A Phase II Multi-Center Trial Of Pentostatin Plus Cyclophosphamide With Ofatumumab (PCO) In Older Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients

Abstract Introduction The seminal phase 3 trial conducted by the German CLL Study Group demonstrated that the addition of the anti-CD20 monoclonal antibody [mAb] rituximab to the FC platform (FCR) improved response rates, progression free survival and also overall survival. However, FCR showed considerable hematologic toxicity, particularly among patients over age 70. Pentostatin demonstrated similar response frequency to other purine analogues in CLL. Furthermore, its relative lack of myelotoxicity has allowed to use it with improved tolerability particularly when administered in combination with myelotoxic agents such as cyclophosphamide. Ofatumumab is a fully human anti-CD20 mAb with clinical activity as a single agent in patients with fludarabine-refractory CLL. Ofatumumab appears to have greater single agent clinical activity than rituximab in patients with previously treated CLL and also has activity in rituximab-refractory patients. Given the reported efficacy of chemo immunotherapy [CIT] in CLL and the activity and toxicity profile of pentostatin combinations, we designed a trial of pentostatin, cyclophosphamide, and Ofatumumab for previously untreated older patients with CLL. Methods Patients with CLL who required therapy (2008 NCI-WG guidelines) aged ≥ 65 years and ECOG PS of 0-2 were enrolled to receive Pentostatin 2 mg/sqm and Cyclophosphamide 600 mg/sqm both as intravenous infusions at day 1 of each 21 day cycle and Ofatumumab administered as intravenous infusions (Cycle 1: 300 mg day 1 and 1000 mg day 2, subsequent cycles: 1000 mg at day 1). Ofatumumab premedication included acetaminophen, antihistamine and glucocorticoid. Treatment duration was of 6 cycles. The primary endpoint was overall response rate (ORR) including detection of minimal residual disease (MRD) and secondary endpoints included, progression-free survival (PFS) overall survival (OS) and safety. Patients 49 patients from 12 centres from the italians regions of Lombardy and Piedmont were included. Baseline demographics were: Median age 72.8 years with 64% aged over 70, among them 32 were males (65%). Disease characteristics in 32 patients evaluable at this point were: 76% Binet stage B and 24% C; 45% of patients had unmutated IGVH, 7 % showed 17p deletions. Results ORR was 93.7% with 41% CR(11)/CR(2) with incomplete marrow recovery [CRi]. All six intended courses of treatment were administered to 30 (94%), and 90% of these patients received full-dose treatment. The reason for discontinuing treatment before completing six courses was myelosuppression occurring in 2 patients. The primary reason for dose reduction was again myelosuppression. Grade ≥3 AEs that occurred from start of treatment until 60 days after the last dose were experienced by 62% of patients receiving PCO with the most common being neutropenia [Total number of patients with at least one Grade 3 or 4 event: 19 patients] while anemia and thrombocytopenia were detected only as grade 1 to 2 in 41% and 25% of cases respectively. Of the grade 1 to 2 toxicities, fever occurred in 2 patients (6%), hypotension occurred in 2 patients (6%), nausea and vomiting occurred in 3 patients (9%), skin rash of grade 1 occurred in 2 patients. Grade 3 infusion-related AEs were reported in 12% of patients. There were no grade 4 toxicities associated with any Ofatumumab infusion. Grade 3 infection was reported in 1 patient (3%) being a pneumonia. No deaths during treatment occurred in these 32 subjects. Conclusion Ofatumumab added to Pentostatin and Cyclophosphamide demonstrated clinically important results and is well tolerated in patients with previously untreated CLL. In this preliminary report the efficacy of this ofatumumab-based CIT compares favorably to the historical rituximab-based CIT using the same chemotherapeutic agents with a more manageable side effect profile in this older population. Further data in a higher number of enrolled patients and including MRD detection will be presented at the Meeting. Disclosures: Montillo: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Rambaldi:Novartis: Honoraria; Sanofi: Honoraria; Italfarmaco: Honoraria.

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Phase IIa Study of Single-Agent MOR208 in Patients with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽

10.1182/blood.v126.23.1528.1528 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1528-1528 ◽

Cited By ~ 4

Author(s):

Wojciech Jurczak ◽

Pier Luigi Zinzani ◽

Gianluca Gaidano ◽

Andre Goy ◽

Mariano Provencio ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Hodgkin's Lymphoma ◽

