th></tr></thead><tbody><tr><td>TTF at 3y</td><td>65%</td><td>62%</td><td>1.04</td><td>0.80-1.36</td><td>0.78</td></tr><tr><td>OS at 3y</td><td>69%</td><td>71%</td><td>1.15</td><td>0.86-1.54</td><td>0.35</td></tr><tr><td>Anemia</td><td>55%</td><td>38%</td><td>1.46</td><td>1.23-1.73</td><td>&lt;0.0001</td></tr><tr><td>Transfusion</td><td>22%</td><td>9%</td><td>2.50</td><td>1.65-3.78</td><td>&lt;0.0001</td></tr><tr><td>Hospitalization</td><td>37%</td><td>26%</td><td>1.45</td><td>1.14-1.84</td><td>0.0028</td></tr></tbody></table>

<figure><img src="image_130.png" /><figcaption>Fig. 1. OS of patients treated with single-agent R or with BR as first-line regimen for SMZL or NMZL</figcaption></figure>

better risk/benefit ratio as first-line therapy for older patients with these indolent lymphomas.

**Keywords:** Bendamustine; nodal marginal zone lymphoma (NMZL); splenic marginal zone lymphoma (SMZL).

177
POST HOC ANALYSES OF PATIENTS WITH RELAPSED/REFRACTORY MARGINAL ZONE LYMPHOMA WHO RECEIVED LENALIDOMIDE PLUS RITUXIMAB (R²) VS RITUXIMAB/PLACEBO (AUGMENT)

C. Thieblemont<fnref n="1" /> | J. Leonard² | M. Trneny³ |
--- | --- | ---
K. Izutsu⁴ | N. Fowler⁵ | X. Hong⁶ | H. Zhang⁷ |
F. Offner⁸ | A. Scheliga⁹ | G. Nowakowski¹⁰ |
A. Pinto¹¹ | F. Re¹² | L. Fogliatto¹³ |
P. Scheinberg¹⁴ | I. Flinn¹⁵ | C. Moreira¹⁶ |
M. Czuczman¹⁷ | S. Kalambakas¹⁸ | P. Fustier¹⁹ |
C. Wu²⁰ | J. Gribben²¹

Tokyo, Japan; ⁵Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States; ⁶Hematology, Fudan University Shanghai Cancer Center, Shanghai, China; ⁷Hematology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; ⁸Hematology, UZ Gent, Gent, Belgium; ⁹Hematology, INCA Instituto Nacional De Câncer, Rio de Janeiro, Brazil; ¹⁰Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, United States; ¹¹Hematology, Istituto Nazionale Tumori, Fondazione 'G. Pascale', IRCCS, Naples, Italy; ¹²Hematology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; ¹³Hematology, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil; ¹⁴Hematology, Hospital A Beneficência Portuguesa de São Paulo, São Paulo, Brazil; ¹⁵Hematology, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, United States; ¹⁶Hematology, Instituto Português de Oncologia Do Porto Francisco Gentil Epe, Porto, Portugal; ¹⁷Global Clinical R&D Hematology/Oncology, Celgene Corporation, Summit, United States; ¹⁸Global Medical Affairs, Celgene Corporation, Summit, United States; ¹⁹Global Medical Affairs, Celgene International Sarl, Boudry, Switzerland; ²⁰BioStatistics, Celgene Corporation, Summit, United States; ²¹Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom

**Introduction:** Initial AUGMENT study results in R/R FL grade 1-3a and MZL patients showed significantly improved PFS for lenalidomide plus rituximab (R²) over R/placebo overall and in subgroups, with the exception of the MZL histology. Given the small MZL sample size, post hoc analyses of baseline characteristics and univariate/multivariate analyses of PFS were further examined.

**Methods:** The AUGMENT phase III study randomized patients 1:1 to R² (lenalidomide PO 20 mg/d, d1-21/28 X12 cycles (c) plus rituximab IV 375 mg/m²/wk c1 and d1 c2-5) or rituximab-placebo (R/placebo; same dosing schedule). The primary endpoint PFS was evaluated by 2007 IWG (without PET). Post hoc Cox regression models evaluated univariate analysis of one risk factor and multivariate analyses for treatment arm and significant risk factors (P<0.05) from the univariate analyses.

**Results:** Of 358 overall patients, 63 (18%) were MZL, including n = 14/16 MALT, n = 9/6 splenic, and n = 8/10 nodal MZL subtypes for R² and R/placebo arms, respectively. Numerical differences for R² vs R-placebo, respectively, were ECOG PS 0 (55% vs 72%), age (≥65 y: 68% vs 59%; ≥70 y: 42% vs 38%), refractory to last regimen (13% vs 3%), Ann Arbor stage IV (65% vs 41%), high-risk MALT-IPI (50% vs 19%), elevated LDH (29% vs 19%), B symptoms (13% vs 3%), and high tumor burden per GELF (65% vs 56%). For MZL patients receiving R² vs R/placebo, respectively, neutropenia (47% vs 16%), pneumonia (3% vs 13%), and leukopenia (10% vs 0) were the most common grade 3/4 AEs. 5 total deaths occurred in the R² arm (most associated with PD; 2 early deaths occurred at 3 and 13 days post-randomization [1 patient before receiving R² and 1 patient 2 days after initiating treatment]) and 2 in the R/placebo arm. Despite worse prognostic features, best response was higher, but not statistically significant, with R² (vs R/placebo): ORR = 65% vs 44% and CR = 29% vs 13%. Median

<footnote n="1">¹Hemato-Oncology, APHP, Hopital Saint-Louis, Paris, France; ²Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, United States; ³General Hospital, Charles University, Prague, Czech Republic; ⁴Hematology, National Cancer Center Hospital,</footnote>
<table><caption>TABLE 1 Cox Proportional Hazard Model for PFS (IRC) in MZL Patients (ITT)</caption><thead><tr><th rowspan="2">Variable</th><th colspan="3">Univariate Model</th><th colspan="3">Final Multivariate Model</th></tr><tr><th>HR</th><th>95% CI</th><th>P Value</th><th>HR</th><th>95% CI</th><th>P Value</th></tr></thead><tbody><tr><td>Treatment (R<sup>2</sup> vs R/placebo)</td><td>1.001</td><td>(0.471, 2.125)</td><td>0.998</td><td>0.509</td><td>(0.202, 1.284)</td><td>0.153</td></tr><tr><td>Age (≥ 70 vs &lt; 70 y)</td><td>2.083</td><td>(0.936, 4.634)</td><td>0.072</td><td></td><td></td><td></td></tr><tr><td>Sex (male vs female)</td><td>1.990</td><td>(0.939, 4.216)</td><td>0.072</td><td></td><td></td><td></td></tr><tr><td>Ann Arbor stage (IV vs I/II/III)</td><td>2.746</td><td>(1.205, 6.258)</td><td>0.016</td><td>2.436</td><td>(0.998, 5.947)</td><td>0.051</td></tr><tr><td>FLIPI (high vs low/medium)</td><td>1.775</td><td>(0.841, 3.745)</td><td>0.132</td><td></td><td></td><td></td></tr><tr><td>ECOG (1-2 vs 0)</td><td>1.228</td><td>(0.562, 2.685)</td><td>0.607</td><td></td><td></td><td></td></tr><tr><td>LDH (elevated vs not elevated)</td><td>2.348</td><td>(1.096, 5.031)</td><td>0.028</td><td>2.792</td><td>(1.131, 6.897)</td><td>0.026</td></tr><tr><td>B symptom (yes vs no)</td><td>0.931</td><td>(0.220, 3.941)</td><td>0.923</td><td></td><td></td><td></td></tr><tr><td>High tumor burden (yes vs no)</td><td>1.465</td><td>(0.662, 3.244)</td><td>0.346</td><td></td><td></td><td></td></tr><tr><td>Chemoresistant (yes vs no)</td><td>0.493</td><td>(0.067, 3.644)</td><td>0.488</td><td></td><td></td><td></td></tr><tr><td>Unfit for chemotherapy (yes vs no)*</td><td>2.377</td><td>(1.043, 5.416)</td><td>0.039</td><td>2.086</td><td>(0.892, 4.876)</td><td>0.090</td></tr></tbody></table>

PFS for MZL was 20.2 mo R² vs 25.2 mo R/placebo (HR = 1.00; 95% CI, 0.47-2.13; P = 1.0). Univariate analyses identified several prognostic factors for MZL patients (P<0.05): Ann Arbor stage IV, elevated LDH, and unfit for chemotherapy (Table). Multivariate analyses of PFS showed an adjusted HR of 0.51 (95% CI, 0.20-1.28) favoring R², similar to the overall PFS HR (HR = 0.46; 95% CI, 0.34-0.63).

**Conclusions:** Overall, these additional analyses in MZL patients suggest that the PFS results were negatively impacted by baseline prognostic factor imbalances and more aggressive disease in the R² over R/placebo arm.

**Keywords:** lenalidomide; marginal zone lymphoma (MZL); rituximab.

**Disclosures:** Thieblemont, C: Consultant Advisory Role: Cellectis, Kite, Janssen, Roche, Novartis, Bayer; Honoraria: Gilead, Janssen, Novartis; Research Funding: Roche; Other Remuneration: Travel: Roche, Gilead, Janssen, Leonard, J: Consultant Advisory Role: Celgene, Biotest, Sunesis Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Epizyme, Pfizer, Bayer, Genentech/Roche, ADC Therapeutics, MEI Pharma, AstraZeneca, Novartis, Merck, Sutter Medical Group, Morphosys, Beigene, Nordic Nanovector, Bristol-Myers Squibb, United Therapeutics, Karyopharm Therapeutics, Sand; Research Funding: all institutional Celgene, Alliance for Clinical Trials in Oncology, Takeda, Pfizer, National Cancer Institute; Other Remuneration: Travel, Accommodations, Expenses: BeiGene.

**Trneny, M:** Consultant Advisory Role: Takeda, BMS, Incyte, Abbvie, Amgen, Roche, Gilead, Janssen, Celgene, MorphoSys; Honoraria: Janssen, Gilead, Takesa, BMS, Amgen, Abbvie, Roche, MorphoSys, Incyte; Other Remuneration: Travel & Expenses: Gilead, Takeda, BMS, Roche, Janssen, Abbvie. **Izutsu, K:** Consultant Advisory Role: Bayer, Celgene; Honoraria: Takeda, Chugai Pharma, Eisai, Kyowa Hakko Kirin, Janssen, Ono Pharmaceutical, Gilead Sciences, Abbie, Novartis, MSD, Otsuka; Research Funding: Eisai, Chugai Pharma. **Fowler, N:** Consultant Advisory Role: Roche/Genentech, TG Therapeutics, Verastem, Bayer, Celgene, Novartis; Research Funding: Roche, Celgene, Gilead Sciences, TG Therapeutics, Novartis, Abbvie, BeiGene. **Nowakowski, G:** Consultant Advisory Role: Celgene, MorphoSys, Genentech; Research Funding: Celgene, NanoString Technologies, MorphoSys. **Pinto, A:** Consultant Advisory Role: Servier,

Roche, MDS Pharma, BMS; Honoraria: Roche, MDS Pharma, Celgene, Servier, BMS; Research Funding: EDO-Mundipharma; Other Remuneration: Speakers' Bureau: Roche, Travel: Roche, Takeda. **Scheinberg, P:** Consultant Advisory Role: Novartis, Abbvie, Alexion Pharmaceuticals, Janssen, Celgene; Honoraria: Novartis; Other Remuneration: Speakers' Bureau: Novartis, Pfizer. **Flinn, I:** Consultant Advisory Role: Abbvie, Seattle Genetics, TG Therapeutics, Verastem; Research Funding: (All institutional): Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals, Roche, TG Therapeutics, Trillium Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, Unum Therapeutics, MorphoSys AG, Abbvie. **Czuczman, M:** Employment Leadership Position: Celgene; Stock Ownership: Celgene. **Kalambakas, S:** Employment Leadership Position: Celgene; Stock Ownership: Celgene, Novartis. **Wu, C:** Employment Leadership Position: Celgene; Stock Ownership: Celgene. **Gribben, J:** Consultant Advisory Role: Abbvie, Acerta Pharma/Astra Zeneca, Celgene. Janssen; Honoraria: Abbvie, Acerta Pharma/Astra Zeneca, Celgene. Janssen, Gilead Sciences, Roche/Genentech, TG Therapeutics; Research Funding: Acerta Pharma/Astra Zeneca, Janssen, Celgene.

## 178
AUGMENT: RELAPSED/REFRACTORY INDOLENT NHL PATIENTS WERE MORE SENSITIVE TO NEXT TREATMENT FOLLOWING LENALIDOMIDE/RITUXIMAB (R²) THAN RITUXIMAB/PLACEBO

J. Gribben¹ | M. Trneny² | K. Izutsu³ |

N.H. Fowler⁴ | X. Hong⁵ | H. Zhang⁶ | F. Offner⁷ |

A. Scheliga⁸ | G. Nowakowski⁹ | A. Pinto¹⁰ |

<footnote>*Defined as age ≥ 70 y, or if 60-69 y and CrCl < 60 mL/min or ECOG PS ≥ 2.</footnote>
F. Re¹¹ | L. Fogliatto¹² | P. Scheinberg¹³ |

I. Flinn¹⁴ | C. Moreira¹⁵ | M. Czuczman¹⁶ |

S. Kalambakas¹⁷ | P. Fustier¹⁸ | C. Wu¹⁹ | J. Leonard²⁰

¹Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom; ²General Hospital, Charles University, Prague, Czech Republic;

³Hematology, National Cancer Center Hospital, Tokyo, Japan;

⁴Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States; ⁵Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; ⁶Hematology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; ⁷Hematology, UZ Gent, Gent, Belgium;

⁸Hematology, INCA Instituto Nacional De Cáncer, Rio de Janeiro, Brazil;

⁹Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, United States; ¹⁰Hematology, Istituto Nazionale Tumori, Fondazione 'G. Pascale', IRCCS, Naples, Italy; ¹¹Hematology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; ¹²Hematology, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil; ¹³Hematology, Hospital A Beneficência Portuguesa de São Paulo, São Paulo, Brazil;

¹⁴Hematology, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, United States; ¹⁵Hematology, Instituto Português de Oncologia Do Porto Francisco Gentil Epe, Porto, Portugal; ¹⁶Global Clinical R&D Hematology/Oncology, Celgene Corporation, Summit, United States;

¹⁷Global Medical Affairs, Celgene Corporation, Summit, United States;

¹⁸Global Medical Affairs, Celgene International Sarl, Boudry, Switzerland;

¹⁹BioStatistics, Celgene Corporation, Summit, United States; ²⁰Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, United States

**Introduction:** Indolent NHL patients need more effective and tolerable therapies to improve remission times with subsequent lines of therapy. The combination of lenalidomide + rituximab (R²) has shown improved efficacy in firstline and relapsed/refractory (R/R) B-cell lymphoma. The objective here was to evaluate the sensitivity of patients to their next treatment following R² or rituximab (R)/placebo.

**Methods:** The multicenter, global phase III AUGMENT study enrolled patients with R/R FL gr 1-3a and MZL after ≥ 1 prior systemic therapy (but were not rituximab refractory). Patients were randomized 1:1 to R² (lenalidomide PO 20 mg/d, d1-21/28 X12 cycles (c) + rituximab [R] IV 375 mg/m²/wk, c1, d1, 8, 15, 22 and c2-5, d1) and R/placebo (same dosing schedule). Progression-free survival (PFS; primary endpoint) and response were per 2007 IWG criteria (without PET). Time to next antilymphoma/chemotherapy treatment (TTNLT/TTNCT) was defined as time from randomization to date of the next antilymphoma/chemotherapy treatment. Per regulatory guidance, PFS2 was defined as time from randomization to first PD or death from any cause after next antilymphoma treatment, or initiation of a third antilymphoma treatment.

**Results:** A total of 358 patients (n = 178 R²; n = 180 R/placebo) were enrolled, including 82% FL grade 1-3a and 18% MZL. Patients had a median age of 63 y, 34% with FLIPI score ≥ 3, and a median of 1 (range, 1-12) prior systemic therapy (84% receiving prior rituximab). The primary endpoint of PFS was met showing superiority for R² over R/placebo (median PFS: 39.4 vs 14.1 mo; HR = 0.46; P < 0.0001). As of 22June2018, the medians for TTNLT, TTNCT, and PFS2 were not reached for R², and were significantly longer than R/placebo with hazard ratios of 0.54 (95% CI, 0.38-0.78), 0.50 (95% CI, 0.32-0.78), and 0.52 (95% CI, 0.32-0.82), respectively. There were 49/178 (28%) R² and 80/180 (44%) R/placebo patients who received a next antilymphoma therapy; their subsequent responses to next treatment were generally higher with R² (57% ORR; 31% CR) than R/placebo (36% ORR; 16% CR; Table).

**Conclusions:** For patients with R/R FL gr 1-3a and MZL, R² showed prolonged time to subsequent treatment, which was associated with longer PFS2 compared with R/placebo, thus enabling greater responses to next therapy. Interestingly, patients were generally more sensitive to subsequent therapy after R² than R/placebo, hypothetically due to the impact of longer disease control, allowing for reemergence of sensitivity to therapy other than rituximab or R².

