Extranodal Presentation in Limited Stage DLBCL As a Prognostic Marker in Three Sequential SWOG Trials S0014, S0313 and S1001 (NCT00005089, NCT00070018, NCT01359592)

Abstract Introduction Several recent pivotal trials have changed the standard of care for patients with limited stage (LS) diffuse large B-cell lymphoma (DLBCL) to minimize the number of chemoimmunotherapy cycles and/or eliminate the need for radiotherapy (RT) without compromising excellent long-term outcomes (Poeschel 2019; Persky 2020; Bologna 2021). However, there may be subsets of patients where an abbreviated treatment approach is insufficient. With this in mind, Bobillo (2021), retrospectively reviewed pts with LS DLBCL treated with RCHOP (4-6 cycles) +/- RT and reported an extranodal (EN) presentation had shorter PFS and OS compared with nodal presentation. In these pts, consolidative RT prolonged survival in pts with EN disease, especially those with a positive PET scan at the end of chemotherapy. We sought to validate these findings by analyzing patients with LS DLBCL treated on 3 consecutive SWOG studies (S0014, S0313, S1001). Methods From 4/1/00 - 6/1/16, 234 eligible patients with non-bulky (exception of 2 patients on S0014) LS DLBCL were accrued to S0014 (n=60), S0313 (n=43), or S1001 (n=131), Enrolled pts received therapy with RCHOP x 3 + involved field radiotherapy (IFRT; 26%); RCHOP x 3 + IFRT + ibritumomab tiuxetan (24%); or RCHOP x 4 (51%). In S1001, an interim PET (iPET) scan was performed after RCHOP x 3 and considered negative if the Deauville Score was ≤3. Fisher's exact test compared the distribution of the characteristics and treatments received at 2-sided a of .05. PFS was calculated from date of randomization until progression/relapse/death. OS was calculated from date of randomization until death. PFS and OS estimates were calculated using the Kaplan-Meier method. Results Median follow-up is 7 years (range 1.1 - 15.8 years). Median age was 62 (range 18 - 85) and 68% had stage-modified international prognostic index (sm-IPI) of 0-1. Of the 234 pts, 104 (44%) had EN disease. Most common sites of EN disease were head & neck (n=55; nasopharynx=14; oral cavity=17; orbit=2; parotid=4; sinus=7; submandibular gland=1; thyroid=9; vocal cord=1), skin/soft tissue/muscle (n=12), gastrointestinal tract (n=11), bone (n=6), and breast (n=6). Clinical characteristics (age, stage, LDH, sm-IPI) and treatments received between EN and nodal disease groups were not statistically different. For the whole group, estimated 10-year PFS and OS were 71% (95% CI: 64% - 77%) and 77% (95% CI: 69% - 83%), respectively. For patients with extranodal versus nodal disease, there was no difference in the estimated 10-year PFS (74% vs 68%; 2-sided logrank p-value=.51, Figure 1A) or 10-year OS (77% vs 77%; 2-sided logrank p-value=.65; Figure 1B). For the 55 pts with EN disease of the head & neck, estimated 10-year PFS and OS were 61% (44% - 74%) and 77% (63% - 87%). Among the 104 pts with EN disease who received versus did not receive IFRT, there was no difference in the estimated 5-year PFS (83% vs 87%; 2-sided logrank p-value=.52) or 5-year OS (85% vs 92%; 2-sided logrank p-value=.28). Of 55 pts with EN disease treated on S1001, 5 (9%) pts had iPET+, 47 (85.5%) pts had iPET-, and 3 (5.5%) pts did not have iPET. In the 5 pts with EN disease and iPET+, all received IFRT and 1 progressed. There were 50 pt deaths. Of these, cause of death was lymphoma in 16 (32%), second cancer in 6 (12%), other in 15 (30%), and unknown in 13 (26%). Conclusions Patients with LS DLBCL treated on 3 SWOG studies had excellent and prolonged PFS and OS regardless of EN versus nodal presentation, or whether they received consolidative IFRT or not. Our dataset does not support EN disease as an adverse prognostic factor for pts with LS DLBCL. As such, we do not recommend consolidation with radiotherapy in pts with non-bulky LS DLBCL presenting with EN disease. There were too few patients with EN disease treated on S1001 that had iPET+ to make a recommendation for PET-adapted IFRT. The majority of pts in our dataset had EN disease of the head & neck, which appears to have similar survival as nodal presentation. As seen in previous studies, there was a continuous rate of relapse without plateau of the PFS curves. Most common known cause of death in was lymphoma, which supports the need for long term follow-up. Figure 1 Figure 1. Disclosures Stephens: Celgene: Consultancy; Mingsight: Research Funding; Arqule: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; JUNO: Research Funding; Novartis: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; CSL Behring: Consultancy; Epizyme: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Leonard: ADC Therapeutics, AstraZeneca, Bayer, BMS/Celgene, Epizyme, Inc., Genmab, Gilead/Kite, Karyopharm, BMS/Celgene, Regeneron, MEI Pharma, Miltenyi, Roche/Genentech, Sutro: Consultancy; Roche/Genentech: Consultancy. Kahl: Abbvie, ADCT, AstraZeneca, Beigene, Celgene, Teva, Janssen, MTEM, Bayer, InCyte, Adaptive, Genentech, Roche, MEI, KITE, TG Therapeutics, Epizyme, Takeda: Consultancy; Abbvie, BeiGene, AstraZeneca, Acerta: Research Funding; Research to Practice: Speakers Bureau. Smith: Celgene, Genetech, AbbVie: Consultancy; Alexion, AstraZeneca Rare Disease: Other: Study investigator. Friedberg: Bayer: Other: DSMC ; Novartis: Other: DSMC ; Acerta: Other: DSMC . OffLabel Disclosure: ibritumomab tiuxetan is not FDA approved for marketing in DLBCL