Clinical Activity ◽

Advisory Committees ◽

Cd20 Antibody ◽

Grade 3

Abstract Introduction: There remains a high unmet medical need for new therapies for patients with relapsed or refractory (R-R) B-cell non-Hodgkin's lymphoma (NHL). CD19 is a B-lymphocyte, lineage-specific surface antigen that is highly expressed by most B-cell NHLs. CD19 expression is maintained on lymphoma cells which have CD20 expression downregulated following treatment with the CD20 antibody, rituximab. Consequently, MOR208 (XmAb5574; MOR00208), an Fc-engineered, humanized, monoclonal antibody that targets CD19, may have clinical utility as a new therapeutic approach to R-R NHL. A phase I study showed MOR208 to be safe and well-tolerated with encouraging single-agent activity in patients with chronic lymphocytic leukemia (CLL); an intravenous dose of 12 mg/kg was recommended for phase II studies. Methods: This is a non-randomized, open-label, multicenter, two-stage, phase IIa study of MOR208 in adult patients with R-R NHL whose disease had progressed after at least one prior therapy containing the CD20 antibody, rituximab. In stage 1, 10 patients were to be enrolled into each of four NHL subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent NHL (iNHL) and mantle cell lymphoma (MCL). Patients were to receive single-agent MOR208, 12 mg/kg intravenously, weekly, for 8 weeks (2 cycles). Those with at least stable disease by the 2007 International Response Criteria could continue MOR208 treatment for an additional 4 weeks (total of 12 weeks of therapy). Patients with a complete or partial response (CR or PR) after 12 weeks could then receive MOR208 as maintenance therapy, every 2 or 4 weeks depending on the investigator's decision, until progression. In stage 2, cohorts with ≥2 responses (CR or PR) were to be expanded by at least 20 additional patients. The primary endpoint was the overall response rate (ORR). Key secondary endpoints included duration of response, safety, immunogenicity of MOR208, pharmacokinetics and pharmacodynamics. Results: The DLBCL and FL cohorts were expanded (to N=35 and N=34 patients, respectively), leading to a total enrollment of 92 patients: 56 (61%) were male; median age was 66.5 (range 35-90) years; 80 (87%) had stage III-IV disease; 41 (45%) had received ≥3 prior lines of therapy and 10 (11%) had received a prior stem-cell transplant. The investigator-assessed ORR across all NHL subtypes was 23% (21/92 patients; 16 not evaluable at cutoff) with clinical activity seen in the DLBCL (26% [9/35]; 2 CR, 7 PR); FL (26% [9/34]; 3 CR, 6 PR) and iNHL (27% [3/11]; 2 CR, 1 PR) cohorts (MCL, 0/12 responses). The iNHL cohort was not expanded as the response pattern in this subgroup was heterogeneous according to lymphoma subtype. The longest durations of response recorded to date are 15.4 months for FL and 14.2 months for DLBCL (both ongoing). Grade ≥3 non-hematologic and hematologic treatment-emergent adverse events (TEAEs) were recorded in 24 (26%) and 14 (15%) of 92 patients, respectively. The most commonly reported grade ≥3 hematologic TEAEs were neutropenia (7 [8%] of 92 patients, anemia (4 [4%]), and thrombocytopenia (4 [4%]); such TEAEs were seen most frequently in the DLBCL cohort (10 [29%] of 35 patients overall; neutropenia, 5 [14%], anemia, 4 [11%], thrombocytopenia, 2 [6%]). Dyspnea was the most commonly reported grade ≥3 non-hematologic TEAE (4 [4%] of 92 patients). Infusion-related reactions were seen in 9 (10%) of 92 patients; all were grade 1-2, except for one case of dyspnea, grade 4. There were no treatment-related deaths. Clinical activity in patients with R-R DLBCL appeared to be dependent on attaining a defined cumulative exposure (AUC0-t) over 8 weeks of around 11,000 day*µg/mL; i.e., at the data cutoff date, all 8 patients with a PR after 2 cycles showed an exposure above this potential threshold level. Conclusions: MOR208 demonstrated encouraging single-agent activity with CRs observed in patients with R-R DLBCL, FL, and iNHL. MOR208 was well tolerated without significant infusional toxicity. These data support further development of MOR208 in combination with other agents (including lenalidomide and bendamustine), and protocols for studies in patients with R-R DLBCL are now being developed. Disclosures Jurczak: CELLTRION, Inc,: Research Funding. Zinzani:Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Gaidano:Celgene: Research Funding; MorphoSys; Roche; Novartis; GlaxoSmithKline; Amgen; Janssen; Karyopharm: Honoraria, Other: Advisory boards. Goy:Celgene: Consultancy, Research Funding, Speakers Bureau; Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau. Robak:Janssen: Consultancy, Research Funding; MorphoSys AG: Consultancy, Honoraria, Research Funding. Maddocks:Novartis: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Research Funding. Buske:Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy. Korolkiewicz:MorphoSys AG: Employment. Striebel:MorphoSys AG: Employment. Blum:Morphosys: Research Funding; Gilead: Research Funding; Millenium: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene: Research Funding.

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Progression-Free Survival and Overall Survival Among a Patient Cohort of Relapsed/Refractory Mycosis Fungoides in France, Germany, Italy, Spain and the United Kingdom

Blood ◽

10.1182/blood-2019-126246 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5879-5879

Author(s):

Martine Bagot ◽

Timothy Illidge ◽

Nicola Pimpinelli ◽

Mehul Dalal ◽

Athanasios Zomas ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Mycosis Fungoides ◽

Systemic Therapy ◽

Research Funding ◽

Index Date ◽

Progression Free Survival ◽

High Rate ◽

Advisory Committees ◽

Free Survival

Background and Aim: Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL) wherein those with advanced stage have a poor prognosis. The objective of this study was to describe clinical characteristics and survival in MF patients who were refractory or had relapsed after a first systemic therapy. Methods: A retrospective chart review study was conducted at 27 sites in Europe. Patients enrolled had a diagnosis of MF and proved to be relapsed/refractory (R/R) prior to 1-Jan-2016 after a first systemic therapy. Overall survival (OS) and progression-free survival (PFS) were estimated from the date of R/R event (defined as the index date) using Kaplan-Meier estimates. PFS was defined as death, progression, second relapse or refractory, or presence of subsequent treatment after index date. Results: This study included 104 advanced R/R MF patients with a median age of 54.5 years (range: 21-82). The median follow-up was 3.5 years (range: 0-20.7) after index date. In total 80% of patients experienced a second R/R, with a median time to second R/R of 15.8 months (range: 0.6-174.6). The median age at death was 65 years (range: 42-85). In total 39 deaths (37.5%) were observed. Among those patients who had a known cause of death (N=35), 18 died of CTCL progression, 11 of CTCL complication or drug toxicity and 7 of other causes. The estimated median OS was 11.5 years (95% CI: 6.5 - not reached). The median PFS was 1.3 years (95% CI: 1.0-2.1). Conclusions: The high rate of R/R and low PFS suggest that the clinical burden of R/R MF is significant in five European countries, and recently approved targeted therapies have the potential of improving outcomes. Disclosures Bagot: Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Illidge:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics, Inc.: Research Funding; Div of Cancer Sciences, Faculty of Biology, Medicine and Health, Univ of Manchester, National Institutes of Health and Research Biomedical Research Center, Manchester Academic Health Sciences, Christie Hospital National Health Service Foundation Trust: Employment. Dalal:Takeda: Employment. Zomas:Takeda: Employment. Trinchese:Takeda: Employment. Little:Takeda: Employment. Bent-Ennakhil:Takeda Pharmaceuticals International AG: Employment. Ortiz-Romero:Actelion: Consultancy, Membership on an entity's Board of Directors or advisory committees; 4SC: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; miRagen: Membership on an entity's Board of Directors or advisory committees; PLCG1: Patents & Royalties; Kyowa: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; MEDA: Research Funding.