**Keywords:** indolent lymphoma; lenalidomide; rituximab.

<table><caption>TABLE 1 Response to next treatment after R² and R/placebo</caption><thead><tr><th rowspan="2">Treatment (R² n, R/placebo n)</th><th colspan="2">Response after R²</th><th colspan="2">Response after R/placebo</th></tr><tr><th>ORR, %</th><th>CR, %</th><th>ORR, %</th><th>CR, %</th></tr></thead><tbody><tr><td>Single agent chemo (n = 8, 14)</td><td>63</td><td>38</td><td>36</td><td>21</td></tr><tr><td>Other R-Chemo combo (n = 7, 11)</td><td>43</td><td>29</td><td>64</td><td>18</td></tr><tr><td>Other (n = 9, 10)</td><td>44</td><td>22</td><td>40</td><td>30</td></tr><tr><td>Combo chemo (n = 2, 15)</td><td>0</td><td>0</td><td>27</td><td>0</td></tr><tr><td>Single agent targeted therapy (n = 7, 8)</td><td>43</td><td>14</td><td>13</td><td>0</td></tr><tr><td>R-Benda (n = 5, 10)</td><td>100</td><td>40</td><td>40</td><td>30</td></tr><tr><td>R monotherapy (n = 3, 4)</td><td>67</td><td>67</td><td>25</td><td>0</td></tr><tr><td>O-Chemo (n = 3, 3)</td><td>100</td><td>67</td><td>67</td><td>33</td></tr><tr><td>R-CHOP (n = 3, 2)</td><td>67</td><td>33</td><td>0</td><td>0</td></tr><tr><td>Combo targeted therapies (n = 2, 3)</td><td>50</td><td>0</td><td>33</td><td>33</td></tr></tbody></table>
**Disclosures:** Gribben, J: Consultant Advisory Role: Abbvie, Acerta Pharma/Astra Zeneca, Celgene. Janssen; Honoraria: Abbvie, Acerta Pharma/Astra Zeneca, Celgene. Janssen, Gilead Sciences, Roche/Genentech, TG Therapeutics; Research Funding: Acerta Pharma/Astra Zeneca, Janssen, Celgene. Trneny, M: Consultant Advisory Role: Takeda, BMS, Incyte, Abbvie, Amgen, Roche, Gilead, Janssen, Celgene, MorphoSys; Honoraria: Janssen, Gilead, Takesa, BMS, Amgen, Abbvie, Roche, MorphoSys, Incyte; Other Remuneration: Travel & Expenses: Gilead, Takeda, BMS, Roche, Janssen, Abbvie. Izutsu, K: Consultant Advisory Role: Eisai, MSD, Takeda, Ono, AstraZeneca, Abbvie, Bayer, Novartis, Chugai, Daiichi Sankyo, Otsuka; Honoraria: Kyowa Hakko Kirin, Eisai, MSD, Takeda, Janssen, Dainippon Sumitomo, Mundipharma, Nihon Mediphysics, Abbvie, Chugai, Zenyaku, Bristol Myers Squibb, Astellas; Research Funding: HUYA bioscience, MSD, Astellas Amgen, AstraZeneca, Abbvie, Eisai, Ono, Sanofi, ARIAD, Symbio, Zenyaku, Celgene, Solaisia, Takeda, Daiichi Sankyo, Chugai, Novarsis, Bayer, Pfizer. Fowler, N: Consultant Advisory Role: Roche/Genentech, TG Therapeutics, Verastem, Bayer, Celgene, Novartis; Research Funding: Roche, Celgene, Gilead Sciences, TG Therapeutics, Novartis, Abbvie, BeiGene. Nowakowski, G: Consultant Advisory Role: (author's institution for all) Celgene, MorphoSys, Genentech; Research Funding: (author's institution for all) Celgene, NanoString Technologies, MorphoSys. Pinto, A: Consultant Advisory Role: Servier, Roche, MDS Pharma, BMS; Honoraria: Roche, MDS Pharma, Celgene, BMS; Other Remuneration: Speakers' Bureau: Roche; Patents, Royalties or Intellectual Property: EDO-Mundipharma; Travel: Roche, Takeda. Scheinberg, P: Consultant Advisory Role: Novartis, Abbvie, Alexion Pharmaceuticals, Janssen, Celgene; Honoraria: Novartis; Other Remuneration: Speakers' Bureau: Novartis, Pfizer. Flinn, I: Consultant Advisory Role: (All instituional): Abbvie, Seattle Genetics, TG Therapeutics, Verastem; Research Funding: (All institutional): Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals, Roche, TG Therapeutics, Trillium Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, Unum Therapeutics, MorphoSys AG, Abbvie. Czuczman, M: Employment Leadership Position: Celgene; Stock Ownership: Celgene. Kalambakas, S: Employment Leadership Position: Celgene; Stock Ownership: Celgene. Fustier, P: Employment Leadership Position: Celgene; Stock Ownership: Celgene. Wu, C: Employment Leadership Position: Celgene; Stock Ownership: Celgene. Leonard, J: Consultant Advisory Role: Celgene, Biotest, Sunesis Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Epizyme, Pfizer, Bayer, Genentech/Roche, ADC Therapeutics, MEI Pharma, AstraZeneca, Novartis, Merck, Sutter Medical Group, Morphosys, Beigene, Nordic Nanovector, Bristol-Myers Squibb, United Therapeutics, Karyopharm Therapeutics, Sand; Research Funding: (all institutional): Celgene, Alliance for Clinical Trials in Oncology, Takeda, Pfizer, National Cancer Institute; Other Remuneration: Travel, Accommodation, Expenses: BeiGene.

## 179
# EFFICACY AND SAFETY OF PROLONGED MAINTENANCE WITH SUBCUTANEOUS RITUXIMAB IN PATIENTS WITH RELAPSED OR REFRACTORY INDOLENT NHL: RESULTS OF THE PHASE III MABCUTE STUDY

S. Rule¹ | W.G. Barreto² | J. Briones³ |

A.M. Carella⁴ | O. Casasnovas⁵ | C. Pocock⁶ |

C.M. Wendtner⁷ | F. Zaja⁸ | S. Robson⁹ |

R.R. Tschopp¹⁰ | M. Dreyling¹¹

¹Department of Haematology, Derriford Hospital and Plymouth University Medical School, Plymouth, United Kingdom; ²Hematology and Hemotherapy, Hemocentro Ribeirão Preto, University of São Paulo, São Paulo, Brazil; ³Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; ⁴Division of Hematology and Stem Cell Transplantation Unit, I’Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria "San Martino" - Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; ⁵Service d’Hématologie Clinique, Centre Hospitalier Universitaire François Mitterand, Dijon, France; ⁶Department of Haematology, Kent & Canterbury Hospital, Canterbury, United Kingdom; ⁷Department I of Internal Medicine, Klinikum Schwabing, Munich, Germany; ⁸SC Ematologia, Azienda Sanitaria Universitaria Integrata di Trieste, Trieste, Italy; ⁹Product Development Medical Affairs, Biometrics, F. Hoffmann-La Roche Ltd, Basel, Switzerland; ¹⁰Product Development Medical Affairs, Oncology, F. Hoffmann-La Roche Ltd, Basel, Switzerland; ¹¹Department of Medicine III, Klinikum der Universität München (LMU), Munich, Germany

**Background:** Rituximab (R)-chemotherapy (chemo) induction plus R maintenance (maint) is an established treatment for indolent NHL (iNHL), but the optimum duration of R maint is unknown. A subcutaneous (SC) form of R (R-SC) is now available. MabCute (NCT01461928) is a randomised Phase III trial evaluating the efficacy and safety of prolonged R-SC maint after standard R-SC-based induction and maint in relapsed or refractory (R/R) iNHL pts. We report the primary analysis.

**Methods:** Eligible pts were aged ≥18 years with R/R CD20+ follicular lymphoma (grade [Gr] 1, 2 or 3a) or other iNHL. Pts received 8 cycles (Cs) of R (375mg/m² IV in C1 then 1400mg SC in Cs 2–8) in combination with 6–8 Cs of chemo as induction. Responders (CR/PR) then received a 2 year maint comprising 12 Cs of 1400mg R-SC every 8 weeks. Responding pts (CR/PR) were randomised 1:1 to prolonged R-SC maint or observation (observ) until PD. The primary endpoint was PFS from randomisation (PFSrand) in all randomised pts (ITTrand). Sample size calculation assumed a median PFSrand of 38 months (mo) in the R-SC arm and 23 mo in the observ arm. On this basis, 129 PFSrand events were needed to achieve 80% power for the log-rank test at a significance level of 5%. To observe this number of
<table><caption>Table 1: Patient and disease characteristics in the randomised patient groups</caption><thead><tr><th>Characteristic</th><th>Maintenance (n=138)</th><th>Observation (n=138)</th></tr></thead><tbody><tr><td>Median age, years (range)</td><td>64 (26-89)</td><td>65 (34-86)</td></tr><tr><td>Male, n (%)</td><td>74 (53.6)</td><td>68 (49.3)</td></tr><tr><td>Ann Arbor stage IV, n (%)</td><td>88/134 (65.7)</td><td>78/135 (57.8)</td></tr><tr><td>Bone marrow involvement, n (%)</td><td>60 (43.5)</td><td>59 (42.8)</td></tr><tr><td>FL, n (%)</td><td>73 (52.9)</td><td>77 (55.8)</td></tr><tr><td>FLIPI low / intermediate / high, %</td><td>34.2 / 30.1 / 35.6</td><td>36.4 / 35.1 / 28.6</td></tr><tr><td>Median duration of disease, months (range)</td><td>65.0 (4-303)</td><td>62.4 (4-275)</td></tr></tbody></table>

<figure><img src="image_131.png" /><figcaption>Figure 1: Kaplan-Meier curve of PFS<sub>rand</sub> in the ITT<sub>rand</sub> population</figcaption></figure>

events, approximately 300 pts were needed and followed for ≥15 mo. In the observ arm, Gr 1 and 2 AEs were collected until 28 days after the last R administration, leading to an imbalance in AE collection between the arms. End of study was the time when all randomised pts had been followed for ≥15 mo, or earlier if at least 129 PFS events had been observed.

**Results:** Of 693 pts who entered induction, 276 were randomised to prolonged maint or observ (n = 138 in both arms). Pt and disease characteristics were generally well balanced (Table). A total of 46 PFS<sub>rand</sub> events were observed (19 in maint and 27 in observ), corresponding to 36% of the 129 events needed to achieve 80% power. Median PFS<sub>rand</sub> was not reached in either arm (Figure) and the difference in PFS<sub>rand</sub> between the two treatment arms was not statistically significant (p = 0.410, stratified log rank test). At end of study, 10 pts in the maint group and 8 pts in the observ group had died. Median OS was not reached. Gr >3 AEs (34.8% vs 29.0%) and serious AEs (22.5% vs 23.2%) were reported with a similar frequency in the maint and observ arms, respectively. Common (≥2%) Gr ≥3 AEs were: neutropenia (8.7% vs 5.8%); pneumonia (5.1% vs 2.9%); decreased neutrophil count (2.2% vs 0%); and hypertension (2.2% vs 0%). The most common serious AE was pneumonia (5.8%

vs 2.9%). Five pts (3.6%) in each arm died due to an AE. ORR (CR/PR) at end of induction (EOI) was 84.7%, and 77 of 357 pts with a PR at EOI achieved a CR by end of initial maint (conversion rate: 21.6%).

**Conclusions:** MabCute was unable to fully address the primary study endpoint of PFS<sub>rand</sub> due to the limited number of events observed. The safety profile of R-SC during prolonged maint was consistent with the known profile of R-SC.

**Acknowledgment:** Third-party medical writing assistance, under the direction of Simon Rule, was provided by Zoe Toland and Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.

**Keywords:** follicular lymphoma (FL); non-Hodgkin lymphoma (NHL); rituximab.

**Disclosures:** Rule, S: Consultant Advisory Role: Janssen, Astra-Zeneca, Roche, Sunesis, Pharmacyclics, Celgene, Celltrion, Kite; Research Funding: Janssen; Other Remuneration: Janssen. Barreto, W: Employment Leadership Position: Bloods Bank Ribeirão Preto - University of São Paulo; Consultant Advisory Role: Director. Briones, J: Consultant Advisory Role: Takeda, Jansen, Celgene, Gilead; Honoraria: Roche, Takeda, Celgene, Novartis, Gilead; Research Funding: Roche; Other
Remuneration: Roche, Takeda, Celgene, Jansen, Gilead. **Casasnovas, O:** Consultant Advisory Role: Roche, Takeda, BMS, Merck, Gilead, Janssen; Honoraria: Roche, Takeda, BMS, Merck, Gilead, Janssen; Research Funding: Roche, Takeda, Gilead, Abbvie; Other Remuneration: Roche, Takeda, Janssen. **Pocock, C:** Employment Leadership Position: East Kent Hospitals (main NHS employer). **Wendtner, C:** Consultant Advisory Role: Hoffmann-La Roche, Janssen-Cilag, Gilead, AbbVie; Honoraria: Hoffmann-La Roche, Janssen-Cilag, Gilead, AbbVie; Research Funding: Hoffmann-La Roche, Janssen-Cilag, Gilead, AbbVie; Other Remuneration: Hoffmann-La Roche, Janssen-Cilag, Gilead, AbbVie. **Zaja, F:** Consultant Advisory Role: Sandoz, Roche, Janssen Cilag, Gilead, Celgene, Abbvie, Celgene, Takeda, Novartis; Honoraria: Roche, Janssen Cilag, Gilead, Celgene, Abbvie, Celgene, Takeda, Novartis; Research Funding: Celgene, Novartis; Other Remuneration: Roche, Celgene, Abbvie, Celgene, Takeda, Novartis. **Robson, S:** Employment Leadership Position: F. Hoffmann-La Roche Ltd. Tschopp, R: Employment Leadership Position: Roche. **Dreyling, M:** Consultant Advisory Role: Acerta, Bayer, Celgene, Gilead, Janssen, Novartis, Roche, Sandoz; Honoraria: Bayer, Celgene, Gilead, Janssen, Roche; Research Funding: Celgene, Janssen, Mundipharma, Roche.

## 180 OUTCOMES AFTER EARLY TRANSFORMATION (tPOD24) VS. EARLY FOLLICULAR LYMPHOMA PROGRESSION (fPOD24) IN FOLLICULAR LYMPHOMA TREATED WITH FRONTLINE IMMUNOCHEMOTHERAPY

M.J. Maurer<fnref n="1" /> | L.H. Jakopsen<fnref n="2" /> | T.M. Habermann³ |

G.S. Nowakowski³ | S.M. Ansell³ | C.A. Thompson³ |

P.D. Brown⁴ | J.M. Jørgensen⁵ | H. Frederiksen⁶ |

S. Syrbu<fnref n="7" /> | A.L. Feldman⁸ | A.J. Novak³ |

L.M. Rimsza<fnref n="9" /> | J.R. Cerhan<fnref n="1" /> | T.C. El-Galaly<fnref n="2" /> |

B.K. Link¹⁰

**Introduction:** Early events within 24 months (e.g. EFS24, POD24) after initiation of frontline immunochemotherapy (IC) are associated with poor survival in follicular lymphoma (FL). The incidence and outcomes of early transformation compared to early progression of FL remain understudied. We now examine the types of early events and subsequent outcomes by event type in IC treated FL.

**Methods:** Patients prospectively enrolled in the University of Iowa/Mayo Clinic SPORE MER between 2002-2015 with FL grade 1-3A and treated with frontline R-CVP, R-CHOP, and R-bendamustine IC were included. Early event was defined as progression, re-treatment, or death within 24 months of start of IC. Early-events were classified into biopsy proven transformation (tPOD24), biopsy proven FL progression (fPOD24), progression without biopsy (oPOD24), and death without progression or retreatment. Early event frequencies were determined via cumulative incidence. Overall survival (OS) from POD24 was defined as date of progression until death. Validation was performed in patients with grade 1-2 FL treated with R-CVP, R-CHOP, or R-bendamustine enrolled in the Danish LYFO from 2006-2017.

**Results:** 439 patients treated with IC at diagnosis in the MER were evaluated with 28% receiving R-CVP, 44% R-CHOP and 28% B-R based IC. Median age was 59 years (range 23-86), 55% were male, 26% were grade 3A, and FLIPI was high in 35%. Early event rate at 24 months was 6.5% tPOD24, 8.2% fPOD24, 6.3% oPOD24, and 3.3% early deaths, Table. OS after tPOD24 (OS5 = 27%, ref) was inferior to fPOD24 (5-year OS = 54%, HR = 0.36; 95% CI: 0.19-0.70) and oPOD24 (5-year OS = 44%, HR = 0.51; 95% CI: 0.26-1.00), Figure. 630 patients were evaluated in the Danish LYFO cohort with 46% receiving R-CVP, 29% R-CHOP and 25% B-R based IC. Median age was 65 years (range 29-90), 52% were male, and FLIPI was high in 46%. Early event rate was 3.0% tPOD24, 8.0% fPOD24, 2.6% oPOD24, and 5.2% early deaths, Table. OS after tPOD24 (OS5 = 31%, ref) was inferior to fPOD24 (5-year OS = 61%, HR = 0.45; 95% CI: 0.22-0.89), and similar to oPOD24 (5-year OS = 30%, HR = 0.86; 95% CI: 0.39-1.92), Figure.

<table><caption>TABLE 1</caption><thead><tr><th>Cohort</th><th>MER</th><th>MER</th><th>MER</th><th>MER</th><th>LFYO</th><th>LYFO</th><th>LYFO</th><th>LYFO</th></tr></thead><tbody><tr><td>Therapy</td><td>R-CVP</td><td>R-CHOP</td><td>B-R</td><td>Total</td><td>R-CVP</td><td>R-CHOP</td><td>B-R</td><td>Total</td></tr><tr><td>N Initiating Therapy</td><td>123</td><td>192</td><td>124</td><td>439</td><td>288</td><td>184</td><td>158</td><td>630</td></tr><tr><td>Achieve EFS24 Rate</td><td>73.6%</td><td>77.3%</td><td>75.4%</td><td>75.7%</td><td>77.7%</td><td>82.8%</td><td>86.9%</td><td>81.2%</td></tr><tr><td>tPOD24 Rate</td><td>2.5%</td><td>5.8%</td><td>11.7%</td><td>6.5%</td><td>4.2%</td><td>1.1%</td><td>2.6%</td><td>3.0%</td></tr><tr><td>fPOD24 Rate</td><td>9.1%</td><td>11.1%</td><td>2.6%</td><td>8.2%</td><td>9.1%</td><td>10.6%</td><td>2.8%</td><td>8.0%</td></tr><tr><td>oPOD24 Rate</td><td>12.3%</td><td>4.2%</td><td>3.5%</td><td>6.3%</td><td>3.8%</td><td>1.7%</td><td>0.9%</td><td>2.6%</td></tr><tr><td>Early Death Rate</td><td>2.5%</td><td>1.6%</td><td>6.8%</td><td>3.3%</td><td>5.2%</td><td>3.8%</td><td>6.8%</td><td>5.2%</td></tr></tbody></table>

<footnote n="1">¹Health Sciences Research, Mayo Clinic, Rochester, United States;</footnote>

<footnote n="2">²Clinical Medicine, Aalborg University, Aalborg, Denmark; ³Medicine, Mayo Clinic, Rochester, United States; ⁴Hematology, Rigshospitalet, Copenhagen, Denmark; ⁵Hematology, Aarhus University Hospital, Århus, Denmark; ⁶Hematology, Odense University Hospital, Odense, Denmark;</footnote>

<footnote n="7">⁷Pathology, University of Iowa, Iowa City, United States; ⁸Laboratory Medicine and Pathology, Mayo Clinic, Rochester, United States;</footnote>

<footnote n="9">⁹Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, United States; ¹⁰Internal Medicine, University of Iowa, Iowa City, United States</footnote>
<figure><img src="image_132.png" /></figure>

**Conclusions:** Follicular lymphoma progression is more common than transformation in biopsy-proven early events of IC-treated FL. OS is poor after both tPOD24 and fPOD24 and both represent an unmet clinical need. These histology specific results have implications for clinical trial development and interpretation. Biopsy of early progression in IC-treated FL is necessary for 2^nd^line management and prognostication.

**Keywords:** follicular lymphoma (FL).

**Disclosures:** Maurer, M: Consultant Advisory Role: Morphosys;

Research Funding: Celgene, Nanostring, Jørgensen, J: Consultant Advisory Role: Gilead.

181
HEALTH-RELATED QUALITY OF LIFE (HRQoL) IN RELAPSED/REFRACTORY (R/R) INDOLENT NHL IN THE PHASE 3 AUGMENT TRIAL OF RITUXIMAB (R) PLUS LENALIDOMIDE (R²) VERSUS R PLUS PLACEBO

J.P. Leonard<fnref n="1" /> | M. Trněny² | K. Izutsu<fnref n="3" /> |
N.H. Fowler⁴ | X. Hong⁵ | H. Zhang⁶ | F. Offner⁷ |
A. Scheliga⁸ | G. Nowakowski⁹ | A. Pinto¹⁰ |
F. Re¹¹ | L.M. Fogliatto¹² | P. Scheinberg¹³ |
I.W. Flinn¹⁴ | C. Moreira¹⁵ | A. Tabah¹⁶ |
S. Abouzaid¹⁷ | S. Kalambakas¹⁸ | P. Fustier¹⁹ |
C. Wu²⁰ | J.G. Gribben²¹

Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States; ⁵Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; ⁶Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; ⁷Department of Clinical Hematology, Universitair Ziekenhuis (UZ) Gent, Gent, Belgium; ⁸Oncology Clinic, Instituto Nacional De Câncer (INCA), Rio de Janeiro, Brazil; ⁹Center for Individualized Medicine, Mayo Clinic, Rochester, United States; ¹⁰Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Giovanni Pascale, IRCCS, Naples, Italy; ¹¹Ematologia e Centro Trapianti Midollo Osseo (CTMO), Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; ¹²Serviço Hematologia e Transplante de Medula Ossea, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil; ¹³Division of Hematology, Hospital A Beneficência Portuguesa, São Paulo, Brazil; ¹⁴Sarah Cannon Research Institute (SCRI), Tennessee Oncology Nashville, Nashville, United States; ¹⁵Instituto Português de Oncologia, Porto Francisco Gentil Epe, Porto, Portugal; ¹⁶US Health Economics and Outcomes Research, Celgene Corporation, Summit, United States; ¹⁷Global Pricing and Market Access, Celgene Corporation, Summit, United States; ¹⁸Clinical Research Science, Celgene Corporation, Summit, United States; ¹⁹Clinical Research Science, Celgene International, Boudry, Switzerland; ²⁰Statistics, Celgene International, Boudry, Switzerland; ²¹Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom

**Introduction:** In the AUGMENT study (NCT01938001), median progression-free survival (PFS) for patients (pts) treated with R² was 39.4 months vs 14.1 months for pts treated with R-placebo (PBO) (P < 0.0001) in 358 pts with R/R indolent NHL [Leonard, 2019]. The effect of R² vs R-PBO on HRQoL, an exploratory endpoint, is presented here.

**Methods:** HRQoL data were collected using the EORTC QLQ-C30 and EQ-5D-3L questionnaires. The QLQ-C30 global health status/QoL (GHS/QoL) domain score was the prespecified primary

<footnote n="1">¹Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, United States; ²First Department of Medicine, Charles University Hospital, Prague, Czech Republic;</footnote>

<footnote n="3">³Department of Hematology, National Cancer Center Hospital, Tokyo, Japan; ⁴Department of Lymphoma and Myeloma, Division of Cancer</footnote>
<table><caption>TABLE 1 QLQ-C30 completion rates</caption><thead><tr><th>Visit</th><th>Definition of denominator</th><th>R<sup>2</sup> n/N (%)</th><th>R-PBO n/N (%)</th><th>P value</th></tr></thead><tbody><tr><td>Screening</td><td>ITT population</td><td>174/178 (97.8)</td><td>177/180 (98.3)</td><td>0.723</td></tr><tr><td>C4D1</td><td>Received ≥ 1 dose at or after C4</td><td>158/163 (96.9)</td><td>165/169 (97.6)</td><td>0.747</td></tr><tr><td>C7D1</td><td>Received ≥ 1 dose at or after C7</td><td>140/148 (94.6)</td><td>140/148 (94.6)</td><td>1.000</td></tr><tr><td>C10D1</td><td>Received ≥ 1 dose at or after C10</td><td>121/131 (92.4)</td><td>106/119 (89.1)</td><td>0.390</td></tr><tr><td>TC (C12)</td><td>Received ≥ 11 doses at C12 and progression-free at C13D1</td><td>113/119 (95.0)</td><td>86/92 (93.5)</td><td>0.767</td></tr><tr><td>FU1 (6 months post-TC/TD)</td><td>QoL visit recorded during FU period or alive and progression-free for ≥ 24 weeks after last dose</td><td>121/137 (88.3)</td><td>90/103 (87.4)</td><td>0.844</td></tr><tr><td>FU2 (12 months post-TC/TD)</td><td>QoL visit recorded during respective FU period or alive and progression-free for ≥ 24 weeks after last FU visit</td><td>103/115 (89.6)</td><td>70/85 (82.4)</td><td>0.149</td></tr><tr><td>FU3 (18 months post-TC/TD)</td><td>QoL visit recorded during respective FU period or alive and progression-free for ≥ 24 weeks after last FU visit</td><td>84/95 (88.4)</td><td>45/57 (78.9)</td><td>0.160</td></tr><tr><td>FU4 (24 months post-TC/TD)</td><td>QoL visit recorded during respective FU period or alive and progression-free for ≥ 24 weeks after last FU visit</td><td>60/74 (81.1)</td><td>31/39 (79.5)</td><td>1.000</td></tr><tr><td>FU5 (30 months post-TC/TD)</td><td>QoL visit recorded during respective FU period or alive and progression-free for ≥ 24 weeks after last FU visit</td><td>49/60 (81.7)</td><td>24/27 (88.9)</td><td>0.535</td></tr><tr><td>FU6 (36 months post-TC/TD)</td><td>QoL visit recorded during respective FU period or alive and progression-free for ≥ 24 weeks after last FU visit</td><td>36/45 (80.0)</td><td>20/20 (100)</td><td>0.048</td></tr><tr><td>FU7 (42 months post-TC/TD)</td><td>QoL visit recorded during respective FU period or alive and progression-free for ≥ 24 weeks after last FU visit</td><td>24/26 (92.3)</td><td>15/17 (88.2)</td><td>1.000</td></tr><tr><td>FU8 (48 months post-TC/TD)</td><td>QoL visit recorded during respective FU period or alive and progression-free for ≥ 24 weeks after last FU visit</td><td>18/19 (94.7)</td><td>12/13 (92.3)</td><td>1.000</td></tr><tr><td>FU9 (54 months post-TC/TD)</td><td>QoL visit recorded during respective FU period or alive and progression-free for ≥ 24 weeks after last FU visit</td><td>13/14 (92.9)</td><td>7/7 (100)</td><td>1.000</td></tr><tr><td>FU10 (60 months post-TC/TD)</td><td>QoL visit recorded during respective FU period or alive and progression-free for ≥ 24 weeks after last FU visit</td><td>5/6 (83.3)</td><td>6/6 (100)</td><td>1.000</td></tr><tr><td>FU11 (66 months post-TC/TD)</td><td>QoL visit recorded during respective FU period or alive and progression-free for ≥ 24 weeks after last FU visit</td><td>2/2 (100)</td><td>1/1 (100)</td><td>1.000</td></tr><tr><td>TD</td><td>Received &lt; 12 doses at C12</td><td>42/57 (73.7)</td><td>75/88 (85.2)</td><td>0.131</td></tr></tbody></table>

Abbreviations: C, cycle; D, day; FU, follow-up; ITT, intention to treat; QoL, quality of life; R, rituximab; R², rituximab + lenalidomide; R-PBO, R + placebo; TC, treatment completion; TD, treatment discontinuation.

outcome. Mean QLQ-C30 changes from baseline were compared within and between treatment arms using ANCOVA tests. The proportion of pts with clinically meaningful deterioration in HRQoL over time and time to deterioration were determined using mixed-model repeated-measure analysis and Cox regression analysis, respectively.

**Results:** 338 pts completed the baseline QLQ-C30 questionnaire and ≥ 1 post-baseline measurement (HRQoL evaluable population). Baseline characteristics were generally similar between arms. Median age was 61.6 years and 161 pts (48%) were male (R²: 41%; R-PBO: 54%). QLQ-C30 completion rates did not differ between arms and remained > 70%, although the number of responders decreased over time (Table). Mean QLQ-C30 baseline scores across all domains did not

differ between arms. No clinically meaningful changes in GHS/QoL within or between arms were seen across post-baseline measurements (Figure). Changes in other domains were observed during treatment: clinically meaningful worsening diarrhea for R-PBO, worsening fatigue, appetite loss, constipation, diarrhea, and overall health status (based on EQ-5D VAS) for R²; these scores returned to baseline levels after treatment completion. Median time to deterioration was not statistically significant between pts receiving R² and R-PBO (P = 0.16). HRQoL changes over time were not associated with disease histology, response status, or presence of grade 3-4 adverse events (AEs).

**Conclusions:** HRQoL was maintained over time in the R² arm of the AUGMENT study and no clinically meaningful difference in HRQoL
<figure><img src="image_133.png" /></figure>

was observed between treatment arms. AEs had little effect on HRQoL and improved after treatment was completed or stopped. Adding lenalidomide to R significantly extended PFS without compromising HRQoL. Post-progression HRQoL was not included in the analysis. Therefore, potential worsening of HRQoL due to disease and treatment after progression and the impact of fewer or delayed progressions with R² were not captured.

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

**Disclosures:** **Leonard, J:** Consultant Advisory Role: Celgene Corporation, Juno, BMS, Sutro, Gilead, Genentech/Roche, Pfizer, Bayer, Biotest, United Therapeutics, Karyopharm, ADC Therapeutics, MEI Pharma, AstraZeneca, Novartis. **Trněny, M:** Consultant Advisory Role: Roche, Celgene Corporation, Incyte, Takeda, Janssen, Morphosys; Honoraria: Gilead, Roche, Celgene Corporation, Takeda. **Izutsu, K:** Consultant Advisory Role: Eisai, Takeda, AbbVie, Chugai, Ono, AstraZeneca, Bayer, Novartis, Daiichi Sankyo, Otsuka; Honoraria: Kyowa Hakko Kirin, Eisai, MSD, Takeda, Janssen, Dainippon Sumitomo, Mundipharma, Nihon Mediphysics, AbbVie, Chugai, Zenkayu, Bristol Myers Squibb, Astellas; Research Funding: Eisai, MSD, Takeda, AbbVie, Chugai, Zenkayu, Astellas, Ono, AstraZeneca, Bayer, Novartis, Daiichi Sankyo, HUYA Bioscience, Amgen, Sanofi, ARIAD, Symbio, Celgene Corporation, Solaisia, Pfizer. **Fowler, N:** Consultant Advisory Role: Celgene Corporation, Roche, AbbVie, Janssen; Research Funding: Celgene Corporation, Roche, AbbVie, Janssen. **Nowakowski, G:** Consultant Advisory Role: Celgene Corporation, Morphsys, Bayer, Selvita, AbbVie; Research Funding: Celgene Corporation, Morphsys, Bayer, Curis, Nanostrings. **Pinto, A:** Consultant Advisory Role: Roche/Genentech, Merck Sharp & Dohme, Servier; Other Remuneration: Roche/Genentech, Merck Sharp & Dohme, Bristol Myers Squibb, Celgene Corporation, Servier, EDO-Mundipharma.

**Scheinberg, P:** Consultant Advisory Role: Novartis, Celgene Corporation, AbbVie, Alexion, Janssen; Other Remuneration: Novartis, Celgene Corporation, AbbVie, Alexion, Janssen. **Flinn, I:** Consultant Advisory Role: AbbVie, Seattle Genetics, TG Therapeutics, Verastem; Research Funding: AbbVie, TG Therapeutics, Acerta Pharma, Agios, Calithera Biosciences, Celgene Corporation, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals, Roche, Trillium Therapeutics, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca, Juno Therapeutics, Unum Therapeutics, Morphosys, AG. **Tabah, A:** Employment Leadership Position: Celgene Corporation. **Abouzaid, S:** Employment Leadership Position: Celgene Corporation. **Kalambakas, S:** Employment Leadership Position: Celgene Corporation. **Fustier, P:** Employment Leadership Position: Celgene Corporation; Stock Ownership: Celgene Corporation. **Wu, C:** Employment Leadership Position: Celgene Corporation; Stock Ownership: Celgene Corporation. **Gribben, J:** Consultant Advisory Role: Celgene Corporation, Roche, AbbVie, Janssen, Pharmacyclics; Honoraria: Celgene Corporation, AbbVie, Acerta, Roche, Kite; Research Funding: Celgene Corporation, Janssen, Acerta.

182
WhiMSICAL (WALDENSTRÖM'S
MACROGLOBULINEMIA STUDY
INVOLVING CArt-wheeL): A GLOBAL
PATIENT-DERIVED DATA REGISTRY
MAPPING TREATMENT AND QUALITY
OF LIFE
I. Tohidi-Esfahani<fnref n="1" /> | A. Warden² | E. Malunis³ |
P. DeNardis³ | J. Bomsztyk⁴ | S. D'Sa⁴ |
M. Kersten⁵ | M. Palomba⁶ | R. Spearing⁷ |
S. Thomas⁸ | A.J. Olszewski⁹ | C. Scott¹⁰ |
C. Harrington³ | J. Trotman<fnref n="1" />

¹Haematology, Concord Repatriation General Hospital, Sydney, Australia;

²Australian Patient Support Group for WM, WMozzies, Sydney, Australia;

³International Waldenstrom's Macroglobulinemia Foundation, IWMF, Sarasota, United States; ⁴UCLH Centre for Waldenström's Macroglobulinemia and Related Conditions, University College London Hospitals NHS Foundation Trust, London, United Kingdom; ⁵Department of Hematology, Amsterdam UMC, University of Amsterdam and LYMMCARE, Amsterdam, Netherlands; ⁶Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States; ⁷Department of Haematology, Christchurch Hospital, Christchurch, New Zealand; ⁸Lymphoma and Myeloma, MD Anderson Cancer Centre, Houston, United States; ⁹Division of Hematology-Oncology, Rhode Island Hospital, Providence, United States;

¹⁰Department of Medical Oncology, Royal Melbourne Hospital, Melbourne, Australia

**Introduction:** Patient-derived data and reported outcomes (PROs) can increase breadth of knowledge in rare cancers like Waldenström's Macroglobulinemia (WM). This study utilised www.cart-wheel.org, an ethically approved online rare cancer database for patient-derived data, to develop a continuously expanding dataset for hypothesis generation around WM.

**Methods:** An ethically approved WM-specific extension to the www.cart-wheel.org questionnaire was developed by clinician and patient investigators. Patients complete consent online and enter their symptom, pathology and treatment data. Recruitment strategies driven by the International Waldenström's Macroglobulinemia Foundation investigators utilised multiple social media platforms. Inclusion of the EORTC QLQ C30 quality of life (QoL) questionnaire went live in October 2018, with targeted recruitment messaging sent out in February 2019.

**Results:** 355 patients from 17 countries have been recruited, predominantly from USA (48%) and male (62%). Median age at diagnosis was 61 years (24-83), median IgM 27.4 g/L (IQR 13.1-40.3 g/L, n = 130) and median hemoglobin 112 g/L (IQR 97-128 g/L, n = 134). Fatigue was the most common symptom listed at diagnosis (44%). Using the Impact of Event Scale for symptoms of posttraumatic stress disorder (PTSD) related to cancer, the mean score was 5.8 (no stress = 0, maximal stress = 24, n = 305), with 29 (10%) scoring ≥13 (PPV 94% for PTSD, Thoresen et al, 2010). 41 unique first line therapeutic combinations were documented by 238 patients. Median time from diagnosis to first treatment for USA patients was 50 days (IQR 15-423, n = 104) vs Rest of World (ROW) 170 days (IQR 22-775, n = 120) (p = 0.06). Of the 213 therapies listed by USA patients (n = 108), 59 (28%) were reported as accessed by government or public program and 8 (4%) via clinical trials, whereas among ROW patients (n = 113), 122/225 (54%)

were government/public program accessed and 31/225 (14%) via clinical trials (p = 0.0001 and p = 0.0002, respectively). 156 patients responded to the QoL questions within 3 weeks from targeted messaging. Raw scores for overall health (Q29) and overall quality of life (Q30), ranging from 1: very poor to 7: excellent, demonstrated means of 5.1 and 5.8, respectively. Respondents who received BTK inhibitors (BTKi, n = 33) had comparable Q29 and Q30 scores compared to those who received non-BTKi treatment (n = 84): Q29 means 5.8 vs 5.5, Q30 6.1 vs 5.7 (p = 0.2 and p = 0.13, respectively). This was despite median 2 (IQR 1-4) lines of treatment in the BTKi group compared to median 1 (IQR 1-2) in the non-BTKi group.

**Conclusions:** WhiMSICAL is a robust global patient-derived data platform providing insight into patient symptoms, diversity of therapies and QoL. Further recruitment (Project 1000) and ongoing data entry will increase its utility. As it grows, WhiMSICAL has the potential to map real-world PROs to treatments and provide a scientific and ethically approved portal for patients' voices globally.

**Keywords:** BTK inhibitors; Waldenström's macroglobulinemia (WM).

**Disclosures:** D'Sa, S: Consultant Advisory Role: Janssen Cilag, Amgen; Honoraria: Janssen Cilag, Amgen; Research Funding: Janssen Cilag, Amgen; Other Remuneration: Janssen Cilag (Education grant). Kersten, M: Honoraria: Kite Pharma, Novartis Pharmaceuticals Corporation, MSD, BMS, Gilead Sciences, Mundipharma, Millennium/Takeda, Celgene, Roche, Amgen; Research Funding: Millennium/Takeda, Celgene, Roche. Harrington, C: Stock Ownership: AbbVie, Gilead.

## 183
PATIENT-REPORTED OUTCOMES (PROs) IN WALDENSTRÖM MACROGLOBULINEMIA (WM) PATIENTS TREATED WITH IBRUTINIB-RITUXIMAB IN THE INNOVATE STUDY

A. Tedeschi<fnref n="1" /> | M.A. Dimopoulos² | J. Trotman³ |

R. García-Sanz⁴ | D. Macdonald⁵ | B. Mahe⁶ |

C. Herbaux⁷ | L.T. Heffner⁸ | C.S. Tam⁹ |

M. Varettoni¹⁰ | M.L. Palomba¹¹ | J.V. Matous¹² |

C. Shustik¹³ | E. Kastritis² | S.P. Treon¹⁴ | J. Li¹⁵ |

E.G. Poulsen¹⁶ | B. Hauns¹⁷ | C. Buske¹⁸ | V. Leblond¹⁹

<footnote n="1">¹Department of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; ²Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, Greece; ³Hematology, Concord Hospital, University of Sydney, Concord, NSW, Australia; ⁴Hematology, Hospital Universitario de Salamanca, Salamanca, Spain; ⁵Hematology, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada; ⁶Hematology, Centre Hospitalier Universitaire de Nantes, Nantes, France; ⁷Institute of Hematolog- Tranfusion, Centre Hospitalier Régional Universitaire de Lille, Lille, France; ⁸Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States; ⁹Clinical Hematology, Peter MacCallum Cancer Centre & St. Vincent's Hospital</footnote>
<table><caption>**TABLE 1** Patients with clinically meaningful improvement in PROs</caption><thead><tr><th>Patients, %</th><th>IR (n=75)</th><th>R (n=75)</th><th>P</th></tr></thead><tbody><tr><td>FACIT-F<sup>a</sup></td><td>69</td><td>57</td><td>0.13</td></tr><tr><td>FACT-An TS<sup>b</sup></td><td>73</td><td>59</td><td>0.06</td></tr><tr><td>FACT-An AS<sup>c</sup></td><td>64</td><td>48</td><td>0.05</td></tr><tr><td>EQ-VAS<sup>b</sup></td><td>49</td><td>55</td><td>0.54</td></tr><tr><td>EQ-US<sup>d</sup></td><td>43</td><td>36</td><td>0.37</td></tr></tbody></table>

<sup>a</sup>Increase of ≥3 points.

<sup>b</sup>Increase of ≥7 points.

<sup>c</sup>Increase of ≥6 points.

<sup>d</sup>Increase of ≥0.08 points.

and the University of Melbourne, Melbourne, VIC, Australia; <sup>10</sup>Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy;

<sup>11</sup>Hematology/Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States; <sup>12</sup>Blood Cancer, Colorado Blood Cancer Institute, Denver, CO, United States; <sup>13</sup>Cedars Cancer Center, Royal Victoria Hospital at McGill University Health Centre, Montreal, QC, Canada; <sup>14</sup>Bing Center for Waldenström's Macroglobulinemia Research, Dana-Farber Cancer Institute, Boston, MA, United States; <sup>15</sup>Biostatistics, Pharmacyclys LLC, an AbbVie Company, Sunnyvale, CA, United States;

<sup>16</sup>Regulatory Affairs, Pharmacyclys LLC, an AbbVie Company, Sunnyvale, CA, United States; <sup>17</sup>Clinical Science, Pharmacyclys LLC, an AbbVie Company, Sunnyvale, CA, United States; <sup>18</sup>Department of Internal Medicine III, Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital of Ulm, Ulm, Germany;

<sup>19</sup>Département d' Hématologie, Hôpital Pitié-Salpêtrière APHP, Sorbonne Université Paris, Paris, France

**Introduction:** Anemia and fatigue are known to impair quality of life in patients with WM. Ibrutinib, a first-in-class, once-daily inhibitor of BTK, is approved in the EU for the treatment of WM after ≥1 prior therapy or as first-line therapy in patients unsuitable for chemo-immunotherapy. In the US, ibrutinib is approved for the treatment of WM as a single agent or in combination with rituximab. In patients with rituximab-refractory WM, single-agent ibrutinib induced clinically meaningful improvements in PROs (Trotman, EHA 2017). In the iNNOVATE study, the combination of ibrutinib and rituximab (IR) produced higher rates of sustained hemoglobin improvement and clinically meaningful improvements in PROs when compared with placebo-rituximab (R) (Dimopoulos NEJM 2018). Here, we report a more detailed analysis of PROs from iNNOVATE.