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Phase 2 Study of Nilotinib 400 Mg Twice Daily in Newly Diagnosed Patients with Accelerated Phase of Chronic Myeloid Leukemia, Results after 5.7 Years of Follow-up

Blood ◽

10.1182/blood-2018-99-120155 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3011-3011 ◽

Cited By ~ 1

Author(s):

Lucia Masarova ◽

Jorge E. Cortes ◽

Keyur P. Patel ◽

Susan M. O'Brien ◽

Graciela M. Nogueras González ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Phase 2 ◽

Advisory Committees ◽

Free Survival ◽

Genetics Research ◽

Phase 2 Study ◽

Grade 3

Abstract OBJECTIVES Nilotinib is a potent, second generation inhibitor of BCR-ABL tyrosine kinase (TKI) and represent a standard of care for patients with chronic myeloid leukemia (CML), including accelerated phase (AP-CML). In 2005, we initiated a phase 2 study of nilotinib 400 mg twice daily as a frontline therapy in patients with AP-CML, and herein present the efficacy and safety data after a median follow-up of 68.4 months (range, 0.3-124.8). METHODS This was a prospective, single institution, phase 2 study in patients of age ≥18 years with a newly diagnosed, untreated AP-CML (except for <1 month of previous imatinib) defined according to MD Anderson criteria (Kantarjian, 1988). Patients were treated with nilotinib 400 mg twice daily (BID). Data are presented on an intention to treat analysis with a cutoff date of June 30st, 2018. Response criteria are standard. Fisher exact test and χ2 were used for analysis of categorical variables; and survival probabilities were estimated using the Kaplan-Meier method. Time to events (e.g., overall survival, event free survival) was calculated from the date of treatment to the date of an event or to last follow-up as previously reported (Cortes et al, 2010). RESULTS Twenty two patients of a median age of 53.7 years (range, 26-79.7) were enrolled. Table 1 summarizes clinical characteristics of all patients. The median treatment duration was 47.3 months (range; 0.3-124.4), and the median follow-up 68.4 months (range, 0.3-124.8). All patients discontinued study as of January 2017 due to planned study closure; but 11 patients (50%) continued on nilotinib off protocol at data cut-off (400 mg BID [3]; 300 mg BID [2]; and 200 mg BID [6]). Median time to treatment discontinuation in the remaining 11 patients was 12.9 months (range, 0.3-112); reason for discontinuation was: inadequate response [3], toxicity [2], non-compliance/financial [4]; elective discontinuation after sustained MR4.5 >2 years [1]; and death due to stroke [1]. Sixteen patients (73%) achieved complete hematologic response (CHR). Overall rates of CCyR, MMR, MR4.5 and CMR (undetectable transcripts with at least 100,000 ABL copies) were 73%, 73%, 55%, and 41%, respectively. Median times to CCyR, MMR, and MR4.5 were 2.9 months (range, 2.7-6.4), 5.7 months (range, 2.7-99.2) and 6.0 months (range, 2.7-36), respectively. Seven patients (32%) achieved sustained MR4.5 >2 years. In total, 4 patients lost their best achieved response (CHR [1], CCyR [2] and MR4.5 [1]) while on study. All events were associated with acquired ABL domain mutation; Y253H [2], T315I [1], and F359I [1] with a median time to detection of 16.7 months (range, 7-40). During the study conduct, one patient progressed to blast phase after 2 months on nilotinib. Two patients died while on study, one due to stroke and one due to unrelated medical condition, after being on therapy for 3 and 0.4 months, respectively. One patient electively discontinued nilotinib after being in sustained MR4.5 for 107 months, and remains in MR4.5 after 6 months off therapy. Estimated overall survival and event free survival at 5 years were 84% and 70%, respectively (Figures 1a & 1b). On univariate analysis, age >55 years was associated with lower rate of MMR (p = 0.034; HR 0.34; 95% CI 0.12-0.92); MR4 (p = 0.013; HR 0.25; 95% CI 0.08-0.75); and MR4.5 (p = 0.01; HR 0.15; 95% CI 0.04-0.63). Overall survival was inferior in patients older than 55 years (p = 0.014; HR 2.4; 95% CI 2.36-not estimated); and in those with > 1 AP-CML defining abnormality (p = 0.018; HR 9.53; 95% CI 0.98-92). The most frequent non-hematologic adverse events (AEs) were hyperbilirubinemia (63% of patients), rash (63%), hypertension (59%), and transaminitis (50%). Grade ≥3 AEs observed in more than one patient were hyperbilirubinemia (n=2), and transaminitis (=2). Two patients developed arterio-thrombotic AEs: stroke and myocardial infarction (one each). Hematologic AEs included (all grades; grade ≥3): anemia (36%; 9%), thrombocytopenia (32%; 14%) and neutropenia (14%; 9%). Two patients (9%) discontinued therapy due to nilotinib related AE, one for G3 peripheral neuropathy and one for G3 hyperbilirubinemia with G2 thrombocytopenia. CONCLUSION Nilotinib is safe and highly effective in patients with AP-CML, and induces fast and durable responses. More than 50% of patients can achieve MR4.5. Clinical trial.gov: NCT00129740. Disclosures Cortes: novartis: Research Funding. O'Brien:Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Alexion: Consultancy; Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; TG Therapeutics: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; abbvie: Research Funding; cellectis: Research Funding. Verstovsek:Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kadia:Celgene: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Novartis: Consultancy; Takeda: Consultancy; Celgene: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding.