**Methods:** Patients with symptomatic WM requiring therapy were randomized to once-daily oral ibrutinib (420 mg) or placebo; both groups were given rituximab (375 mg/m²/week IV at weeks 1–4 and 17–20). PRO measures included FACIT-Fatigue (FACIT-F), FACT-An total score (TS) and anemia subscale score (AS), and the visual analog scale (EQ-VAS) and utility score (EQ-US) of EQ-5D-5L (© EuroQol Research Foundation. EQ-5D™ is a trademark of the EuroQol Research Foundation).

**Results:** A total of 150 patients were randomized with 75 patients in each arm. Across both arms, the most common reasons for

<figure><img src="image_134.png" /><figcaption>**Figure: Proportion of Patients With Clinically MeaningFUL Improvement in PROs Over Time**</figcaption></figure>
initiating therapy were fatigue (61%), constitutional symptoms (32%), and anemia (32%). Baseline PRO scores were comparable in both arms. At the interim analysis (median follow-up, 26.5 months), a greater proportion of patients showed clinically meaningful improvements in FACIT-F, TS, and AS with IR than R (Table and Figure). The median time to improvement was about 1-2 months in both arms. At week 25, the Pearson correlation coefficients for changes in hemoglobin levels with IR vs changes in FACIT-F, TS, and AS were 0.28, 0.29, and 0.26, respectively; no meaningful correlations were observed for R. The correlation coefficients for changes in IgM levels for IR vs changes in FACIT-F, TS, AS, and EQ-VAS were -0.32, -0.33, -0.35, and -0.26, respectively, and for R vs changes in FACIT-F and TS were 0.29 and 0.35, respectively.

**Conclusions:** Clinical response and improvements in anemia with IR are consistent with more patients showing clinically meaningful improvements in PROs vs R. Changes in IgM were also found to correlate with improvements in PROs.

**Keywords:** ibrutinib; rituximab; Waldenström's macroglobulinaemia (WM).

**Disclosures:** Tedeschi, A: Consultant Advisory Role: AbbVie, Gilead, Janssen SpA, and Sunesis; Other Remuneration: Speakers' bureau for Janssen. Dimopoulos, M: Consultant Advisory Role: Amgen, Bristol-Myers Squibb, Celgene, Janssen, Novartis and Takeda; Honoraria: Amgen, Bristol-Myers Squibb, Celgene, Janssen and Takeda. Trotman, J: Research Funding: Pharmacyclics LLC, an AbbVie Company. García-Sanz, R: Consultant Advisory Role: Bristol-Myers Squibb and Takeda; Honoraria: Amgen, Janssen, and Takeda; Research Funding: Gilead and Incyte, and institution research funding from Amgen and Janssen; Other Remuneration: Patents, royalties, or other intellectual property for IVS (Biomed 2 - Euroclonality); travel expenses from Janssen and Takeda. Macdonald, D: Consultant Advisory Role: Janssen; Honoraria: AbbVie, Gilead, Roche and Teva. Heffner, L: Consultant Advisory Role: Pharmacyclics LLC, an AbbVie Company; Research Funding: Amgen, ADC Therapeutics, Biotest, Genentech, Gilead, Idera, Kite, Micromet, Pfizer, and Pharmacyclics LLC, an AbbVie Company; Other Remuneration: Travel expenses from Pharmacyclics LLC, an AbbVie Company. Tam, C: Honoraria: Janssen, and Pharmacyclics LLC, an AbbVie Company; Research Funding: Janssen. Varettoni, M: Consultant Advisory Role: Janssen and Roche; Other Remuneration: Travel expenses from Gilead and Janssen. Palomba, M: Consultant Advisory Role: Celgene, Merck, and Pharmacyclics LLC, an AbbVie Company; Honoraria: Juno and Seres; Other Remuneration: Patents, royalties, or other intellectual property for Juno and Seres. Matous, J: Consultant Advisory Role: Celgene; Other Remuneration: Speakers' bureau for Celgene. Shustik, C: Consultant Advisory Role: Amgen, Celgene, and Takeda. Kastritis, E: Consultant Advisory Role: Amgen, Genesis Pharma, Janssen, Prothena and Takeda; Honoraria: Amgen and Takeda; Other Remuneration: Travel expenses from Janssen and Takeda. Treon, S: Consultant Advisory Role: Janssen and Pharmacyclics LLC, an AbbVie Company; Research Funding: Pharmacyclics LLC, an AbbVie Company; Other Remuneration: Expert testimony for Johnson & Johnson; travel expenses from Janssen and

Pharmacyclics LLC, an AbbVie Company. Li, J: Employment Leadership Position: Pharmacyclics LLC, an AbbVie Company; Stock Ownership: AbbVie, AcelRx, Agenus, Akebia, BeiGene, Celgene, Fibrogen, Gilead, La Jolla Pharmaceutical, Merk, Nektar, and TG Therapeutics. Poulsen, E: Employment Leadership Position: AbbVie and Pharmacyclics LLC, an AbbVie Company; Stock Ownership: AbbVie. Hauns, B: Employment Leadership Position: Pharmacyclics Switzerland GmbH; Stock Ownership: AbbVie. Buske, C: Consultant Advisory Role: Gilead, Janssen, Pfizer, Roche; Research Funding: Janssen, Roche; Other Remuneration: Speakers' bureau for Gilead, Janssen, Pfizer, and Roche. Leblond, V: Consultant Advisory Role: AbbVie, Gilead, Janssen, and Roche; Honoraria: AbbVie, Amgen, Gilead, Janssen, and Roche; Research Funding: AbbVie, Janssen, and Roche; Other Remuneration: Speakers' bureau for AbbVie, Gilead, and Janssen; travel expenses from AbbVie and Roche.

## MANTLE CELL LYMPHOMAS

184

# CLINICO-BIOLOGICAL CHARACTERISTICS AND TREATMENT OUTCOMES FOR AGGRESSIVE MANTLE CELL LYMPHOMA PATIENTS INCLUDED IN CLINICAL TRIALS. A LYSA STUDY

M. Baldacini¹ | B. Burroni² | S. Le Gouill³ |

R. Gressin⁴ | O. Hermine⁵ | A. Traverse-glehen⁶ |

A. Martin⁷ | A. Moreau⁸ | M. Bene⁹ | P. Fogarty¹⁰ |

D. Canioni¹¹ | L. Fornecker¹

¹Hematology Department, Strasbourg University Hospital, Strasbourg, France; ²Pathology Department, Cochin University Hospital, Assistance Publique-Hopitaux de Paris (APHP), Paris, France; ³Hematology Department, Nantes University Hospital, Nantes, France; ⁴Hematology Department, Grenoble University Hospital, La Tronche, France; ⁵Hematology Department, Necker University Hospital, Assistance Publique-Hopitaux de Paris (APHP), Paris, France; ⁶Pathology Department, Lyon University Hospital, Hospices Civil de Lyon, Lyon, France; ⁷Pathology Department, Avicenne Hospital, Assistance Publique-Hôpitaux de Paris, Bobigny, France; ⁸Pathology Department, Nantes University Hospital, Nantes, France; ⁹Hematology Biology, Nantes University Hospital, Nantes, France; ¹⁰Lymphoma Academic Research Organisation (LYSARC), Centre Hospitalier Lyon Sud, Pierre-Bénite, France; ¹¹Pathology Department, Necker University Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France

**Introduction:** Aggressive Mantle Cell Lymphoma (A-MCL), including blastoid and pleomorphic variants, is a rare morphological subtype of MCL with a more adverse prognosis. Few data are available in the literature focusing specifically on this rare subtype of MCL. The aim of our study was to perform a retrospective analysis of all
A-MCL from the LYSA cohort included in clinical trials in order to compare their clinico-biological characteristics and outcomes to classical variants.

**Methods:** Individual data from patients enrolled in 5 studies were analysed, respectively RiPAD+C (Houot R. et al, Ann Oncol 2011), RiBVD (Gressin R. et al, Haematologica 2018), MCL Younger (Hermine O. et al, Lancet 2016), MCL Elderly (Kluin-Nelemans H.C. et al, NEJM 2012) and LYMA (Le Gouill S. et al, NEJM 2017) trials. A centralized pathological review of all cases was performed at the time of inclusion in each clinical trial, but an additional central review, according to 2017 WHO classification, was specifically achieved by expert pathologists from the LYSA for all A-MCL. Univariate analysis of Progression-Free Survival (PFS) and Overall Survival (OS) were performed and a stratified multivariate Cox model was used to assess the correlation between histologic subtypes and outcomes.

**Results:** Data from 773 patients were collected, 59 with an A-MCL (53 pleomorphic and 6 blastoid) and 714 with a classical form. The two cohorts were similar in age (median: 61.2 y; range: 27-83), ECOG status, B symptoms, extra-nodal involvement, MIPI risk group (low: 39%; intermediate: 30%; high: 31%) and haematological parameters. A-MCL patients differed significantly in Ann Arbor stage (stage III-IV: 86% in A-MCL vs 96%, p = 0.002), bulky disease (31% in A-MCL vs 19%, p = 0.040), LDH level (LDH > normal limit: 63% in A-MCL vs 40% p<0.001) and Ki67 (Ki67 > 30%: 87% in A-MCL vs 29%, p<0.001). With a median follow up of 60 months, univariate PFS was significantly lower for A-MCL with a median of 28 mo (95% CI = 15-NR) vs 59 mo (95% CI = 54-72) for classical variants (p = 0.048). Univariate OS was also significantly lower for A-MCL patients with a median of 65 mo (95% CI: 29-NR) vs 109 mo (95% CI: 94-NR) (p = 0.005). In multivariate analysis stratified by studies, A-MCL subtype (HR (95% CI) for PFS 1.50 (1.03-2.19), OS 1.82 (1.21-2.74)) elevated LDH level (PFS 1.62 (1.3-2.03), OS 1.79 (1.36-2.35)) and intermediate/high MIPI scores (intermediate MIPI: PFS 1.64 (1.21-2.22), OS 1.82 (1.24-2.67); high MIPI: PFS 2.71 (1.96-3.74), OS 3.56 (2.4-5.29)) were significantly associated with a worse PFS and OS.

**Conclusion:** This study describes one of the largest cohorts of well-characterized A-MCL patients included in clinical trials. All A-MCL were strictly classified according to the 2017 WHO classification. A-MCL variant was associated with high LDH level, Ki67 > 30% and bulky disease. PFS and OS were significantly lower for A-MCL compared to classical form.

**Keywords:** mantle cell lymphoma (MCL).

185
COMPREHENSIVE ANALYSIS OF
PROGNOSTIC FACTORS, OUTCOMES AND
MUTATION PROFILE IN PATIENTS WITH
AGGRESSIVE HISTOLOGY
(BLASTOID/PLEOMORPHIC) OR

TRANSFORMED MANTLE CELL
LYMPHOMA

P. Jain<fnref n="1" /> | R. Kanagal-Shamanna² | S. Zhang<fnref n="3" /> |
C. Ok² | G. Nogueras Gonzalez⁴ | O. Gonzalez-Pagan⁵ |
A. Ghorab<fnref n="1" /> | P. Boddu<fnref n="1" /> | W. Chen<fnref n="1" /> | H. Ju Lee<fnref n="1" /> |
K. Nomie<fnref n="1" /> | L. Fayad<fnref n="1" /> | J. Westin<fnref n="1" /> | L. Nastoupil<fnref n="1" /> |
K. Patel² | S. Ahmed<fnref n="1" /> | S.P. Iyer<fnref n="1" /> | S. Parmar<fnref n="1" /> |
R. Champlin⁶ | S. Neelapu<fnref n="1" /> | J.L. Medeiros² |
J. Romaguera<fnref n="1" /> | N. Fowler<fnref n="1" /> | L. Wang<fnref n="3" /> | M.L. Wang<fnref n="1" />

**Introduction:** Analysis of clinical, molecular features and prognostic factors in aggressive histology MCL (AH-MCL; blastoid or pleomorphic) is not described. AH-MCL can be [de novo (dnMCL) or transformed from classic morphology (t-MCL)].

**Methods:** We reviewed 183 pts with AH-MCL (108 were *dn*-MCL and 75 were *t*-MCL). Overall, 152 were blastoid and 31 pleomorphic. Pt characteristics were collected at the time of diagnosis in *dn*MCL and at transformation. Overall survival (OS) - time of initial diagnosis of AH-MCL to death/last follow-up and failure free survival (FFS) - time of starting first-line treatment of AH-MCL to treatment discontinuation. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed from biopsy samples from 44 pts (*dn*MCL = 32, *t*-MCL = 12).

**Results:** Median follow up after diagnosis of AH-MCL was 19.6 months (0.1-168). Clinical features of AH-MCL were - 20% B symptoms, 6% had ECOG PS (3-4), CNS involvement in 4%, 19% with GI involvement, 67% with marrow involvement and 27% had leukemic phase. The median Ki-67% was 70% (10-100), complex karyotype 13%, LDH > ULN in 45%, Sox-11 positive in 81%, median β2M of 2.9 mg/dL. Pts with t-MCL were distinct from *dn*MCL in having significantly higher median age, poor PS, lower WBC count, lower marrow involvement and lower rate of achieving CR with first line treatments. All pts with t-MCL had prior treatment for MCL before transformation with median lines of prior therapy 2 (range 1-8). The median OS after diagnosis of AH-MCL was 33 months (48 and 14 months for *dn*MCL and *t*-MCL respectively; p = 0.001; **Figure-1A-B**). Univariate and multivariate (MVA) analyses were performed. Recursive partitioning analysis revealed that Ki-67% ≥50% (**Fig. 1C**), LDH ≥1519, β2M ≥ 4, hemoglobin <14 and platelet count <63,000 had increased risk of death. In MVA, factors significantly associated with inferior OS in AH-MCL were age (>72 yrs), *t*-MCL category, Ki-67% ≥50%, ECOG-PS (1-4 compared to 0). Presence of *t*-MCL, high Ki-67%, CNS involvement were predictive of inferior FFS. Pts who received ibrutinib based or R-HCVAD based therapies had lower hazard ratio for FFS. Subset analysis of blastoid vs pleomorphic MCL did not reveal any significant

<footnote n="1">¹Lymphoma and Myeloma, UT MD Anderson Cancer Center, Houston, United States; ²Hematopathology, UTMDACC, Houston, United States;</footnote>

<footnote n="3">³Genomic Medicine, UTMDACC, Houston, United States; ⁴Biostatistics, UTMDACC, Houston, United States; ⁵Internal Medicine, UT Houston, Houston, United States; ⁶Stem Cell Transplantation, UTMDACC, Houston, United States</footnote>
<figure><img src="image_135.png" /><figcaption>Figure 1 (A-E) Survival of patients with aggressive histology MCL (AH- Blastoid or pleomorphic) - overall, by MCL category (denovo AH vs transformed MCL) and Ki-67%. D) Failure free survival by type of first line treatment at diagnosis of AH-MCL. E) Oncoprint showing the somatic mutations identified by whole exome sequencing by Ki-67% in AH-MCL (High n=32; Ki-67 ≥50%) and (Low n=10; Ki-67 <50%).</figcaption></figure>

difference in clinical features of survival but FFS was inferior in pleomorphic category.

Frequently mutated genes in AH-MCL were ATM, CCND1, NOTCH1, KMT2D, KMT2C, TP53, SPEN, SMARCA4 and NSD2. There was no statistically significant difference in the mutation profile of dnMCL vs t-MCL. Significant differences in the mutation burden between pts with high Ki-67 (≥50%) and those with low Ki-67%, were noted - ATM (p = 0.001), CCND1 (p<0.001), NOTCH1(p = 0.001), TP53 (p = 0.006), SMARCA4 (p = 0.006), NSD2 (p = 0.02), NOTCH3 (p = 0.02) **Figure-1E**.

**Conclusions:** We have shown that pts with AH-MCL with t-MCL and/or Ki-67% ≥ 50% are a very high risk category of MCL. Further analysis are ongoing and will be reported.

**Keywords:** mantle cell lymphoma (MCL).

S. Husby<fnref n="1" /> | C.W. Eskelund<fnref n="1" /> | F. Favero² |

F.G. Rodriguez-Gonzalez² | A. Kolstad³ |

L.B. Pedersen<fnref n="1" /> | R. Räty⁴ | C.H. Geisler<fnref n="1" /> |

M. Jerkeman⁵ | J. Weischenfeldt² | K. Grønbæk<fnref n="1" />

<footnote n="1">¹Dept. of Hematology, Rigshospitalet, Copenhagen N, Denmark; ²Biotech Research & Innovation Center (BRIC), University of Copenhagen,</footnote>
<figure><img src="image_136.png" /></figure>

Copenhagen N, Denmark; ³Dept. of Oncology, Oslo University Hospital, Oslo, Norway; ⁴Dept. of Hematology, Helsinki University Hospital, Helsinki, Finland; ⁵Dept. of Oncology, Lund University Hospital, Lund, Sweden

**Introduction:** Patients with lymphoma often carry somatic mutations in their hematopoietic stem cells, also called clonal hematopoiesis (CH). These mutations can be detected in both peripheral blood (PB) and bone marrow (BM), and increase the risk of later therapy-related malignancy (Takahashi *et al*., Lancet Oncology 2017). It is unknown how CH clones evolve during and after treatment for lymphoma. The clinical impact is also unclear.

We therefore investigated CH in consecutive samples from a cohort of homogeneously treated mantle cell lymphoma (MCL) patients with available minimal residual lymphoma-disease (MRD) status and long-term follow-up.

**Methods:** Newly diagnosed patients with MCL were enrolled in the two Nordic trials, MCL2 and MCL3, and treated with six alternating cycles of R-CHOP and R-HD-AraC followed by high-dose chemotherapy (BEAM/BEAC) and autologous stem cell transplant (ASCT). From 148 patients with available MRD status, we retrieved samples (BM and/or PB) before treatment, during induction chemotherapy and ASCT, and in the follow-up period (median 4.0 years after ASCT). CH was investigated by targeted next-generation sequencing with the use of unique molecular identifiers allowing deep sequencing.

A total of 378 consecutive samples were analyzed. Patients were screened for mutations down to a variant allele frequency (VAF) cut-off of 0.01 in MRD negative samples (n = 148) taken shortly after

ASCT. Identified mutations were tracked with deep sequencing (down to 0.001 VAF) in samples before chemotherapy, during induction treatment as well as in follow-up samples.

**Results:** In 148 MCL patients with samples taken after ASCT (all MRD negative) we identified 63 CH mutations in 51 patients (34%, median VAF 0.033). The mutated genes were mainly DNMT3A (n = 51), TET2 (n = 6), PPM1D (n = 5), TP53 (n = 4), and ASXL1 (n = 4). Of these mutations, 30 were also identified before administration of chemotherapy with VAF ranging from 0.0019 to 0.414 (Figure 1). After induction chemotherapy, high-dose chemotherapy, and ASCT the size of the CH clones had grown significantly with a median increase of 129.3% (IQR = 6.8%-245.7%, paired samples Wilcoxon test p = 0.0003). This amounted to a 162.7% median increase per year. In the follow-up period after ASCT, with no pressure from chemotherapy, the mutations did not continue to increase in size (5.0% median increase per year, [IQR = -7.6%-59.4%], paired samples Wilcoxon test p = 0.165). CH was in this cohort of first line treated MCL patients not associated with an inferior overall survival (HR 0.98, 95%CI 0.52-1.80). Analysis of other outcomes are ongoing and will be presented at the meeting.

**Conclusions:** The pressure of induction chemotherapy and ASCT significantly increased the size of CH clones. Many were detectable already at diagnosis at very low frequencies. However, after end of chemotherapy, the mutated clones became stable and ceased to grow. CH was not associated with an inferior survival in MCL patients treated with immunochemotherapy and ASCT in first line.