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A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.74.74 ◽

2012 ◽

Vol 120 (21) ◽

pp. 74-74 ◽

Cited By ~ 8

Author(s):

Jatin J. Shah ◽

Edward A. Stadtmauer ◽

Rafat Abonour ◽

Adam D Cohen ◽

William I. Bensinger ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Grade 3

Abstract Abstract 74 Background: Carfilzomib, a novel proteasome inhibitor (PI), and pomalidomide, an immunomodulatory agent (IMiD), have both demonstrated promising activity as single agents or in combination with dexamethasone in relapsed/refractory multiple myeloma. IMiD+PI combinations including lenalidomide, bortezomib, dexamethasone and lenalidomide, carfilzomib, dexamethasone have had high response rates and good tolerability. We aimed to combine carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) for the first time and hypothesized that this regimen would be highly active in patients with relapsed/refractory multiple myeloma. Here, we report the first findings from the Phase I dose-escalation and expansion portions of the first phase I/II trial of Car-Pom-d in patients with relapsed/refractory multiple myeloma (NCT01464034). Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of Car-Pom-d. Secondary objectives included determination of overall response rate, time to progression, progression free survival, and time to next therapy. All patients had to be refractory to prior lenalidomide, and must have been relapsed/refractory to their most recent therapy. Treatment consisted of 28-day cycles of oral pomalidomide once daily on days 1–21, intravenous (IV) carfilzomib over 30 minutes on days 1, 2, 8, 9, 15, and 16, and oral or IV dexamethasone 40 mg on days 1, 8, 15, and 22. Dose-escalation of carfilzomib started with 27mg/m2 carfilzomib/4mg pomalidomide/40 mg dexamethasone using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Carfilzomib was initiated at 20 mg/m2for Cycle 1, days 1–2 at all dose levels. Investigators were permitted to adjust the dose of dexamethasone at any point based on their discretion. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria. Results: In the Phase I dose-escalation portion of the trial, a total of 12 patients were enrolled from 6 centers. The median age was 61 years (range 44–78), 67% were male. The median number of prior regimens was 6 (range 2–15), and median time from diagnosis was 5.1 years. Four (33%) patients had prior stem cell transplant, 11 (92%) had prior bortezomib, and all were lenalidomide-refractory. Cytogenetic abnormalities included 5 patients with del(17p), 2 patients with t(4;14), and 1 patient each with del(13), t(11;14), and t(14;16). In these first 12 patients, drug-related AEs occurring in >20% of patients included fatigue (42%), anemia (33%), pneumonia (33%), dyspnea (25%), and thrombocytopenia (25%). Six (50%) patients experienced grade ≥3 AEs including 2 incidence each of neutropenia and febrile neutropenia. The MTD was established as the starting dose level (carfilzomib 20/27 mg/m2, pomalidomide 4mg, dexamethasone 40 mg). At this dose, 1 of 6 patients experienced a protocol-defined DLT of febrile neutropenia. At dose level 2 (carfilzomib 20/36 mg/m2, pomalidomide 4 mg, dexamethasone 40 mg), 2 of 6 patients experienced DLTs, consisting of grade 4 thrombocytopenia and grade 3 rash. All 12 patients were response evaluable with 2 very good partial response (VGPR), 4 partial response (PR), 2 minor response (MR), 2 stable disease (SD), and 2 progressive disease (PD) for a ≥ MR rate of 67%. The 6 month progression free survival was 70% (95% CI: 37 to 90%). Of the 5 patients with del(17p), 1 achieved VGPR, 2 achieved PR, 1 achieved SD. We then enrolled an expansion cohort of 20 patients from 8 centers resulting in a total study population of 32 patients, with 25 still receiving treatment. Three patients have died, all from progressive multiple myeloma. Early response assessments in 27 out of 32 patients show 2 VGPR, 7 PR, 6 MR, 8 SD, and 4 PD for a ≥MR rate of 56%. Conclusions: The Car-Pom-d regimen is well tolerated and achieves a high response rate in a heavily pre-treated, lenalidomide-refractory population with prior bortezomib exposure. Importantly, we have seen responses in patients with poor risk cytogenetics, specifically del (17p). We are beginning enrollment in a larger phase 2 cohort, and updated safety and efficacy data for all patients will be presented at the meeting. Disclosures: Shah: Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Array: Consultancy. Stadtmauer:Celgene: Consultancy, Speakers Bureau; Millennium: Consultancy, Speakers Bureau. Abonour:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau. Cohen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bensinger:Onyx: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau. Gasparetto:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kaufman:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy. Lentzsch:Celgene: Consultancy, Research Funding. Vogl:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Research Funding; Otsuka: Consultancy; Acetylon: Research Funding. Orlowski:Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding. Durie:Onyx: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Amgen: Consultancy.

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High-Dose Melphalan in 1 Day Versus over 2 Days Followed By Autologous Stem Cell Transplantation As Consolidation Treatment in Patients with Multiple Myeloma

Blood ◽

10.1182/blood-2021-147860 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3944-3944

Author(s):