**Keywords:** clonal hematopoiesis; mantle cell lymphoma (MCL); R-CHOP.
# 187 MAGNIFY PHASE IIIB INTERIM ANALYSIS: FIRST REPORT OF INDUCTION R² FOLLOWED BY MAINTENANCE IN PATIENTS WITH RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA

J. Sharman¹ | M. Coleman² | A. Yacoub³ |
J. Melear⁴ | S. Fanning⁵ | K. Kolibaba⁶ |
F. Lansigan⁷ | C. Reynolds⁸ | K. Foon⁹ | J. Li¹⁰ |
M. Llorente⁹ | M. Rummel¹¹ | D. Andorsky¹²

¹Willamette Valley Cancer Institute and Research Center, US Oncology Research, Eugene, United States; ²Clinical Research Alliance Inc., Weill Cornell Medicine, New York, United States; ³Hematology, University of Kansas Cancer Center, Westwood, United States; ⁴Texas Oncology - Austin, US Oncology Research, Austin, United States; ⁵Greenville Health System, US Oncology Research, Greenville, United States; ⁶Compass Oncology, US Oncology Research, Vancouver, United States; ⁷Hematology, Dartmouth-Hitchcock Medical Center, Lebanon, United States; ⁸Hematology, IHA Hematology Oncology Consultants - Ann Arbor, Ypsilanti, United States; ⁹Global Medical Affairs, Celgene Corporation, Summit, United States; ¹⁰BioStatistics, Celgene Corporation, Summit, United States; ¹¹Hematology, Justus-Liebig Universität, Giessen, Germany; ¹²Rocky Mountain Cancer Centers, US Oncology Research, Boulder, United States

**Introduction:** The combination of lenalidomide + rituximab (R²) has demonstrated efficacy comparable to standard chemoimmunotherapy regimens in the frontline setting, and improved efficacy compared to rituximab monotherapy in the relapsed/refractory (R/R) setting among patients with indolent B-cell NHL. The multicenter, non-registrational phase IIb MAGNIFY trial enrolled patients with R/R follicular, marginal zone, and mantle cell lymphomas (NCT01996865). This evaluation focuses on MCL patients, an aggressive though uncommon form of NHL, to determine the optimal duration of induction and maintenance therapy.

<table><caption>TABLE 1 Efficacy for induction R² in evaluable R/R MCL patients</caption><thead><tr><th></th><th>ORR, %</th><th>CR, %</th><th>Median TTR, mo (range)</th><th>Median DOR, mo (95% CI)*</th><th>Median PFS, mo (95% CI)*</th></tr></thead><tbody><tr><td>All MCL patients</td><td>54</td><td>38</td><td>2.9 (2.4-9.9)</td><td>27.4 (14.6-31.6)</td><td>10.6 (5.5-30.9)</td></tr><tr><td>R-refractory status</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>31</td><td>31</td><td>2.8 (2.7-6.6)</td><td>31.6 (NR-NR)</td><td>5.3 (2.3-34.3)</td></tr><tr><td>No</td><td>63</td><td>40</td><td>2.9 (2.4-9.9)</td><td>27.4 (5.9-NR)</td><td>14.7 (5.7-30.9)</td></tr></tbody></table>

**Methods:** R² treatment includes lenalidomide 20 mg/d, d1-21/28 + rituximab 375 mg/m²/wk cycle 1 and q8wk cycles 3+ for 12 cycles of induction followed by 1:1 randomization to continued R² vs rituximab maintenance in patients with stable disease or better. Rituximab refractory was defined as a best response of progressive/stable disease to rituximab-containing treatment or partial/complete response for < 6 mo following the last dose of rituximab. These analyses evaluate the interim primary endpoint of ORR by 1999 IWG criteria for induction R² in efficacy-evaluable MCL patients receiving ≥ 1 treatment and with baseline/post-baseline assessments, including those who were rituximab refractory.

**Results:** Seventy MCL patients were enrolled with a median age of 69.5 y (range, 51-88), 90% stage III/IV disease, 43% bulky disease, and 100% had received prior rituximab-containing therapy. At a median follow-up of 14.6 mo, efficacy-evaluable MCL patients showed a 54% ORR and 38% CR (Table). Median TTR was 2.9 mo, median DOR was 27.4 mo, and median PFS was 10.6 mo. Seventeen of 70 patients have been randomized and entered maintenance. The most common all-grade adverse events (AEs; ≥ 20%) were 45% neutropenia, 40% fatigue, 24% constipation, 24% dyspnea, 22% anemia, 21% diarrhea, and 21% nausea. Grade 3/4 neutropenia was 39%; all other grade 3/4 AEs were ≤ 10%.

**Conclusions:** This first report of patients with R/R MCL from the MAGNIFY study showed that R² therapy is active with a tolerable safety profile, including improving activity among patients considered sensitive to prior rituximab.

**Keywords:** lenalidomide; mantle cell lymphoma (MCL); rituximab.

**Disclosures:** Sharman, J: Employment Leadership Position: US Oncology; Consultant Advisory Role: Pharmacyclics, Celgene, TG Therapeutics, Genentech, Abbvie, Acerta Pharma/Astra Zeneca; Research Funding: (all institutional) Pharmacyclics, Genentech, Celgene, Acerta Pharma, Gilead Sciences, Seattle Genetics, TG Therapeutics, Merck, Takeda; Other Remuneration: Expert Testimony: Gilead Sciences. Colman, M: Consultant Advisory Role: Medaptive Health; Stock Ownership: Medaptive Health; Other Remuneration: Speakers' Bureau: Medaptive Health. Yacoub, A: Consultant Advisory Role: Medadaptive; Other Remuneration: Speakers' Bureau: Medaptive Health. Melear, J: Employment Leadership Position: Medaptive Health. Fanning, S: Consultant Advisory Role: Medaptive Health; Stock Ownership: Medaptive Health; Other Remuneration: Speakers' Bureau: Medaptive Health. Kolibaba, K: Employment Leadership Position: Compass Oncology; Consultant Advisory Role: Gilead Sciences; Honoraria: TG Therapeutics; Research Funding: (all institutional) Acerta, Celgene, Cell Therapeutics, Genentech/Roche, Gilead Sciences, Janssen, Pharmacyclics, Novartis, Seattle Genetics, TG Therapeutics; Other Remuneration: Travel: TG Therapeutics. Lansigan, F: Consultant Advisory Role: Spectrum; Research Funding: Spectrum. Li, J: Employment Leadership Position: Celgene; Stock Ownership: Celgene, Medaptive. Llorente, M: Employment Leadership Position: Celgene; Stock Ownership: Celgene, Medaptive. Rummel, M: Consultant Advisory Role: Medadaptive; Honoraria: Medadaptive; Research Funding: Medadaptive; Other

<footnote>*If patients were already in maintenance at data cutoff, then response assessments also contributed to DOR and PFS.</footnote>
Remuneration: *Travel: Medadaptive. Andorsky, D:* Consultant Advisory Role: *Medadaptive; Research Funding: Medaptive.*

# 188 EARLY PROGRESSION OF MANTLE CELL LYMPHOMA DEPICTS A HIGH-RISK DISEASE WITH POOR RESPONSE TO SUBSEQUENT THERAPIES AND A DISMAL OUTCOME

C.W. Eskelund¹ | A. Kolstad² | I. Glimelius³ |
R. Räty⁴ | L.R. Gjerdrum⁵ | K. Sonnevi⁶ |
P. Josefsson⁷ | H. Nilsson-Ehle⁸ | H. Bentzen⁹ |
U. Fagerli¹⁰ | O. Kuittinen¹¹ | J. Haaber¹² |
L.B. Pedersen¹ | M.T. Larsen¹ | C.H. Geisler¹ |
M. Hutchings¹ | M. Jerkeman¹³ | K. Grønbæk¹

¹Dept of Hematology, Rigshospitalet, Copenhagen O, Denmark; ²Dept of Oncology, Oslo University Hospital, Oslo, Norway; ³Dept of Oncology, Uppsala University and Uppsala Akademiska Hospital, Uppsala, Sweden;

⁴Dept of Hematology, Helsinki University Hospital, Helsinki, Finland;

⁵Dept of Pathology, Zealand University Hospital, Roskilde, Denmark;

⁶Dept of Hematology, Karolinska University Hospital, Stockholm, Sweden;

⁷Dept of Hematology, Herlev Hospital, Herlev, Denmark; ⁸Dept of Hematology, Sahlgrenska University Hospital, Göteborg, Sweden; ⁹Dept of Hematology, Aarhus University Hospital, Aarhus, Denmark; ¹⁰Dept of Oncology, St. Olav's Hospital, Trondheim, Norway; ¹¹Dept of Oncology, Kuopio University Hospital, Kuopio, Finland; ¹²Dept of Hematology, Odense University Hospital, Odense, Denmark;

¹³Dept of Oncology, Lund University Hospital, Lund, Sweden

**Introduction:** The prognosis of mantle cell lymphoma (MCL) has improved in recent years due to intensified frontline therapy. However, the disease remains very heterogeneous, and the only potential cure is allogeneic stem cell transplant (allo-SCT). After relapse,

prognosis is generally poor and there is no consensus about therapy.

**Methods:** We conducted a retrospective cohort study of all 149 patients with progression/relapse of disease (POD) after initial treatment in the Nordic MCL trials, MCL2 and MCL3 - both representing intensive cytarabine-containing frontline regimens followed by auto-SCT.

**Results:** Median time from diagnosis to POD was 36 months (range 1-164), and median OS and PFS after POD (OS-2 and PFS-2) were 22 and 12 months, respectively. Median follow-up from POD was 85 months.

As previously shown (Visco et al, BJH, 2018), time to POD was highly prognostic. Patients with early POD (TTP <24 months, n = 49), showed a median OS-2 of 6.6 months compared to 46 months for patients with late relapses (p<0.001, HR: 3.2 (95% CI 2.2-4.8)). Likewise, PFS-2 was 3.6 and 18 months, respectively (p<0.001, HR: 3.5 (2.2-5.5)). Early POD was associated with MIPI high-risk (p = 0.08), Ki-67>30% (p = 0.007) and TP53-mutations (p<0.001).

Data on later lines of therapy was available for 114 (2nd line), 65 (3rd line) and 34 patients (4th line). Treatment responses gradually decreased. After 2nd, 3rd, and 4th line, respectively, 73% (CR 44%), 63% (CR 37%) and 46% (CR 24%) responded to therapy, and TTP decreased from 11.5, through 6.7, to 2.9 months. Furthermore, patients with early POD after frontline therapy, responded significantly worse to all succeeding lines of therapy (2nd line: p<0.001, 3rd line: p = 0.04, and 4th line: p = 0.02, Figure 1). Not surprisingly, shorter duration from previous line of therapy in general was associated with significantly poorer TTP (p<0.001).

Allo-SCT was performed in 25 patients. Median PFS from allo-SCT was 34 months; however, again patients with early POD (n = 3) showed significantly inferior outcomes (3.6 vs. 35 months, p<0.001, HR 11.8 (2.6-54)). Seven (28%) patients remained alive in CR after a median of 72 months from the allo-SCT.

Comparing different regimens, R-bendamustine seemed superior to other combination chemo-immunotherapies (2nd line: HR 0.46 (0.25-0.86); 3rd line: 0.26, (0.08-0.80); 4th line: 0.15, (0.03-0.7); however, when adjusting for duration from last line of therapy, this became insignificant.

Ibrutinib was administered at only 7 occasions. Despite the low number, these patients showed prolonged responses, even when adjusting for duration from last line of therapy (HR = 0.076, (0.01-0.55)).

**Conclusions:** We present data of patients who experienced POD after initial treatment in the Nordic trials, MCL2 and MCL3. We confirm the significance of time to POD as both a prognostic and predictive marker. Allo-SCT did not seem to omit this difference, but data on newer targeted agents for early progressors is much needed. R-bendamustine was superior to other more intensive combination chemo-immunotherapies, but in general, it seemed to have been administered in less aggressive states of disease.

**Keywords:** autologous stem cell transplantation (ASCT); mantle cell lymphoma (MCL).

<figure><img src="image_137.png" /></figure>
189
THE EFFICACY OF IBRUTINIB IN PATIENTS WITH RELAPSED MANTLE CELL LYMPHOMA AFTER FIRST LINE INTENSIVE CHEMO-IMMUNOTHERAPY AND ASCT – A RETROSPECTIVE STUDY FROM THE LWP-EBMT

C.N. Burney¹ | S. Robinson¹ | A. Boumendil² |
H. Finel² | I. Khvedelidze² | H. Hunter³ | X. Poire⁴ |
B. Lioure⁵ | K. Peggs⁶ | R. Foa⁷ | S. Pillai⁸ |
T. van Meerten⁹ | J. Bargay Lleonart¹⁰ | C. Schmid¹¹ |
V. Vergote¹² | A. Ganser¹³ | L. Castagna¹⁴ |
G. Mufti¹⁵ | S. Montoto¹⁶

¹Department of Haematology, University Hospitals Bristol NHS Trust, Bristol, United Kingdom; ²Lymphoma Working Party, European Society for Blood and Marrow Transplantation, Paris, France; ³Department of Haematology, University Hospitals Plymouth NHS Trust, Plymouth, United Kingdom; ⁴Section of Haematology, Cliniques Universitaires St-Luc, Brussels, Belgium; ⁵Onco-Hematologie, Nouvel Hopital Civil, Strasbourg, France; ⁶Department of Haematology, University College London Hospitals NHS Trust, London, United Kingdom; ⁷Division of Haematology, Univ. La Sapienza, Rome, Italy; ⁸Department of Haematology, University Hospital of North Staffordshire, Stoke-On-Trent, United Kingdom; ⁹Hematologie Groningen, University Medical Center, Groningen, Netherlands; ¹⁰Department of haematology, Hospital son Llatzer, Palma de Mallorca, Spain; ¹¹Department of oncology and hematology, Klinikum Augsburg, Augsburg, Germany; ¹²Department of haematologie, University Hospital Gasthuisberg, Leuven, Belgium; ¹³Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany; ¹⁴Bone Marrow Transplant Unit, Istituto Clinico Humanitas, Rozzano, Milan, Italy; ¹⁵Department of Haematological Medicine, GKT School of Medicine, London, United Kingdom; ¹⁶Centre for Haemato-Oncology, Barts NHS Health Trust, London, United Kingdom

**Introduction:** Current first line therapy for fit patients with mantle cell lymphoma (MCL) is cytarabine and chemo-immunotherapy induction followed by an autologous stem cell transplant (ASCT). Responses are excellent but there is a continuous pattern of relapse. Ibrutinib is an effective therapy for relapsed MCL, but there is no published data of its efficacy in the post ASCT setting.

**Methods:** This was a retrospective analysis of the EBMT registry. Inclusion criteria:- patients with MCL ≥18 years old, 1st line therapy containing cytarabine and rituximab, ASCT in first CR/PR between 2009 and 2016, received ibrutinib for first relapse after ASCT.

**Results:** 66 patients were included (Table 1). Relapse occurred at a median of 25 months (range 15-33) after ASCT and ibrutinib was started at a median of 30 days after relapse (range 10-54). Overall response rate (ORR) was 74% [32 (48%) CR, 18 (27%) PR]. The median duration of response from the start of ibrutinib was

<table><caption>TABLE 1 Patient characteristics</caption><thead><tr><th>Patient characteristics</th><th></th><th>n (%)</th></tr></thead><tbody><tr><td>Age (years)</td><td>Median (range)</td><td>59 (39-73)</td></tr><tr><td rowspan="2">Sex</td><td>Male</td><td>59 (89)</td></tr><tr><td>Female</td><td>7 (11)</td></tr><tr><td rowspan="4">MIPI score at diagnosis</td><td>High</td><td>15 (27)</td></tr><tr><td>Intermediate</td><td>22 (33)</td></tr><tr><td>Low</td><td>19 (34)</td></tr><tr><td>Unknown</td><td>10 (15)</td></tr><tr><td rowspan="3">Stage at diagnosis</td><td>III</td><td>9 (14)</td></tr><tr><td>IV</td><td>56 (85)</td></tr><tr><td>Unknown</td><td>1 (2)</td></tr><tr><td rowspan="7">Induction chemoimmunotherapy</td><td>Rituximab containing</td><td>66 (100)</td></tr><tr><td>HD cytarabine containing</td><td>66 (100)</td></tr><tr><td>CHOP like</td><td>30 (45)</td></tr><tr><td>CHOP/DHAP alternating</td><td>15 (23)</td></tr><tr><td>DHAP</td><td>7 (11)</td></tr><tr><td>R-AraC alone</td><td>6 (9)</td></tr><tr><td>Oxaliplatin based</td><td>5 (8)</td></tr><tr><td>Other</td><td>3 (5)</td></tr><tr><td>Lines of therapy to achieve CR/PR pre ASCT</td><td>Median (range)</td><td>1 (1-3)</td></tr><tr><td rowspan="2">Response pre ASCT</td><td>CR</td><td>43 (65)</td></tr><tr><td>PR</td><td>23 (35)</td></tr><tr><td>Time from diagnosis to ASCT (months)</td><td>Median (range)</td><td>7 (3-70)</td></tr><tr><td rowspan="4">Conditioning for ASCT</td><td>BEAM</td><td>48 (73)</td></tr><tr><td>LEAM</td><td>7 (11)</td></tr><tr><td>FEAM</td><td>4 (6)</td></tr><tr><td>Other</td><td>7 (11)</td></tr><tr><td>TBI conditioning for ASCT</td><td></td><td>2 (3)</td></tr><tr><td>Engrafted post ASCT</td><td></td><td>66 (100)</td></tr><tr><td rowspan="2">Response at 100 days post ASCT</td><td>CR</td><td>54 (82)</td></tr><tr><td>PR</td><td>12 (18)</td></tr></tbody></table>

16 months (range 2-40); 22, 15 and 2 months for those achieving CR, PR, SD respectively. The median duration of ibrutinib therapy was 5 months (range 0.2-39). At last follow-up, 23 (35%) patients remain on ibrutinib. In 16 patients ibrutinib was stopped because of a subsequent SCT, in 13 because of relapse and in 5 due to toxicity (cytopenia, infection, tachycardia, hepatitis and poor tolerance, 1 case each). In 9 cases ibrutinib was stopped due to other/unknown reasons. 21 patients (33%) relapsed post ibrutinib (in 8 cases ibrutinib had been stopped for second SCT or toxicity), at a median of 12 months (range 1-34), of whom 17 (81%) received further therapy.
Twenty-three patients (38%; 16 in CR/PR after ibrutinib only) had a subsequent SCT. 22 patients had an alloSCT (11 MUD, 5 MSD, 6 mismatch related) with reduced intensity conditioning in 19, and 1 patient had a 2nd ASCT. Acute GvHD occurred in 50% of the patients and chronic in 50% (extensive in 3). With a median follow up of 17 months post alloSCT, 18 (63%) are in remission.

With a median follow-up of 22 months after starting ibrutinib, 49 patients are alive, with 35 (71%) in CR and 4 (8%) in PR. Causes of death were MCL in 14 cases (82%), alloSCT toxicity in 2 patients and unknown in 1 case. 2-year OS after starting ibrutinib was 72% (69% for alloSCT patients) and 2-year PFS 62%.

**Conclusion:** Although ibrutinib results in a high ORR, the median response duration is 16 months, suggesting that consolidative alloSCT should be considered in fit patients with an available donor. Ibrutinib does not seem to increase the toxicity of alloSCT.

**Keywords:** autologous stem cell transplantation (ASCT); ibrutinib; mantle cell lymphoma (MCL).

## 190 IBRUTINIB COMPARED TO STANDARD CHEMOTHERAPY FOR CENTRAL NERVOUS SYSTEM RECURRENCE OF MANTLE CELL LYMPHOMA

C. Rusconi<fnref n="1" /> | D. Tucker² | S. Bernard³ | C. Muzi<fnref n="1" /> |
L. Crucitti<fnref n="1" /> | P. Stefani⁴ | M. Cox⁵ | G. Gini⁶ |
A. Re⁷ | R. Sciarra⁸ | A. Liberati⁹ | L. Morello¹⁰ |
A. Arcari¹¹ | D. Mannina¹² | O. Vitagliano¹³ |
R. Sartori¹⁴ | A. Chiappella¹⁵ | M. Balzarotti¹⁰ |
U. Vitolo¹⁵ | C. Thieblemont³ | S. Rule¹⁶ | C. Visco¹⁷

<figure><img src="image_138.png" /><figcaption>Fig1: Progression free survival in patients treated with standard CT compared with patients treated with ibrutinib</figcaption></figure>

NHTrust, Truro, Cornwall, United Kingdom; ³Service d'Onco-Hématologie, Hôpital Saint-Louis, AP-HP, Paris, France; ⁴U.O.C. di Ematologia, Dipartimento di Medicina Specialistica, Unità Locale Socio-Sanitaria della Marca Trevigiana, Treviso, Italy; ⁵Haematology Unit, Department of Clinical and Experimental Medicine, Sapienza University, AO Sant'Andrea, Rome, Italy; ⁶Division of Hematology, Azienda Ospedaliera Universitaria Ospedali Riuniti di Ancona, Ancona, Italy; ⁷U.O. Ematologia, Spedali Civili di Brescia, Brescia, Italy; ⁸Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; ⁹Università di Perugia, AO Santa Maria di Terni, Terni, Italy; ¹⁰Department of Medica Oncology and Hematology, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy; ¹¹Hematology Unit, Ospedale Guglielmo da Saliceto, Piacenza, Italy; ¹²UOC di Ematologia, Azienda Ospedaliera Papardo, Messina, Italy; ¹³Division of Hematology, Cardarelli Hospital, Naples, Italy; ¹⁴Hematology Department, Castelfranco Veneto Hospital, ULSS 2 Marca Trevigiana, Castelfranco Veneto, Treviso, Italy; ¹⁵Hematology, AO Città della Salute e della Scienza di Torino, Turin, Italy; ¹⁶Plymouth University, Peninsula Schools of Medicine ad Dentistry, Plymouth, United Kingdom; ¹⁷Department of Medicine, Section of Hematology, University of Verona, Verona, Italy

**Background:** Central nervous system (CNS) relapse of Mantle Cell Lymphoma (MCL) is a rare condition for which a standard of care has not been identified. Responses to conventional treatment for CNS-MCL are poor and prognosis is dismal, with median survival of less than 6 months. Ibrutinib is approved for relapsed/refractory MCL; small series demonstrated its efficacy on CNS localization thanks to the capability to cross the blood-brain barrier.

**Methods:** We retrospectively analyzed a multi-center series of consecutive patients (pts) with CNS relapse of systemic MCL with the aim to evaluate outcome of pts treated with ibrutinib compared to pts treated with a standard chemotherapy (CT) and previously described in the MANTLE-FIRST study. Overall survival (OS) and progression-free survival (PFS) were estimated from the time of initiation of therapy for CNS-MCL.

**Results:** The entire series consisted of 31 pts: 16 pts (52%) received conventional CT (standard cohort), while 15 pts (48%) received ibrutinib monotherapy (ibrutinib cohort). Median age was 54 years (range: 39-70) in the standard cohort and 60 years (range: 54-76) in the ibrutinib cohort. Blastoid variant was diagnosed in 6 pts in the standard and in 5 pts in the ibrutinib cohort. A ki-67 value was available in 12 pts in the standard cohort (≥30% in these cases), while in the ibrutinib cohort ki-67 was available in 8 pts (≥30% in 5 pts, 62%). MIPI score was high in 46% and 73% of pts in standard and ibrutinib cohort. Upfront treatment for systemic MCL included high-dose cytarabine and autologous stem cell transplantation in 100% and 68% in the standard cohort and in 80% and 33% in the ibrutinib cohort. Median number of therapies for MCL before CNS recurrence was 1 in the standard and 2 (range: 1-3) in the ibrutinib cohort. In the standard cohort, treatment for CNS relapse consisted of rituximab plus high-dose methotrexate in 5 pts (33%), bendamustine in 6 pts (37%),

<footnote n="1">¹Division of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; ²Department of Haematology, Royal Cornwall</footnote>
ifosfamide in 2 pts (12%) and other regimens in 3 pts (18%). Pts treated with ibrutinib received 560 mg p.o. daily. Intratechal CT was added in 5 pts (31%) and 7 pts (47%) in standard and ibrutinib cohort. Radiotherapy was delivered to 3 pts, all in the standard cohort, in one case as consolidation and in 2 cases as salvage. With a median follow-up of 10.4 months, the 1-year PFS and OS of the entire study population are 24% and 46%. A statistically significant difference in 1-year PFS was observed in favor of ibrutinib versus standard CT (49% vs 6%, p = 0.044). The difference in 1-year OS in favor of ibrutinib versus standard CT did not reach statistical significance (57% vs 37%, p = 0.097). In the standard cohort only one pt is alive after allogeneic transplantation.

**Conclusion:** In this study, ibrutinib monotherapy appears to be effective for CNS-MCL; with the usual limitations of a retrospective analysis, our data show a benefit in PFS for CNS-MCL pts treated with ibrutinib in comparison to standard chemoimmunotherapy.

**Keywords:** ibrutinib; mantle cell lymphoma (MCL); salvage treatment.

**Disclosures:** Rusconi, C: Research Funding: Celgene, Takeda (advisory board), Roche, Celgene; Other Remuneration: Takeda, Roche.

# 191 UPDATED SAFETY AND EFFICACY DATA IN THE PHASE 1 TRIAL OF PATIENTS WITH MANTLE CELL LYMPHOMA (MCL) TREATED WITH BRUTON TYROSINE KINASE (BTK) INHIBITOR ZANUBRUTINIB (BGB-3111)

C.S. Tam<fnref n="1" /> | M. Wang² | D. Simpson³ | S. Opat⁴ |
G. Cull⁵ | J. Munoz⁶ | T.J. Phillips⁷ | W. Kim⁸ |
S. Atwal⁹ | R. Wei⁹ | J. Huang⁹ | R. Elstrom⁹ |
J. Trotman¹⁰

**Introduction:** Zanubrutinib, an investigational BTK inhibitor, has demonstrated greater selectivity for BTK vs other TEC- and EGFR-family

kinases in biochemical assays and shown favorable PK/PD properties in preclinical studies. In phase 1 testing, high plasma concentrations were achieved, resulting in complete and sustained 24-hour BTK inhibition in blood and lymph nodes in patients (pts) treated at 160 mg twice daily (bid; Tam. Blood 2016;128:642). Here, we present updated safety and efficacy data from pts with MCL.

**Methods:** This is a global, phase 1 study investigating zanubrutinib in pts with B-cell malignancies with indication-specific expansion cohorts. In the expansion phase, enrolled pts received zanubrutinib 320 mg daily or 160 mg bid (the RP2D). Treatment emergent adverse events (TEAEs) were summarized according to NCI CTCAE v4.03 and responses were assessed by CT scans as per Lugano Classification (Cheson. J Clin Oncol 2014;32:3059).

**Results:** As of 16 Sep 2018, 48 MCL pts were enrolled: 37 relapsed/refractory (R/R) and 11 treatment-naïve (TN) (Table). Of the 48 pts, 45 were evaluable for efficacy; 3 were not efficacy evaluable as they had not yet reached the first 12-week efficacy assessment. Median follow-up for efficacy evaluable pts was 16.0 mo (range, 1.6-38.2). Twenty-six pts discontinued treatment (16 due to progressive disease [PD]; 10 due to TEAEs including peripheral edema, small cell lung cancer, renal hematoma, ANCA-positive vasculitis with acute kidney injury, subdural hematoma, and myelodysplastic syndrome, pneumonia (2 pts), congestive cardiac failure, thalamic infarction). Five pts died due to TEAEs (1 pneumonia, 1 congestive cardiac failure, 1 thalamic infarction, and 2 sepsis/septic shock), none of which were assessed by investigator as related to zanubrutinib. Most common TEAEs of any cause (≥15% of pts) included diarrhea (35%), petechiae/purpura/contusion (31%), upper respiratory tract infection (27%), fatigue (25%), constipation (21%), rash (19%), back pain (17%), headache (17%) and peripheral edema (17%). Overall response rate (ORR) for TN, R/R and overall was 87.5% (7/8), 86.5% (32/37) and 86.7% (39/45) respectively (Table). Responses were based on computed tomography scans for most pts, as positron-emission tomography was not required. Median progression-free survival was 15.4 mo (Table).

**Conclusions:** Zanubrutinib monotherapy was shown to be well tolerated and highly active in pts with MCL, with high ORR and rate of CR.

**Keywords:** BTK inhibitors; mantle cell lymphoma (MCL).

**Disclosures:** Tam, C: Honoraria: Beigene, Janssen, AbbVie, Novartis; Research Funding: Janssen and AbbVie. Wang, M: Consultant Advisory Role: BioInvent; IO Biotech; Celgene; Juno Therapeutics; Janssen; Pharmacyclics; AstraZeneca; MoreHealth; Pulse BioSciences; AxImmune; Stock Ownership: MoreHealth; Honoraria: Janssen; Dava Oncology; OMI; PeerView Institute for Medical Education (PVI); Research Funding: Janssen; AstraZeneca; Acerta Pharma; Kite Pharma; Juno Therapeutics; BeiGene; Novartis; Celgene; BioInvent; Karus; Oncternal; Amgen; Other Remuneration: Travel, Accommodations, Expenses: Janssen; AstraZeneca; Dava Oncology; OMI. Simpson, D: Honoraria: Celgene, Janssen, Abbvie, Roche; Research Funding: Amgen, Pharmacyclics, Acerta, Beigene, Celgene, BMS, Roche, Sanofi, GSK; Other Remuneration: Travel, Accommodations, Expenses: Janssen, Celgene. Opat, S: Consultant Advisory Role: Roche, Janssen, Abbvie, Celgene, Takeda, Merck, Gilead, Mundipharma; Honoraria: Roche, Janssen, Abbvie, Celgene, Takeda, Merck, Gilead, Mundipharma; Research Funding: BeiGene, Roche, Janssen,

<footnote n="1">¹Department of Haematology, Peter MacCallum Cancer Centre, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia; ²Department of Lymphoma & Myeloma, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, United States; ³Waitemata DHB Haematology Service, North Shore Hospital, Auckland, New Zealand; ⁴Clinical Haematology, Monash Health, Monash University, Clayton, Victoria, Australia; ⁵Department of Haematology, Sir Charles Gairdner Hospital, University of Western Australia, Perth, WA, Australia; ⁶Hematology-Oncology, Banner MD Anderson Cancer Center, Gilbert, AZ, United States; ⁷Michigan Medicine Hematology Clinic, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States; ⁸Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; ⁹Research and Development Center, BeiGene (Beijing) Co., Ltd, Beijing, China; BeiGene USA, Inc., San Mateo, United States; ¹⁰Department of Haematology, Concord Repatriation Hospital, The University of Sydney, Concord, NSW, Australia</footnote>
<table><caption>**TABLE 1** Patient Characteristics, Safety, and Efficacy</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td>Patient characteristics</td><td>N = 48</td></tr><tr><td>Median (range) age, y</td><td>71 (42-90)</td></tr><tr><td>ECOG PS, n (%)</td><td></td></tr><tr><td>0</td><td>20 (41.7)</td></tr><tr><td>1</td><td>22 (45.8)</td></tr><tr><td>2</td><td>6 (12.5)</td></tr><tr><td>Stage at study entry, n (%)</td><td></td></tr><tr><td>Stage I</td><td>3 (6.3)</td></tr><tr><td>Stage II</td><td>1 (2.1)</td></tr><tr><td>Stage III</td><td>4 (8.3)</td></tr><tr><td>Stage IV</td><td>40 (83.3)</td></tr><tr><td>MIPI, n (%)</td><td></td></tr><tr><td>Low risk</td><td>12 (25.0)</td></tr><tr><td>Intermediate risk</td><td>18 (37.5)</td></tr><tr><td>High risk</td><td>18 (37.5)</td></tr><tr><td>Disease status, n (%)</td><td></td></tr><tr><td>Treatment-naïve</td><td>11 (22.9)</td></tr><tr><td>Relapsed/refractory</td><td>37 (77.1)</td></tr><tr><td>Median (range) no. of prior therapies</td><td>1 (1-4)</td></tr><tr><td>Median (range) follow-up, mo</td><td>15.1 (0.6-38.2)</td></tr><tr><td>Bulky disease >10 cm, n (%)</td><td>3 (6.3)</td></tr><tr><td>Safety, n (%)</td><td>N = 48</td></tr><tr><td>Any AE</td><td>47 (97.9)</td></tr><tr><td>Grade ≥3 AEs</td><td>28 (58.3)</td></tr><tr><td>Serious AEs</td><td>19 (39.6)</td></tr><tr><td>AEs leading to zanubrutinib discontinuation</td><td>11 (22.9)</td></tr><tr><td>AEs leading to death</td><td>5 (10.4)</td></tr><tr><td>Efficacy</td><td></td></tr><tr><td>Best response per investigator (n)</td><td>TN (n=8)</td><td>R/R (n=37)</td><td>Overall (n=45)</td></tr><tr><td>Overall response rate, n (%); 95% CI</td><td>7 (87.5);<br>47.3, 99.7</td><td>32 (86.5);<br>71.2, 95.5</td><td>39 (86.7);<br>73.2, 94.9</td></tr><tr><td>Complete response, n (%)</td><td>3 (37.5)</td><td>11 (29.7)</td><td>14 (31.1)</td></tr><tr><td>Partial response, n (%)</td><td>4 (50.0)</td><td>21 (56.8)</td><td>25 (55.6)</td></tr><tr><td>Stable disease, n (%)</td><td>0 (0.0)</td><td>2 (5.4)</td><td>2 (4.4)</td></tr><tr><td>Progressive disease, n (%)</td><td>1 (12.5)</td><td>3 (8.1)</td><td>4 (8.9)</td></tr><tr><td>Median follow up (min, max)</td><td>8.6 (1.6, 25.0)</td><td>17.1 (1.9, 38.2)</td><td>16.0 (1.6, 38.2)</td></tr><tr><td>Duration of response (mo)</td><td>R/R (n=32)</td><td></td><td>Overall (n=39)</td></tr><tr><td>Follow up, median (min, max)<sup>a</sup></td><td>14.7 (0.0, 28.2)</td><td>14.3 (0.0, 28.2)</td><td></td></tr><tr><td>Median (95% CI)<sup>b</sup></td><td>14.7 (10.6, 18.5)</td><td>14.7 (10.6, 18.5)</td><td></td></tr></tbody></table>

Abbreviations: AE, adverse event; ECOG PS, Eastern Cooperative Oncology Group performance status; CI, confidence interval.

Abbreviations: **AE**, adverse event; **ECOG PS**, Eastern Cooperative Oncology Group performance status; **CI**, confidence interval; **AE**, adverse event; **Glycomimetics**, Abbvie; **Other Remuneration**: **Travel, Accommodations, Expenses**: **Amgen, Roche.** **Munoz, J**: Consultant Advisory Role: **Pharmacyclics LLC, Bayer, Gilead/Kite Pharma, Bristol-Myers Squibb, Janssen, Juno/Celgene**; **Other Remuneration**: **Speaker's Bureau: Kite Pharma, Gilead, Bayer, Pharmacycyclics/Janssen, AstraZeneca.** **Phillips, T**:

Consultant Advisory Role: **Bayer, Gilead, Seattle Genetics, Genentech, Incyte, Pharmacycyclics**; Research Funding: **Pharmacyclics, Abbvie.** **Kim, W**: Research Funding: **Roche, Takeda, Mundipharma, J&J, Celltrion, Kyowa kirin, Donga.** **Atwal, S**: Employment Leadership Position: **BeiGene**; Stock Ownership: **BeiGene**; Research Funding: **BeiGene**; **Other Remuneration**: **Leadership: BeiGene.** **Wei, R**: Employment Leadership Position: **BeiGene**;

<footnote>ªFollow-up time is estimated by the reverse Kaplan-Meier method.</footnote>

<footnote>ᵇMedian is estimated by Kaplan-Meier method with 95% CIs estimated using the Brookmeyer and Crowley method.</footnote>
Stock Ownership: BeiGene. Huang, J: Employment Leadership Position: BeiGene; Stock Ownership: BeiGene. Elstrom, R: Employment Leadership Position: BeiGene; Stock Ownership: BeiGene. Trotman, J: Research Funding: PCYC, Roche, Janssen, Celgene, BeiGene.

AGGRESSIVE LYMPHOMAS

192
THE CLINICAL COURSE OF DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) OVER TIME: A MULTISTATE SURVIVAL ANALYSIS USING META-DATA FROM 13 FIRST-LINE RANDOMIZED TRIALS

C. Çağlayan<fnref n="1" /> | J.G. Dixon² | G. Salles³ | A. Wall² |

N. Schmitz⁴ | D. Cunningham⁵ | V. Poeschel⁶ |

J. Seymour⁷ | U. Jaeger⁸ | T. Habermann⁹ |

F. Merli¹⁰ | C. Haioun¹¹ | H. Tilly¹² |

H. Ghesiquieres¹³ | M. Ziepert¹⁴ | J. Flament¹⁵ |

Q. Shi² | C. Flowers¹⁶

de Lyon, Lyon, France; ⁴Hematology and Oncology, University Hospital Muenster, Muenster, Germany; ⁵Department of Medicine, The Royal Marsden Hospital, Sutton, United Kingdom; ⁶Medical School, Saarland University, Homburg, Germany; ⁷Clinical Research, Integrated Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia; ⁸Department of Medicine I, Medical University of Vienna, Vienna, Austria; ⁹Cancer Center, Hematology, Mayo Clinic, Rochester, MN, United States; ¹⁰Hematology, AUSL-IRCCS, Reggio Emilia, Italy; ¹¹Unite Hemopathies Lymphoides, Hopital Henri Mondor, Creteil, France; ¹²Hématologie, Centre Henri-Becquerel, Rouen, France; ¹³Service d'Hématologie, Centre Hospitalier Lyon-Sud, Pierre Bénite CEDEX, France; ¹⁴Institut für Medizinische Informatik, Statistik und Epidemiologie, Universität Leipzig, Leipzig, Germany; ¹⁵Medicine and Biology, Celgene Corporation, Boudry, Switzerland; ¹⁶Winship Cancer Institute, Emory University, Atlanta, GA, United States

**Introduction:** The Surrogate Endpoints for Aggressive Lymphoma (SEAL) collaboration established a meta-database integrating individual patient data from 13 first-line randomized clinical trials on previously untreated diffuse large B-cell lymphoma (DLBCL). This meta-database provides an opportunity to investigate the impact of clinical factors and treatment response on DLBCL-specific and other causes of death following initial therapy to define new opportunities for trials and improve survivorship.

**Methods:** Using the SEAL database, we studied DLBCL outcomes for patients receiving anthracycline-based chemotherapy with/without added rituximab (R-Chemo) in a multistate survival analysis model having the model states "Alive with No Progression of Disease (PoD) after Treatment (TX)", "Alive after PoD", "Death from DLBCL", and "Death from Other Causes" (top Figure). The Aalen-Johansen estimator was used to calculate the likelihood of being in each model state and project the course of DLBCL over time (bottom Figure).