Mesire Aydin ◽

Man Wai Tang ◽

Marielle Wondergem ◽

David C. de Leeuw ◽

Jurgen J. Wegman ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

High Dose ◽

Advisory Committees ◽

Free Survival ◽

Consolidation Treatment ◽

Cell Counts ◽

High Dose Melphalan

Abstract Background High-dose melphalan (HDM) at 200 mg/m2 is a myeloablative consolidation treatment prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM) and is administered in 1-day or divided over 2-days. Although the 1-day regimen (lower AUC) has been shown to result in significantly less gastro-intestinal toxicity, it is not completely clear whether this administration strategy has any deleterious effects on efficacy, compared to the 2-day regimen. In this retrospective cohort study, we aimed to evaluate the effects of 1- or 2-day dosing of HDM on disease remission, progression-free survival (PFS) and overall survival (OS) in patients with MM. Methods Data from two academic centers in Amsterdam that have recently merged were used for the analysis, with one of the centers using the 1-day regimen and the other the 2-days regimen. A total of 265 patients with MM divided over the 1-day group (n=174) and 2-day group (n=91) treated between July 2017 and February 2020, were included in the study. The primary endpoint was the proportion of patients with at least very good partial remission (≥VGPR) at day ±90 post-ASCT. Secondary endpoints were overall survival (OS), progression-free survival (PFS), duration of hospitalization post-ASCT, engraftment period of neutrophils and platelets, and complications (other than mucositis) during hospitalization. Results Patient characteristics are summarized in Table 1. Remission status of ≥VGPR was comparable between the 1-day and 2-day groups (84% vs. 80% respectively). After a median follow-up of 21 months, OS (92% vs. 91%) and PFS (80% vs. 81%) were comparable in the 1-day and 2-day group respectively. There were no differences in the incidence of hematologic adverse events between the 1-day and 2-day groups (neutropenia; 98% vs. 100%, thrombocytopenia; 90% vs. 96% respectively). Median time to neutrophil engraftment (ANC >0.5 x10 9 L -1) was significantly shorter in the 2-day group than in the 1-day group (14 days vs. 18 days, p = 0.002). Median time to platelet engraftment (platelets >20 x10 9 L -1) was comparable between the groups. Lower CD34+ cell counts were administered in the 1-day group compared to the 2-day group (2.6 vs. 3.4 x10 6/kg, p <0.0001). A significant negative correlation between the reinfused CD34+ cell counts and time to neutrophil engraftment was found (R= - 0.244). Table 2 shows the number of hospitalization days after ASCT. The median number was 18 days in the 1-day group and 15 days in the 2-day group (OR 1.22, 95% C.I. (1.10-1.35), p <0.0001). Incidences of infectious complications, febrile neutropenia and intensive care unit (ICU) admissions were not different between the groups. Conclusion The use of 1-day HDM as consolidation treatment in MM patients resulted in equal disease response, progression-free survival and overall survival as compared to 2-day HDM. Based on the results of this study showing comparable efficacy and earlier findings of reduced toxicity with the 1-day HDM administration, we recommend the 1-day protocol for HDM. Interestingly, our results also confirmed that patients might benefit from higher counts of reinfused CD34+/enucleated cells. Figure 1 Figure 1. Disclosures Wondergem: Novartis: Honoraria. de Leeuw: Takeda: Membership on an entity's Board of Directors or advisory committees. Biemond: Sanquin: Research Funding; Celgene: Honoraria; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Global Blood Therapeutics: Honoraria, Research Funding, Speakers Bureau. van de Donk: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding. Zweegman: Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nur: Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

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Telomere Length Predicts for Outcome to FCR Chemoimmunotherapy in CLL

Blood ◽

10.1182/blood-2018-99-114448 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1854-1854

Author(s):

Kevin Norris ◽

Peter Hillmen ◽

Andy Rawstron ◽

Robert K. Hills ◽

Duncan M Baird ◽

...

Keyword(s):

Overall Survival ◽

Telomere Length ◽

Board Of Directors ◽

Genomic Instability ◽

Research Funding ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

University Patents ◽

The Mean

Abstract Telomeres are structures that cap the ends of chromosomes and play a critical role in maintaining genomic integrity. Telomere length is a key determinant of telomere function, with short telomeres being subjected to aberrant DNA repair activity that leads to telomere fusion and large scale genomic rearrangements. Single telomere length analysis (STELA) is a high-resolution approach to determine telomere length and is capable of detecting telomeres within the length range at which fusions can occur. Using STELA, we have previously shown a link between short telomeres, telomere fusion and genomic instability in CLL. We went on to define the telomere length threshold at which the chromosome end-capping function is lost resulting in telomere fusion events and genomic instability, the so-called 'fusogenic' range. We have shown that dividing patients with CLL into those with telomeres inside the fusogenic range (IFR) and outside the fusogenic range (OFR) is powerful prognostic tool. Consequently, we developed a high-throughput version of the assay (HT-STELA) to allow for rapid evaluation of large numbers of clinical samples. In this study, we used HT-STELA to evaluate whether telomere length could predict for outcome following fludarabine, cyclophosphamide, rituximab (FCR)-based treatment using samples collected from two concurrent phase II studies, ARCTIC and ADMIRE (n = 275). Patients with a mean telomere length IFR had significantly shorter progression-free survival (P<0.0001; HR=2.17) and shorter overall survival (P=0.0002; HR=2.44) when compared to patients with a mean telomere length OFR. In contrast, CD38 expression and β2-microglobulin were not informative and IGHV mutation status was only predictive of progression-free survival (P=0.0016; HR=1.9). Bifurcation of the IGHV-mutated and unmutated subsets according to telomere length revealed that patients with short, dysfunctional telomeres in each subset had shorter progression-free survival (HR = 4.35 and HR = 1.48 respectively) and shorter overall survival (HR = 3.81 and HR = 2.18 respectively). Although the mean telomere length of the IGHV-unmutated group was significantly shorter than the IGHV-mutated group (P<0.0001), patients with long (OFR) telomeres in both subsets has a significantly better overall survival (P = 0.025; 79% at 5 years and P = 0.006; 83% at 5 years respectively). Indeed, the overall survival of the OFR and IFR subsets were not significantly different regardless of IGHVmutation status (P = 0.61; HR = 1.24 and P = 0.41; HR = 1.47 respectively). In multivariate modelling using Cox proportional hazards with forward selection, telomere length was the dominant co-variable for progression-free survival (P=0.0002; HR=1.85) and overall survival (P=0.05; HR=1.61); when telomere length was added into the model no other parameter retained independent significance in the presence of telomere length. Taken together our data suggest that telomere length is a powerful predictor of outcome to FCR-based treatment and could be used to inform the design of future risk-adapted clinical trials. Figure 1. Stratification of patients by telomere length predicts for progression-free and overall survival following FCR-based treatment. Bifurcation of the patient cohort according to the previously defined telomere length threshold for telomere dysfunction was predictive of (A)PFSand (B) OS. Patients whose telomere length were ≤ the mean of the fusogenic range (IFR) showed shorter PFS and OS than those patients with mean telomere length outside of the fusogenic range (OFR). (C) In terms of OS, the short telomere subsets in both (C)IGHV-mutated and (D)IGHV-unmutated groups showed significantly reduced survival. It is of particular interest that the OS of patients with (E)long telomeres (OFR) and (F) short telomeres (IFR) were not significantly different in IGHV-mutated and IGHV-unmutated groups. Disclosures Norris: Cardiff University: Patents & Royalties: Telomere measurement patent. Hillmen:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Novartis: Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Gilead Sciences, Inc.: Honoraria, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Hills:Daiichi Sankyo: Consultancy, Honoraria. Baird:Cardiff University: Patents & Royalties: Telomere measurement patents. Pepper:Cardiff University: Patents & Royalties: Telomere measurement patents. Fegan:Janssen: Honoraria; Gilead Sciences, Inc.: Honoraria; Abbvie: Honoraria; Napp: Honoraria; Roche: Honoraria.