**Results:** We identified 7,911 DLBCL patients (Figure) with median age 62 (range 18-92) years, 62.1% stage III/IV, 64.7% IPI ≥ 2, including 5,108 treated with R-Chemo. Following initial TX for all patients (or with R- Chemo), 2- and 5-year DLBCL-specific death rate were 7.5% (5.9%) and 8.8% (7.0%) for patients age < 40 at initial TX, 8.9% (7.2%) and 12.8% (10.6%) for age 40-60, 10.4% (9.8%) and 15.2% (14.6%) for age 60-70, and 12.8% (12.5%) and 18.3% (17.6%) for age ≥ 70. Death rates at 2- and 5-year from all other causes were 2.3% (2.1%) and 3.5% (3.8%) for age < 40, 4% (3.1%) and 6.5% (5.1%) for age 40-60, 5.1% (4.8%) and 9.4% (7.9%) for age 60-70, and 11.3% (12.3%) and 18.3% (20.0%) for age ≥ 70. Following R- Chemo (n = 5,108), 2-year PoD rates were 12.3% for patients achieving CR, 24.1% for PR, and 28.4% for SD; 2- and 5-year DLBCL-specific mortality rates were 4.6% and 8.7% for CR, 11.8% and 18.6% for PR, 20.3% and 25.6% for SD, and 69.1% and 71.2% for PD. These rates were similar for "non R-Chemo" regimens. International Prognostic Index (IPI) affected the 2- and 5-year DLBCL-specific mortality rates, which were 4.8% and 8% for IPI = 0 or 1, 7.8% and 11.9% for IPI = 2, 13.3% and 18.6% for IPI = 3, and 24.4% and 29.7% for IPI = 4 or 5 in the whole SEAL population (n = 7,911).

<figure><img src="image_139.png" /></figure>

<footnote n="1">¹Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA, United States; ²Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States; ³Hematology, Hospices Civils</footnote>
**Conclusion:** In young DLBCL patients, lymphoma was the predominant cause of death despite its relatively low 5-year mortality rate, which was still > 2 times higher than other-causes of death. On the contrary, DLBCL- and other causes-related death risk were both high in older (age ≥ 70) patients and became equivalent 5 years following initial TX. High IPI scores increased the DLBCL-specific death risk up to 8 times. Response to initial TX was critical, where patients who had PD had extremely high rates of DLBCL-associated death. Cox models will be used to identify predictors and quantify their impact on the rate/time of critical clinical events.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); immunochemotherapy; R-CHOP.

**Disclosures:** Poeschel, V: Consultant Advisory Role: Spekers's bureau: Hexal; Other Remuneration: Travel, accomodations, expenses: Abbvie, Amgen, Roche.

## 193
COMPARISON OF CLINICAL SCORING SYSTEMS IN AGGRESSIVE B-CELL LYMPHOMAS (BCL): AN INDIVIDUAL PATIENT-LEVEL ANALYSIS ACROSS INTERNATIONAL TRIAL

N.F. Schmitz<fnref n="1" /> | J.G. Dixon² | G. Salles³ | A. Wall² | D. Cunningham⁴ | V. Poeschel⁵ | C. Haioun⁶ | H. Tilly⁷ | H. Ghesquieres³ | M. Ziepert⁸ | J. Flament⁹ | C. Flowers¹⁰ | Q. Shi² | A.S. Ruppert¹¹

<table><caption>TABLE 1</caption><thead><tr><th rowspan="2">Scoring System</th><th rowspan="2">N (%)</th><th colspan="3">% Alive</th><th rowspan="2">c-index</th></tr><tr><th>1-yr</th><th>3-yr</th><th>5-yr</th></tr></thead><tbody><tr><td>IPI</td><td></td><td></td><td></td><td></td><td>0.621</td></tr><tr><td>Low</td><td>818 (32)</td><td>97</td><td>90</td><td>87</td><td></td></tr><tr><td>Low-intermediate</td><td>609 (24)</td><td>91</td><td>83</td><td>77</td><td></td></tr><tr><td>High-intermediate</td><td>609 (24)</td><td>86</td><td>73</td><td>66</td><td></td></tr><tr><td>High</td><td>525 (20)</td><td>75</td><td>60</td><td>54</td><td></td></tr><tr><td>R-IPI</td><td></td><td></td><td></td><td></td><td>0.589</td></tr><tr><td>Very good</td><td>195 (8)</td><td>98</td><td>93</td><td>93</td><td></td></tr><tr><td>Good</td><td>1232 (48)</td><td>94</td><td>86</td><td>81</td><td></td></tr><tr><td>Poor</td><td>1134 (44)</td><td>81</td><td>67</td><td>61</td><td></td></tr><tr><td>NCCN-IPI</td><td></td><td></td><td></td><td></td><td>0.631</td></tr><tr><td>Low</td><td>303 (12)</td><td>98</td><td>92</td><td>92</td><td></td></tr><tr><td>Low-intermediate</td><td>1057 (41)</td><td>95</td><td>88</td><td>83</td><td></td></tr><tr><td>High-intermediate</td><td>945 (37)</td><td>84</td><td>70</td><td>63</td><td></td></tr><tr><td>High</td><td>256 (10)</td><td>66</td><td>54</td><td>48</td><td></td></tr></tbody></table>

United Kingdom; ⁵Internal Medicine 1, Saarland University Medical School, Homburg, Germany; ⁶Unite Hemopathies Lymphoides, Hopital Henri Mondor, Creteil, France; ⁷Hematologie, Hopital Henri Becquerel, Rouen, France; ⁸Medizinische Informatik, Statistik und Epidemiologie, Universität Leipzig, Leipzig, Germany; ⁹Statistics, Celgene Corporation, Boudry, Switzerland; ¹⁰Bone Marrow and Stem Cell Transplantation, Winship Cancer Institute, Atlanta, GA, United States; ¹¹Internal Medicine, The Ohio State University, Columbus, OH, United States

**Background:** In 2010, we reported that the standard IPI developed in the pre-rituximab era remains valid also for DLBCL patients (pts) treated with R(ituximab) plus CHOP (Ziepert et al., JCO 2010; 28: 2373) This study included 1,062 pts with aggressive B-cell lymphoma treated with R-CHOP-14, R-CHOP-21, or dose-escalated R-MegaCHOEP. Here we studied a much larger group of DLBCL pts treated with R-CHOP or variants and compared IPI, R-IPI, and NCCN-IPI to determine which scoring system best identifies subgroups with favorable and poor outcomes that might be well treated with R-CHOP (low-risk) or might benefit most from new approaches (high-risk group). **Methods:** Individual pt data from 7 multicenter trials (1998-2009) of pts with BCL (86% DLBCL) treated front-line with R-CHOP (or variant) were analyzed to determine whether IPI, R-IPI, or NCCN-IPI best discriminated overall survival (OS). The concordance index (c-index) from a proportional hazards model, stratifying on trial and induction therapy, quantified predictive accuracy of each scoring system.

**Results:** 2561 pts (median age 63 yrs, 56% male) were classified into IPI, R-IPI, and NCCN-IPI risk groups (Table). With a median follow-up of 5 yrs, NCCN-IPI had the greatest absolute difference in OS estimates between the highest and lowest risk groups at 1, 3, and 5 yrs, and best discriminated OS (c-index = 0.631, Table).

**Conclusions:** In an independent and large cohort of pts, NCCN-IPI performed best in risk-stratifying pts with BCL, readily distinguishing pts at high and low risk for treatment failure using clinical parameters (5-yr OS between 48 and 92%). Improvement over the simpler IPI was moderate, and IPI may remain a valuable alternative. Pts with low NCCN-IPI have quite favorable survival outcomes and there is little space for further improvement. Work integrating molecular features of the tumor into the (NCCN-) IPI is in progress to better characterize a high risk group where targeted novel approaches are needed most.

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

**Disclosures:** Schmitz, N: Consultant Advisory Role: Riemser, Takeda, Janssen, Gilead, Novartis; Stock Ownership: Celgene; Honoraria: Riemser, Takeda, Janssen, Gilead, Novartis.

## 194
THE ELDERLY PROJECT BY THE FONDAZIONE ITALIANA LINFOMI: A PROSPECTIVE COMPREHENSIVE GERIATRIC ASSESSMENT (CGA) OF 1353 ELDERLY PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA

<footnote n="1">¹Hematology and Oncology, University Hospital Muenster, Muenster, Germany; ²Health Science Research, Mayo Clinic, Rochester, MN, United States; ³Service d'Hematologie, Hospices Civils de Lyon, Lyon, France; ⁴Department of Medicine, Royal Marsden Hospital, Sutton, Surrey,</footnote>
<table><tr><td>M. Spina<sup>1</sup></td><td>F. Merli<sup>2</sup></td><td>B. Puccini<sup>3</sup></td><td>F. Cavallo<sup>4</sup></td></tr><tr><td>M.G. Cabras<sup>5</sup></td><td>A. Fabbri<sup>6</sup></td><td>F. Angrilli<sup>7</sup></td><td></td></tr><tr><td>V.R. Zilioli<sup>8</sup></td><td>D. Marino<sup>9</sup></td><td>M. Balzarotti<sup>10</sup></td><td></td></tr><tr><td>M. Ladetto<sup>11</sup></td><td>M.C. Cox<sup>12</sup></td><td>L. Petrucci<sup>13</sup></td><td></td></tr><tr><td>A. Arcari<sup>14</sup></td><td>G. Gini<sup>15</sup></td><td>A. Chiappella<sup>16</sup></td><td></td></tr><tr><td>S. Hohaus<sup>17</sup></td><td>G. Musuraca<sup>18</sup></td><td>M. Merli<sup>19</sup></td><td></td></tr><tr><td>R. Sartori<sup>20</sup></td><td>L. Nassi<sup>21</sup></td><td>M. Tani<sup>22</sup></td><td>F. Re<sup>23</sup></td></tr><tr><td>L. Flenghi<sup>24</sup></td><td>A. Molinari<sup>25</sup></td><td>S. Kovalchuk<sup>3</sup></td><td></td></tr><tr><td>C. Bottelli<sup>26</sup></td><td>S. Ferrero<sup>4</sup></td><td>D. Dessi<sup>5</sup></td><td>E. Cencini<sup>6</sup></td></tr><tr><td>E. Pennese<sup>7</sup></td><td>L. Marcheselli<sup>27</sup></td><td>C. Mammi<sup>28</sup></td><td></td></tr><tr><td>S. Luminari<sup>2</sup></td><td>A. Tucci<sup>26</sup></td><td></td><td></td></tr></table>

¹Division of Medical Oncology and Immune-related tumors, National Cancer Institute, Aviano (PN), Italy; ²Hematology, Azienda USL-IRCCS, Reggio Emilia, Italy; ³Hematology Department, University of Florence and AOU Careggi, Firenze, Italy; ⁴Division of Hematology, University of Torino, Azienda Ospedaliero Universitaria, Città della Salute e della Scienza di Torino, Torino, Italy; ⁵Division of Hematology, Ospedale Businco, Cagliari, Italy; ⁶Unit of Hematology, Azienda Ospedaliera Universitaria Senese, Siena, Italy; ⁷Lymphoma Unit, Department of Hematology, Ospedale Spirito Santo, Pescara, Italy; ⁸Division of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy; ⁹Medical Oncology 1, Veneto Institute of Oncology IOV IRCCS, Padova, Italy; ¹⁰Department of Medical Oncology and Hematology, Humanitas, Clinical and Research Hospital-IRCCS, Rozzano (MI), Italy; ¹¹Division of Hematology, A.O. SS Antonio e Biagio and Cesare Arrigo, Alessandria, Italy; ¹²Hematology Unit, AOU Sant'Andrea, Roma, Italy; ¹³Institute of Hematology, Dept. of Translational and Precision Medicine "Sapienza", University of Roma, Roma, Italy; ¹⁴Haematology Unit, Azienda AUSL, Piacenza, Italy; ¹⁵Division of Haematology, Ospedali Riuniti, Ancona, Italy; ¹⁶Division of Hematology, Città della Salute e della Scienza Hospital and University, Torino, Italy; ¹⁷Catholic University of the Sacred Heart, University Policlinico Gemelli Foundation, IRCCS, Roma, Italy; ¹⁸Department of Hematology, Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori, Meldola (FC), Italy; ¹⁹Hematology, Ospedale di Circolo e Fondazione Macchi, University of Insubria, Varese, Italy; ²⁰Hematology Department, Castelfranco Veneto Regional Hospital, Castelfranco Veneto (TV), Italy; ²¹Hematology, AOU Maggiore della Carità, Novara, Italy; ²²Department of Hematology, S. Maria delle Croci Hospital, Ravenna, Italy; ²³Hematology and BMT Center, Azienda Ospedaliera, University of Parma, Parma, Italy; ²⁴Hematology, S. Maria della Misericordia Hospital, Perugia, Italy; ²⁵Hematology Unit, Infermi

<table><caption>TABLE 1 Simplified Comprehensive Geriatric Assessment (sCGA)</caption><thead><tr><th></th><th>FIT</th><th>UNFIT</th><th>FRAIL</th></tr></thead><tbody><tr><td>ADL</td><td>6</td><td>5*</td><td>≤4*</td></tr><tr><td>IADL</td><td>8</td><td>7-6*</td><td>≤5*</td></tr><tr><td>CIRS-G</td><td>0 of score 3-4<br>&lt;5 of score 2</td><td>0 of score 3-4<br>5-8 of score 2</td><td>≥ 1 of score 3-4<br>&gt; 8 of score 2</td></tr><tr><td>Age</td><td>-</td><td>≥ 80 FIT</td><td>≥ 80 UNFIT</td></tr></tbody></table>

<figure><img src="image_140.png" /><figcaption>Figure 1: Overall Survival by geriatric groups</figcaption></figure>

Hospital, Rimini, Italy; ²⁶Department of Hematology, ASST Spedali Civili, Brescia, Italy; ²⁷FIL, Fondazione Italiana Linfomi Onlus, Modena, Italy; ²⁸GRADE, Gruppo Amici dell'Ematologia Foundation, Reggio Emilia, Italy

**Introduction:** Treatment choice in elderly patients (pts) with Diffuse Large B-Cell Lymphoma (DLBCL) is challenging. A simplified CGA (sCGA) based on ADL (Activity of Daily Living), IADL (Instrumental ADL) and CIRS-G (Comorbidity Index Rating Scale for Geriatrics) scales has demonstrated to be better than clinical judgement to stratify pts.

To confirm the impact of sCGA, we conducted a prospective observational study on the outcome of a large series of elderly pts with DLBCL.

**Methods:** Pts were enrolled if ≥65 years, with an untreated de novo DLBCL. sCGA was available at a web based platform that classified pts as FIT (F), UNFIT (U), and FRAIL (FR), as shown in Table 1. According to anthracycline doses treatment was classified as curative (≥70%), intermediate (<70%) or palliative (no anthracycline). Primary study endpoint was Overall Survival (OS).

**Results:** Form December 2013 to December 2017, 1353 pts have been registered by 37 centres and 1207 were eligible. Median age was 76 years (65-94), 68% had stage III-IV, and 55% had an IPI ≥3; 500 (42%), 304 (25%), and 403 (33%) were classified as F, U and FR, respectively.

A significant difference among groups was observed in the rate of B symptoms (F 22%, U 27%, FR 31%; p = 0.01), ECOG PS >1 (F 8%, U 15%, FR 38%; p<0.001), anemia (F 34%, U 40%, FR 54%; p<0.001), and IPI ≥3 (F 50%; U 56%; FR 63%; p<0.001).

Data on treatment were available in 1164 pts: curative in 89%, 53%, and 36% of F, U, and FR pts, respectively; intermediate in 10%, 39%, and 31%, palliative in <1%, 8%, and 33% of pts.

<footnote>*Residual Functions</footnote>
With a median follow up of 29 months (1-59) 3y-OS was 64%; according to sCGA the OS was significantly different in the three geriatric groups (Fig. 1).

F pts had a significant better 3y-OS when treated with a curative approach in comparison with intermediate (77% vs 57%, p = 0.003); the use of a curative vs intermediate approach did not affect the outcome of U and FR pts (U: 72% vs 67%, p = 0.257; FR: 63% vs 54%, p = 0.364).

The use of palliative approach had a negative impact in all groups.

**Conclusion:** This large prospective observational study on unselected elderly DLBCL pts shows that sCGA is a useful tool to identify three groups of pts with significant different outcome.

Our results confirm that curative treatment (R-CHOP or like) is the standard of care in F pts.

In U and FR pts, the intermediate approach improves outcome compared to palliation and is superimposable with curative treatment. FR group warrants further characterization to better define the risk/benefit ratio of treatment.

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

195

PET-CR AS A SURROGATE FOR SURVIVAL
OUTCOMES IN DLBCL: A LITERATURE
BASED META-ANALYSIS

D.A. Berry<fnref n="1" /> | K.R. Broglio<fnref n="2" /> | C. Ward³ | D. Sahin⁴ |

T. Nielsen⁴ | F. Mattiello³ | A.E. McGlothlin<fnref n="2" /> |

B.A. Wendelberger<fnref n="2" /> | M. Foster<fnref n="2" /> | G.S. Nowakowski⁵ |

L. Kostakoglu⁶

**Introduction:** Previous studies have reported an association between end of treatment PET results and clinical outcomes, such as overall survival (OS), progression free survival (PFS) and event free survival (EFS), in patients with diffuse large B-cell lymphoma (DLBCL) who received standard first-line chemoimmunotherapy. The development of PET-CR as a novel endpoint may expedite and shorten the duration of clinical development. We conducted a pro- spectively designed individual-level and literature-based meta- analysis to address the use of PET-CR as a possible surrogate end point for drug registration in DLBCL. This work was funded by Genentech/Roche.

**Methods:** We conducted a literature search for studies reporting long-term survival outcomes by PET-CR status in DLBCL patients who had previously untreated DLBCL. We augmented the literature

<figure><img src="image_141.png" /><figcaption>PET-CR Hazard Ratios for PFS By Study Characteristic</figcaption></figure>

studies with previously unpublished patient-level datasets from prospective phase II and III studies (GOYA (NCT01287741), GATHER (NCT01414855), MAYO (NCT00670358). All analyses were prespecified. We took a Bayesian meta-analytic, random-effects approach, comparing the hazard ratio (HR) for PET-CR versus non-PET-CR within and across all studies. We derived hazard ratios and their 95% confidence intervals for long-term survival outcomes by PET-CR status overall and within subgroups defined by study characteristics. We considered progression-free survival (PFS) type endpoints as well as overall survival (OS).

**Results:** We identified 21 studies involving a total of 3960 patients. Of these studies, 18 were from the literature (2464 patients) and 3 were patient-level datasets (1496 patients). In 20/21 studies patients underwent R-CHOP or R-CHOP-like therapies. The other study considered chemotherapy. The overall mean PET-CR rate was 78% and the HR for achieving a PET-CR versus non-CR was 0.16 (95% CI = 0.11, 0.23) for PFS and 0.16 (95% CI = 0.11, 0.25) for OS. The figure shows the modeled HRs and 95% credible intervals for PFS for the overall primary analysis as well as by study characteristic. The predictability of PET-CR was consistent across all study characteristics considered. It was also consistent across all 21 studies, recognizing the limitations of small sample sizes in some studies.

**Conclusions:** Our results support the use of end of therapy PET-CR as a surrogate for PFS and OS in clinical trials that are evaluating experimental therapies. This has the potential for bringing new and effective therapies to patients more quickly.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); non-Hodgkin lymphoma (NHL); positron emission tomography (PET).