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Rapid and Durable Responses with the SYK/JAK Inhibitor Cerdulatinib in a Phase 2 Study in Relapsed/Refractory Follicular Lymphoma-Alone or in Combination with Rituximab

Blood ◽

10.1182/blood-2019-124231 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3981-3981

Author(s):

Stephen D. Smith ◽

Javier Munoz ◽

Don Stevens ◽

Sonali M. Smith ◽

Tatyana A. Feldman ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Employment Equity ◽

Advisory Committees ◽

Prior Therapy ◽

Equity Ownership ◽

Grade 3 ◽

Anti Cd20 ◽

Age Range

Background: Despite recent advances, follicular lymphoma (FL) remains incurable for most patients. Relapsed/refractory (r/r) FL is associated with decremental treatment responses, accumulating toxicity, and poor survival among early failures of 1st line chemoimmunotherapy. Underscored by the recent approvals of idelalisib, copanlisib, and duvelisib, targeting B-cell receptor (BCR) signaling produces ORR of ~50% in r/r patients; however, new agents with a better therapeutic index over long-term administration are needed. SYK is a key regulator of BCR signaling (upstream of BTK and PI3K), and its inhibition results in clinical activity in FL. Compared with unaffected nodes, lymph nodes from FL patients have greater numbers of follicular helper T cells that express high levels of IL-4, which may support the tumor via the JAK1/3 pathway. Cerdulatinib, an oral, reversible inhibitor of SYK and JAK kinases (JAK1, JAK3, TYK2), previously reported a ~45% overall response rate (ORR) in r/r FL as a single agent. Xenograft studies suggest cerdulatinib may combine with rituximab to enhance antitumor activity. We report updated results from a phase 2a study of single-agent cerdulatinib and initial results in combination with rituximab in r/r FL. Methods: This phase 2a study confirmed the safety and efficacy of cerdulatinib 30 mg BID in r/r B- and T-cell lymphoma patients. Dose reductions were permitted to 15 mg BID. Response was assessed by Lugano criteria. Results: A planned interim analysis was performed on July 18, 2019, in which enrollment was 40 patients in the single-agent cohort and 19 patients in the rituximab combination cohort. For the single-agent cohort, median age (range) was 64 (42-81) years and median prior therapies (range) was 3 (1-9). Ninety-five percent of patients had prior anti-CD20 therapy, and 25% had prior therapy with BCR pathway inhibitors. For the combination cohort, median age (range) was 67 (47-85) years and median prior therapies (range) was 3 (1-10). Eighty-eight percent of patients had prior anti-CD20 therapy, and 32% had prior therapy with BCR pathway inhibitors. The safety profile appeared similar in both cohorts. The most common treatment-emergent grade 3+ adverse events in ≥5% of patients for both cohorts were lipase increase (27%), neutropenia (18%), diarrhea (12%), amylase increase (10%), hypertension (8%), nausea (7%), and pneumonia (5%). Grade 3+ infections occurred in 17.5% of single-agent cohort patients and 15.8% of combination cohort patients. Amylase and lipase increases generally were not associated with abdominal pain or pancreatitis. In addition, to date there has been no evidence of cumulative toxicity. The ORR was 45% as a single agent (12.5% complete response [CR], 32.5% partial response [PR], with 25% stable disease [SD] and 5% progressive disease [PD] in 40 evaluable patients) and 59% in the combination cohort (11.7% CR, 47% PR, with 27.8% SD and no PD in 17 evaluable patients). Responses typically occurred after 2 cycles, generally improved over time, and were durable in the single-agent cohort, with 10 patients on drug for >1 year. Enrollment in the combination cohort is ongoing. Updated safety and efficacy will be presented. Conclusion: The recommended cerdulatinib phase 2 dose of 30 mg BID was tolerable and efficacious in heavily pretreated r/r FL. The cerdulatinib + rituximab combination appears to be well tolerated, with tumor reductions in all evaluable patients. The safety profile and unique mechanism of action of cerdulatinib support further combination studies in FL. Disclosures Smith: Pharmacyclics: Research Funding; Denovo Biopharma: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Acerta Pharma BV: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Ignyta (spouse): Research Funding; Ayala (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding. Munoz:AstraZeneca: Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Portola: Research Funding; Incyte: Research Funding. Stevens:Astellas: Consultancy. Smith:Portola Pharmaceuticals: Research Funding. Feldman:Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Roche: Research Funding; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Ye:MingSight: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Takeda: Research Funding; AbbVie: Research Funding; Portola Pharmaceuticals: Research Funding. de Vos:Verastem: Consultancy; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. Miller:Verastem: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau. Birrell:Portola Pharmaceuticals: Employment, Equity Ownership. Leeds:Portola Pharmaceuticals: Employment, Equity Ownership. Coffey:Portola Pharmaceuticals: Employment, Equity Ownership, Research Funding. Conley:Portola Pharmaceuticals: Employment, Equity Ownership. Michelson:Portola Pharmaceuticals: Employment, Equity Ownership. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership.