**Disclosures:** Berry, D: Employment Leadership Position: I am co-owner of Berry Consultants, LLC, a company that provides statistical design and analysis services to pharmaceutical companies (including Genentech/Roche), medical device companies, U.S. NIH cooperative groups, patient advocacy groups, and international consortia.; Consultant

<footnote n="1">¹Biostatistics, M.D. Anderson Cancer Center, Houston, TX, United States;</footnote>

<footnote n="2">²Biostatistics, Berry Consultants, LLC, Austin, United States; ³PDBB, F. Hoffmann-La Roche Ltd., Basel, Switzerland; ⁴PDO, F. Hoffmann-La Roche Ltd., BASEL, Switzerland; ⁵Lymphoma Group, Mayo Clinic Rochester, Rochester, United States; ⁶Radiology, Icahn School of Medicine at Mount Sinai, NY, United States</footnote>
Advisory Role: Berry Consultants, LLC.; Stock Ownership: Berry Consultants, LLC. Broglio, K: Employment Leadership Position: I am an employee of Berry Consultants, LLC, a company that provides statistical design and analysis services to pharmaceutical companies (including Genentech/Roche), medical device companies, U.S. NIH cooperative groups, patient advocacy groups, and international consortia.; Consultant Advisory Role: Berry Consultants LLC. Ward, C: Employment Leadership Position: F. Hoffmann-La Roche Ltd. Sahin, D: Employment Leadership Position: F. Hoffmann-La Roche Ltd.; Stock Ownership: F. Hoffmann-La Roche Ltd. Nielsen, T: Employment Leadership Position: F. Hoffmann-La Roche Ltd.; Stock Ownership: F. Hoffmann-La Roche Ltd. Mattiello, F: Employment Leadership Position: F. Hoffmann-La Roche Ltd. McGlothlin, A: Employment Leadership Position: I am an employee of Berry Consultants, LLC, a company that provides statistical design and analysis services to pharmaceutical companies (including Genentech/Roche), medical device companies, U.S. NIH cooperative groups, patient advocacy groups, and international consortia; Consultant Advisory Role: Berry Consultants, LLC. Wendelberger, B: Employment Leadership Position: I am an employee of Berry Consultants, LLC, a company that provides statistical design and analysis services to pharmaceutical companies (including Genentech/Roche), medical device companies, U.S. NIH cooperative groups, patient advocacy groups, and international consortia.; Consultant Advisory Role: Berry Consultants LLC. Foster, M: Employment Leadership Position: Paid consultant to Berry Consultants LLC, a company that provides statistical design and analysis services to pharmaceutical companies (including Genentech/Roche), medical device companies, U.S. NIH cooperative groups, patient advocacy groups, and international consortia.; Consultant Advisory Role: Berry Consultants LLC. Nowakowski, G: Consultant Advisory Role: Celgene, Morphosys, Bayer, AbbVie, Roche, Genentech, Janssen; Research Funding: Celgene, Morphopsys, Bayer, Curis, Nanostrings, Roche, Genetech. Kostakoglu, L: Consultant Advisory Role: Genenetech, F. Hoffman-La Roche; Honoraria: Novartis, F. Hoffman-La Roche.

196
CLINICAL CHARACTERISTICS AND
OUTCOMES OF STAGE I DIFFUSE LARGE B
CELL LYMPHOMA (DLBCL) IN THE
RITUXIMAB-ERA

S. Bobillo<fnref n="1" /> | E. Joffe<fnref n="1" /> | J. Lavery² | A. Noy<fnref n="1" /> |
L. Palomba<fnref n="1" /> | D.J. Straus<fnref n="1" /> | A. Kumar<fnref n="1" /> |
C. Batlevi<fnref n="1" /> | S. Horwitz<fnref n="1" /> | A. Moskowitz<fnref n="1" /> |
P. Hamlin<fnref n="1" /> | A. Zelenetz<fnref n="1" /> | M. Matasar<fnref n="1" /> |
G. von Keudell<fnref n="1" /> | D. Sermer<fnref n="1" /> | J. Yahalom³ |
A. Dogan⁴ | V. Seshan² | A. Younes<fnref n="1" />

<table><caption>TABLE 1</caption><thead><tr><th></th><th>Extranodal n=224 (%)</th><th>Nodal n=117 (%)</th></tr></thead><tbody><tr><td>Median age (range)</td><td>61 (20-87)</td><td>58 (28-88)</td></tr><tr><td>Sex, male</td><td>111 (50)</td><td>58 (50)</td></tr><tr><td>ECOG &lt;2</td><td>216 (96)</td><td>116 (99)</td></tr><tr><td>Bulky (&gt;7cm)</td><td>21 (11)</td><td>11 (9)</td></tr><tr><td>High LDH (n=317)</td><td>48 (23)</td><td>21 (20)</td></tr><tr><td>Treatment</td><td></td><td></td></tr><tr><td>R-CHOP 3-4</td><td>29 (13)</td><td>23 (20)</td></tr><tr><td>R-CHOP 3-4 + RT</td><td>100 (47)</td><td>46 (44)</td></tr><tr><td>R-CHOP 6</td><td>48 (21)</td><td>20 (17)</td></tr><tr><td>R-CHOP 6 + RT</td><td>51 (23)</td><td>5 (4)</td></tr><tr><td>Radiotherapy</td><td>147 (66)</td><td>74 (63)</td></tr></tbody></table>

Pathology, Memorial Sloan Kettering Cancer Center, New York, NY,
United States

**Introduction:** Diffuse large B-cell lymphoma (DLBCL) presents as stage I in 15-20% of patients and with extranodal (EN) involvement in 50%. Based on recent studies, 4 cycles of immunochemotherapy may be an option for low-risk patients with negative interim PET/CT. However, the optimal treatment and outcome of EN stage I DLBCL are poorly described. This study aimed to analyze the characteristics and outcome of stage I DLBCL in the rituximab era.

**Methods:** We reviewed all newly diagnosed patients with DLBCL at Memorial Sloan Kettering Cancer Center from 2001-2015 treated with frontline rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (RCHOP) or RCHOP-like regimens. All patients underwent staging with PET/CT and bone marrow biopsy. Primary central nervous system (CNS) lymphoma and transformed indolent lymphoma were excluded. We compared survival using a multinomial propensity score weighted analysis across treatment groups adjusted for age, gender, IPI, bulky, nodal and cell of origin.

**Results:** We identified 1986 patients treated with frontline RCHOP-like regimens. Among them, 341 had stage I DLBCL: EN stage I in 224 (66%) and nodal in 117 (34%). The most common EN sites were bone 21%, n=47; stomach 19%, n = 42; testicle 9%, n = 20; intestine 8%, n = 19 and breast 8%, n = 18. Germinal-center was the most frequent phenotype by Hans criteria: 60% EN, 72% nodal. Complete response rate was 99% in EN and 98% in nodal, confirmed by PET/CT in 93% of patients. Twenty-three (7%) patients relapsed, 8% EN and 5% nodal. Median time to relapse was 36 m and 37 m, respectively. Sixteen patients (62%) relapsed as a localized disease, 5 at the initial site. The most common sites at relapse were the CNS, (27%, n = 7; initial site: 2 testicle, 2 breast, 3 nodal) and the lymph nodes (27%, n = 7). With a median follow-up of 5.6 y, EN patients had a worse outcome than nodal [10-y disease-free survival (DFS) 73% EN vs. 91% nodal (p = 0.003); 10-y overall survival (OS) of 74% EN vs. 94% nodal (p = 0.003) (figure 1)]. In the EN group, patients who received radiotherapy (RT) had better outcome than those who did not [10y DFS

<footnote n="1">¹Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States; ²Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States; ³Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States; ⁴Department of</footnote>
<figure><img src="image_142.png" /></figure>

78% RT vs. 72% no RT (p = 0.047); 10y OS 77% RT vs. 72% no RT (p = 0.002)].

**Conclusions:** Patients with stage I DLBCL and EN disease have a worse outcome than those with nodal involvement. Late relapses are common, including CNS relapses, requiring prolonged surveillance. Patients with EN stage I DLBCL may benefit from RT consolidation and is deserving of further study.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); extranodal lymphomas; R-CHOP.

197
POPULATION-BASED STUDY ON
DIFFERENT REGIMENS OF R-CHOP IN
PATIENTS WITH NEWLY DIAGNOSED
DIFFUSE LARGE B-CELL LYMPHOMA IN
THE NETHERLANDS SUPPORTS THE USE
OF 6 CYCLES OF R-CHOP21

D. Issa¹ | A. Dinmohamed² | M. Wondergem³ |
H. Blommestein⁴ | P. Huijgens² | P. Lugtenburg⁵ |
O. Visser² | S. Zweegman³ | M. Chamuleau³

¹Internal Medicine/ Hematology, Jeroen Bosch Hospital, Den Bosch, Netherlands; ²Department of Research, Netherlands Comprehensive Cancer Organisation, Utrecht, Netherlands; ³Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands; ⁴Institute for Medical Technology Assessment, Erasmus School of Health Policy & Management, Rotterdam, Netherlands; ⁵Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands

**Introduction:** Randomized clinical trials (RCTs) showed similar efficacy between R-CHOP14 and R-CHOP21 regimens, and less toxicity with 6 v 8 cycles of R-CHOP when applied as first-line treatment among

elderly (>60 years) DLBCL patients. Likewise, both 6x R-CHOP14 plus two cycles of rituximab (2R) and 8x R-CHOP21 result in comparable efficacy in patients 18-80 years. However, it is unknown whether the interval of 6x R-CHOP can be extended to 21 days especially among younger patients with advanced-stage DLBCL. Unfortunately, this question is unlikely to be addressed in future RCTs. In this regard, population-based studies can lend support to address unanswered hypotheses.

The aims of this population-based study among newly diagnosed DLBCL patients were two-fold. First, we sought to confirm results of RCTs on the effectiveness of R-CHOP21 v R-CHOP14, irrespective of the number of cycles (analysis A) and 6x v 8x R-CHOP, irrespective of dose density (analysis B). Secondly, we specifically assessed in patients aged 18-64 years whether 6x R-CHOP21±2R is equally effective as other R-CHOP regimens (analysis C).

**Methods:** We selected all patients aged ≥18 years diagnosed with advanced-stage DLBCL (stages II-IV) between 2004-2010 from the Dutch Population-based HAematological Registry for Observational Studies (PHAROS) and between 2014-2015 from the nationwide Netherlands Cancer Registry (NCR). Of note, the use of 2R after 6x R-CHOP was not uniformly registered in PHAROS. The primary endpoint was overall survival (OS) in age groups: 18-64, 65-74, and ≥75 years. Multivariable evaluation of OS was applied using Cox regression to account for some imbalances between treatment groups.

**Results:** The cohort for analysis A included 2,338 patients who received ≥1 cycle of R-CHOP outside the setting of a RCT, of whom 637 (27%) received R-CHOP14 and 1,701 (73%) R-CHOP21. Recipients of R-CHOP21, as compared to recipients of R-CHOP14, were older (median age, 68 v 61 years; P<0.001) and more often had an IPI of ≥3 (47% v 38%; P<0.001). The adjusted risk of mortality was similar between both groups across all age groups (Fig 1A for patients <65 years).
<figure><img src="image_143.png" /></figure>

<figure><img src="image_144.png" /></figure>

<figure><img src="image_145.png" /></figure>

For analysis B, 1,887 (80%) of 2,338 patients were included who received 6x (45%) or 8x (55%) R-CHOP. Recipients of 6 cycles, as compared to recipients of 8 cycles, were older (median age, 71 v 61 years; P<0.001), whereas IPI score distribution was not significantly different (P = 0.099). The adjusted risk of mortality was similar between both groups across all age groups (Fig 1B for patients <65 years).

Lastly, for analysis C, 897 (48%) of 1,887 patients were included, of whom most received 8x R-CHOP21 (49%) followed by 8x R-CHOP14 (26%), 6x R-CHOP21 (13%), and 6x R-CHOP14 (12%). Recipients of 6 R-CHOP21±2R, as compared to recipients of other regimens, were not older (median age, 55 v 55 years; P = 0.602), but had slightly less often an IPI of ≥3 (24% v 27%; P = 0.004). The adjusted risk of mortality was similar between 6xR-CHOP21±2R and the other regimens (Fig 1C).

**Conclusion:** Our population-based analyses add support to the notion from several RCTs that R-CHOP21 and R-CHOP14, and 6x and 8x R-CHOP are equally effective. Furthermore, 6x R-CHOP21±2R was found to be equally effective compared to all other regimens in all age groups. Therefore, 6xR-CHOP21 (±2R) should be considered the

preferred first-line regimen for all patients with advanced-stage DLBCL. The question whether 2R after 6x CHOP21 can be omitted without compromising efficacy remains a topic for future studies.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); R-CHOP.

198
PET-DRIVEN RADIOTHERAPY IN PATIENTS
WITH LOW RISK DIFFUSE LARGE B-CELL
LYMPHOMA (DLBCL): THE DLCL10
MULTICENTER PHASE 2 TRIAL BY
FONDAZIONE ITALIANA LINFOMI (FIL)

M. Balzarotti¹ | U. Ricardi² | M. Spina³ |

C. Monagheddu⁴ | A. Tucci⁵ | F. Cavallo⁶ |

M. Zanni⁷ | A. Arcari⁸ | C. Rusconi⁹ | R. Sartori¹⁰ |

F. Merli¹¹ | F. Re¹² | U. Vitolo¹³ | D. Dessi¹⁴ |

L. Melis¹⁵ | G. Gaidano¹⁶ | A. Chiti¹⁷ |

M. Deidda¹⁸ | A. Santoro¹ | G. Ciccone⁴ |

S. Chauvie¹⁹ | M. Cabras¹⁴
¹Medical Oncology and Hematology, Humanitas Clinical and Research Hospital-IRCCS-Humanitas University, Rozzano Milano, Italy;

²Radiotherapy, AOU Città della Salute e della Scienza, University of Torino, Torino, Italy; ³Medical Oncology, IRCCS CRO, Aviano, (PN), Italy;

⁴Epidemiologia Clinica e Valutativa, AOU Città della Salute e della Scienza e CPO, Torino, Italy; ⁵Hematology, Spedali Civili, Brescia;

⁶Hematology, Universita' Città' della Salute e della Scienza, Torino, Italy;

⁷Hematology, ASO ss Antonio e Biagio e Arrigo, Alessandria, Italy;

⁸Hematology, OspedaleUGlielmo da Saliceto, Piacenza, Italy;

⁹Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy; ¹⁰Hematology, Azienda ULSS 2 Marca Trevigiana, Castelfranco Veneto, Treviso, Italy; ¹¹Hematology, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; ¹²Hematology, AOU Parma, Parma, Italy;

¹³Hematology, AO Città della Salute e della Scienza, Torino, Italy;

¹⁴Hematology, Ospedale Oncologico Armando Businco, Cagliari, Italy;

¹⁵Nuclear Medicine, Ospedale Oncologico Armando Businco, Cagliari, Italy; ¹⁶Hematology, AOU Maggiore della Carità di Novara, Novara, Italy;

¹⁷Nuclear Medicine, Humanitas Clinical and Research Hospital-IRCCS - Humanitas University, Rozzano, Milano, Italy; ¹⁸Radiotherapy, Ospedale Oncologico Armando Businco, Cagliari, Italy; ¹⁹Medical Physics, Santa Croce e Carle Hospital, Cuneo, Italy

**Background:** Historically, in DLBCL bulky sites at diagnosis are irradiated after rituximab-chemotherapy (R-CT), whereas residual uptake area (RUA) at other sites are considered as failure. As PET negativity is mandatory to define complete remission (CR), some groups postulated that PET-neg areas after R-CT do not need consolidation RT.

**Aims:** To assess the role of RT in PET-neg and in PET-pos low-risk DLBCL patients after R-CT

**Methods:** The DLCL10 protocol was a phase II study of patients (pts) > = 18 years with low risk DLBCL according to the MiNT trial, (aa IPI 0 and bulky, aa IPI 1 +/- bulky) conducted in 19 FIL centers. Pts were treated with 6 courses of RCHOP and final response was evaluated with FDG-PET. Both pre and post treatment PET scans were centrally reviewed through the Widen web platform by a panel of 5 nuclear medicine experts. Positive scans were those centrally classified with Deauville score 3-4-5 by the first 2 concordant reviewers. Pts with one UA received RT, 36 Gy involved-field, regardless of bulky disease at onset, while those with multiple RUA were shifted to salvage systemic therapy. Primary aim was to obtain a 2-year PFS of at least 85% for post R-CT PET-neg pts. Secondary endpoints were OS and response.

**Results:** From January 2012 to December 2017, 115 consecutive pts were enrolled, and 109 were evaluable. Median age 58 years (47-65); M:F 60/49; DLBCL de novo 90%, aa IPI 0 15, aa IPI 1 94 (20 with bulky mass); RCHOP-14 /RCHOP-21 72/37. Median follow-up was 36 months and 6 pts died (2 lymphoma, 3 toxicitiy, 1 unknown). A total of 105 pts completed the R-CT program, while four were discontinued for lymphoma progression (1), toxicity (2, both died) and unknown cause (1). At end of treatment, 83 patients had PET-neg, whereas 17 had single RUA and received RT. In PET-neg patients, PFS was 90.6% (95% CI 81.1-95.4) at 2 years and 88.7% (95% CI

78.4-94.3) at 3 years. After RT, 15 pts reached CR, one PR and one was not evaluable. None of them relapsed. Thus, all patients with positive focal RUA after R-CT were cured with IF RT. Concerning the 35 pts with bulky disease, 20 reached PET-neg and 15 had single RUA after R-CT and were thus irradiated (1 PD). There were two relapses in the PET-neg/not irradiated group, but only one in previously bulky site. In the PET-pos /RT group no relapse occurred. In the total population, 3-year PFS and OS are 85.1% (95%, CI 76.4-89.3) and 94% (95%, CI 87.3-97.7), respectively.

**Conclusion:** Our data suggest that irradiating only sites of unique PET RUA, regardless of bulky at onset, can be considered as a reasonable strategy for low risk DLBCL pts. In cases with bulky disease, PET-driven RT allowed RT sparing in approximately half of patients. Moreover, consolidation RT in those with focal residual PET positivity, guaranteed excellent prognosis (17/17 cured) and could be recommended as a valid option.

**Keywords:** diffuse large B-cell lymphoma (DLBCL); positron emission tomography (PET).

## 199
# SAFETY ANALYSIS OF AUSTRALASIAN LEUKAEMIA & LYMPHOMA GROUP NHL29: A PHASE II STUDY OF IBRUTINIB, RITUXIMAB AND MINI-CHOP IN VERY ELDERLY PATIENTS WITH NEWLY DIAGNOSED DLBCL

E.K. Verner¹ | A.J. Johnston² | N. Pati³ |

E. Hawkes⁴ | H. Lee⁵ | T. Cochrane⁶ | C.Y. Cheah⁷ |

R. Filshie⁸ | D. Purtill⁹ | A.K. Enjeti¹⁰ | C. Brown¹¹ |

N. Murphy¹² | J. Curnow² | S. Cake¹³ |

J. Carlson¹³ | B.E. Butcher¹⁴ | J. Trotman¹⁵ |

¹Haematology, Concord Repatriation General Hospital, Concord, Australia; ²Haematology, Westmead Hospital, Westmead, Australia;

³Haematology, Canberra Hospital, Canberra, Australia; ⁴Medical Oncology, Eastern Health, Box Hill, Australia; ⁵Haematology, Flinders Medical Centre, Adelaide, Australia; ⁶Haematology, Gold Coast University Hospital, Southport, Australia; ⁷Haematology, Sir Charles Gairdner Hospital, Perth, Australia; ⁸Haematology, St Vincent's Hospital, Fitzroy, Australia; ⁹Haematology, Fiona Stanley Hospital, Murdoch, Australia;

¹⁰Haematology, Calvary Mater Hospital, Newcastle, Australia;

¹¹Haematology, Royal Prince Alfred Hospital, Camperdown, Australia;

¹²Haematology, Royal Hobart Hospital, Hobart, Australia; ¹³Trial Centre, Australasian Leukaemia and Lymphoma Group, Richmond, Australia;

¹⁴Biostatistics & Medical Writing, WriteSource Medical Pty Ltd, Lane Cove, Australia; ¹⁵Medicine, University of Sydney, Camperdown, Australia

**Introduction:** The optimal treatment strategy for very elderly patients (pts) with Diffuse Large B Cell Lymphoma (DLBCL) remains controversial. R-mini-CHOP has been shown to be tolerable, albeit with limited