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Extending Metronomic Therapy to 28 Days (metro28) for Relapsed Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood.v126.23.5395.5395 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5395-5395

Author(s):

Xenofon Papanikolaou ◽

Carolina Schinke ◽

Sharmilan Thanendrarajan ◽

Adam Rosenthal ◽

Nathan Petty ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Clinical Outcomes ◽

Research Funding ◽

Progression Free Survival ◽

Advisory Board ◽

University Of Arkansas ◽

Medical Sciences ◽

Advisory Committees ◽

Free Survival

Abstract Introduction: Despite the enormous progress in MM therapy brought about by the rapid development of many novel agents, many patients end up with limited treatment options. We have previously reported on the efficacy and safety of metro16 in RRMM (Papanikolaou, Haematology 2013). Here we are reporting on an extension of such treatment to 28 d (metro28). Patients and Methods: The treatment consisted of a cycle of 28d continuous iv infusions of ADR and DDP each at 1mg/m2/d, along with thalidomide 50 to 100mg/d x 28; bortezomib 0.8 to 1.0mg/m2 on days 1, 4, 7, 10, 13, 16, 19, 22, 25, 28; DEX 8 to 12mg on days 1-4, 7-10, 13-16, 19-22, 25-28; some patients also received vincristine 0.07mg flat dose by CI for 28 days. This was off-protocol therapy that patients provided written informed consent for. The IRB permitted data retrieval and analysis. Results: 150 patients were identified, virtually all had received prior tandem transplants, bortezomib, lenalidomide, carfilzomib and pomalidomide. The median age was 64yr; B2M was elevated >=3.5mg/L in 48%, abnormal cytogenetics (CA) were present in 86%, and 44% had GEP70-defined high risk MM. Figure 1 portrays clinical outcomes. As of April 2015, 60 patients had died, and the 2-yr OS estimate was 45% (Figure 1A); the 6-mo PFS estimate was 31% although 15% had no progression at 18mo (Figure 1B). Analysis by GEP70 and GEP5 risk revealed 18-mo OS estimates of 80% among the 53 patients with low risk in both models, whereas the presence of high risk (HRMM) in either model conferred a significantly reduced 18-mo OS estimate of 25% (p<0.0001) (Figure 1C). On Cox regression analysis, OS was independently adversely affected by GEP5 HRMM (47%, HR=3.43, p<0.001), LDH >=ULN (25%, HR=3.46, p<0.001), low albumin (39%, HR=2.68, p=0.003), B2M >=3.5mg/L (51%, HR+2.63, p=0.014) and thrombocytopenia <50,000/uL (15%, HR=2.3, p=0.043). GEP5 HRMM was the sole adverse variable affecting PFS (HR=2.37, p<0.001). Most patients received metro28 in the outpatient setting, and side effects were mild. Conclusion: Metro28 represents a well-tolerated additional tool in the treatment armamentarium for RRMM. Figure 1. Clinical outcomes A: Overall survival B: Progression-free survival C: Overall survival according to GEP70 and GEP5 risk designations Figure 1. Clinical outcomes. / A: Overall survival. / B: Progression-free survival. / C: Overall survival according to GEP70 and GEP5 risk designations Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Schinke: University of Arkansas for Medical Sciences: Employment. Thanendrarajan:University of Arkansas for Medical Sciences: Employment. Rosenthal:Cancer Research and Biostatistics: Employment. Petty:University of Arkansas for Medical Sciences: Employment. Zangari:University of Arkansas for Medical Sciences: Employment; Onyx: Research Funding; Millennium: Research Funding; Novartis: Research Funding. Heuck:Celgene: Consultancy; Foundation Medicine: Honoraria; Janssen: Other: Advisory Board; University of Arkansas for Medical Sciences: Employment; Millenium: Other: Advisory Board. van Rhee:University of Arkansa for Medical Sciences: Employment. Epstein:University of Arkansas for Medical Sciences: Employment. Yaccoby:University of Arkansas for Medical Sciences: Employment. Morgan:Weismann Institute: Honoraria; CancerNet: Honoraria; MMRF: Honoraria; University of Arkansas for Medical Sciences: Employment; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Davies:University of Arkansas for Medical Sciences: Employment; Celgene: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Onyx: Consultancy. Barlogie:University of Arkansas for Medical Sciences: Employment.

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Interim or End of Treatment FGD-PET Complete Response Does Not Have Adequate Predictive Value in Mature T/NK Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.1813.1813 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1813-1813

Author(s):

Tatyana Feldman ◽

Larysa Sanchez ◽

Patrick Toth ◽

David Panush ◽

Lori A Leslie ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Predictive Value ◽

Research Funding ◽

Nk Cell ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Significant Difference

Abstract Introduction: Cure rate of Mature T/NK cell lymphoma (TCL) is rather low and multiple trials are being conducted to improve frontline therapy outcomes. Consolidation with autologous stem cell transplant is becoming widely used as a mean of improving survival (SCT). Based on data from several retrospective trials, pts who achieve CR may not benefit from consolidative SCT. There is no data available on the role of PET-CR as defined by using Deauville criteria (which became standard in response assessment of NHL (The Lugano Classification 2014)). We performed retrospective analysis of 59 pts with TCL examining the correlation between PFS/OS and iPET and eotPET. Methods: 59 pts newly diagnosed pts with TCL treated between 2008-2016 for whom interim and eotPET scan were available. It was our routine practice to obtain baseline, interim (after 3 cycles of chemotherapy) and eotPET. Pathology slides of outside cases were centrally evaluated by a hematopathologist to confirm diagnosis. Baseline, interim and eotPET were centrally reviewed by a nuclear medicine radiologist blinded to clinical outcomes who assigned Deauville score (DS) to every PET. Responses were recorded according to the Lugano classification 2014. Descriptive statistics and Kaplan Meier method was used to calculate the Progression-free survival (PFS) and Overall survival (OS), two-sided Log-rank test was used to compare OS and PFS between PET groups. Results: Detailed demographic is presented in Table1. Median age at diagnosis is 59, sixty two percent males, 37% female; ALCL 34%, PTCLnos 22%, AITL 19%, and ATLL 10%; most of pts were advanced stage. Most common chemotherapy regimens used were CHOP/CHOEP, HCVAD, and CODOX, SMILE. Median follow up time for the entire cohort was 22.7mo. Forty nine percent of pts progressed and 29% of pts died during follow up. Cause of death for majority of pts was disease progression. Following Deauville scores were assigned on iPET and eotPET respectively: DS1 in 37% and 39%, DS2 in 30% and 35%, DS3 in 15% and 6%, DS4 in 9% and 4%, DS5 in 9% and 16%. We analyzed mPFS and mOS for PET-CR using DS1-2 or DS1-3 to define it. Sixty seven percent and 82% were considered in PET-CR on iPET based on DS 1-2 and DS 1-3 respectively. PET-CR went up to 77% and 83% respectively on eotPET. For final analysis, DS1-2 was used to define PET-CR as no statistically significant difference in mPFS and mOS was noted between DS1-2 and DS1-3. With median follow up of 22.7mo, two-year mPFS and mOS for the cohort were 50% and 74% respectively. Two- year mPFS for iPET-CR and eotPET-CR were 62%. Two-year mOS for iPET-CR and eotPET-CR were 86%% and 83%. Two-year mPFS for iPET-PR and eotPET-PR were 37% and 67%. Two-year mOS for iPET-PR and eotPET-PR were 70% and 100 % (not statistically significant difference with PET-CR mPFS and mOS). None of the pts with PD on iPET were alive at two year. Two-year mOS for eotPET-SD and eotPET-PD are 40%. Negative predictive value of iPET and eotPET is 61%, positive predictive value is 65% and 72% respectively. Conclusion: While PET-SD and PD is quite predictive of poor survivorship, significant number of PET-CR pts will relapse. Even though PET-CR rate to frontline therapy is high, it does not translate into durable responses for significant number of pts with TCL. Thus, PET-CR is not a sensitive enough measure to be considered as a predictor of long-term remission in TCL. It is important to develop response assessment tools which will correlate better with long term survivorship of TCL patients. Figure 1 Overall survival stratified on PET response Figure 1. Overall survival stratified on PET response Figure 2 Progression free survival stratified on PET response Figure 2. Progression free survival stratified on PET response Disclosures Feldman: Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Skarbnik:Pharmacyclics: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Mato:Theradex: Research Funding; TG Therapeutics: Research Funding; ProNAi: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma: Research Funding; Abbvie: Research Funding; TG Therapeutics: Consultancy; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy; Abbvie: Consultancy. Chow:Seattle Genetics: Speakers Bureau. Protomastro:COTA: Employment. Leslie:Celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau. Goy:Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Safety and Clinical Activity of Temsirolimus in Combination with Rituximab and DHAP in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma - Report of the Prospective, Multicenter Phase II STORM Trial

Blood ◽

10.1182/blood.v128.22.3028.3028 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3028-3028

Author(s):

Mathias Witzens-Harig ◽

Andreas Viardot ◽

Ulrich Keller ◽

Christian Buske ◽

Anne Crombé ◽

...

Keyword(s):

Overall Survival ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Free Survival ◽

Multicenter Phase

Abstract Purpose. To evaluate the safety, tolerability and efficacy of the combination of the mTOR inhibitor Temsirolimus and a standard salvage regimen (R-DHAP) in patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL). Methods. This is a prospective, multicenter, phase II, open-label study. Patients with relapsed or refractory DLBCL with a maximum of two prior treatment lines were eligible. The STORM regimen consisted of Rituximab 375 mg/m² (day 2) and DHAP (Dexamethasone 40mg day 3-6, Cisplatine 100 mg/m² day 3, Cytarabine 2x2 g/m² day 4) with Temsirolimus added on day 1 and 8 of a 21 d cycle, with 2-4 cycles planned. In part I, dose levels of 25, 50, 75 and 100 mg for Temsirolimus were predefined. Based on the observed toxicity profile, the independent data safety committee recommended a Temsirolimus dose of 25 mg given on day 1 and 8 for the part II extension cohort of the trial. Results. We here report on 46 patients (pts), 15 from part I and 31 from part II. Seven pts were not evaluable for response. Of the evaluable 39 patients, median age was 63 and median number of prior regimen was 1. Temsirolimus dose was 50 mg on day 1 and 8 in 7 pts from the part I of the trial and 25 mg in the remaining 39 pts. The overall response rate was 82% (32/39pts) with 22 partial and 10 complete responses. After a median follow up of 10 months for the total study population, median PFS and OS have not been reached (Figure 1A and 1B). Early safety analysis includes preliminary data of 22 pts. The most frequent non-hematologic side effects were nausea (14 pts, 64%), epistaxis (11 pts, 50%), fatigue (12 pts, 55%), fever (11 pts, 50%) and diarrhea (11 pts, 50%). Frequent grade 3/4 events (n>2) included leukopenia (21 pts, 95%), thrombocytopenia (20 pts, 91%), lymphopenia (11pts, 50%), anemia (8 pts, 36%), neutropenia (10 pts, 45%), renal failure (3 pts, 20%) and infections (7 pts, 32%, bladder infection, esophagus infection, central venous access infection, soft tissue infection, mucositis). Two therapy-related deaths occurred (one patient died from sepsis during neutropenia, another from cerebral bleeding, both events occurring after cycle 3). Conclusion. Temsirolimus can be safely added to DHAP and Rituximab with promising activity. Figure 1 Progression free survival Figure 1. Progression free survival Figure 2 Overall survival Figure 2. Overall survival Disclosures Witzens-Harig: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Viardot:Pfizer: Honoraria; Takeda: Other: travel support; Roche: Honoraria; BMS: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Keller:Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Spectrum Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees. Buske:Celltrion, Inc.: Consultancy, Honoraria. Meissner:Amgen: Other: Travel Support; Takeda: Other: Travel Support; Teva: Other: Travel Support; Celgene: Other: Travel Support. LaRosee:Pfizer: Honoraria. Marks:Pfizer: Honoraria. Hess:Celgene: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Janssen: Honoraria; Roche: Honoraria; Pfizer: Honoraria; Novartis: Honoraria.

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