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Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

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Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

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ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽

10.1182/blood-2019-128198 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1565-1565 ◽

Cited By ~ 1

Author(s):

Patrizia Mondello ◽

Irene Dogliotti ◽

Jan-Paul Bohn ◽

Federica Cavallo ◽

Simone Ferrero ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advanced Stage ◽

Advisory Committees ◽

Free Survival ◽

High Risk Patients ◽

Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with >90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= <0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS <3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Rituximab Plus Three Cycles of Dexamethasone In the Treatment of Immune Thrombocytopenia (ITP): a Pilot Study.

Blood ◽

10.1182/blood.v116.21.3697.3697 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3697-3697

Author(s):

Rebecca Elstrom ◽

Soo Y. Lee ◽

James B. Bussel

Keyword(s):

Platelet Count ◽

Pilot Study ◽

Board Of Directors ◽

Initial Treatment ◽

Research Funding ◽

Advisory Committees ◽

Equity Ownership ◽

Almost All

Abstract Abstract 3697 Introduction: Rituximab has been a useful treatment for patients with ITP; many hundreds of patients have been treated. 30–40% of patients will achieve a complete remission (CR: platelet count >150 × 109/l) with initial treatment and, of this group, the CR will last at least a year in almost all patients. However, emerging data suggests that at least 40% of these patients in CR will relapse between 1 and 3 years from initial treatment suggesting that long-term “cures” only occur in 20% of the initial patients. Therefore it would be desirable if CR's could be achieved in more patients and especially if these would be durable in more than 20%. One approach would be to use rituximab maintenance, however it results in suppression of B-cells for more than 2 years. Dexamethasone has also been used to achieve “cure” in ITP especially in adults at or near diagnosis. Cheng's study suggested that approximately 50% of patients would achieve a long-term response with only one 4-day cycle of high dose (40 mg/day) dexamethasone (N Engl J Med, 2003). A follow up study from GIMEMA suggested that 3–4 cycles of dexamethasone would be better than 1 cycle (Blood, 2007). Finally, Zaja's study suggested that rituximab plus one cycle of dexamethasone was superior to dexamethasone alone with a > 50% CR rate at 6 months (Blood, 2010). Therefore, we elected to perform a pilot study to explore the combination of rituximab with three cycles of dexamethasone at 14 day intervals. Methods: Patients with ITP with platelet counts < 30,000 off therapy and in need of treatment were enrolled. The standard dose (4 infusions of 375mg/m2) rituximab was given on days 1, 8, 15 and 22 and dexamethasone 40 mg (adjusted for size) on days 1–4, 15–18, and 29–32. Results: Fourteen patients between the ages of 4 and 53 years with ITP were treated with rituximab and dexamethasone (R&D) (Table 1). All had received previous steroid therapy as well as other treatments. The median platelet count was 40,000 at initiation of rituximab (range 7,000-230,000); several patients with low counts started with dexamethasone prior to initiating Rituximab to sustain their counts during initial treatment. Patients received rituximab weekly for between 2 and 4 doses and dexamethasone for either 2 or 3 courses at intervals between 1 and 8 weeks (median 2 week intervals). A summary of the results is shown in table 2 demonstrating short-lived platelet increases in response to dexamethasone in almost all patients. With short follow up, there were 7 CR's, 3 PR's and 4 NR's. If this was divided by duration of ITP prior to R&D, there were 4 CR's and 1 NR for ≤ 12 months and 3 CR, 3 PR, and 3 NR for > 12 months. More of the children who were treated had chronic disease than did adults explaining their apparently poorer response. Observed toxicities included hyperglycemia, grade 1 and 2 liver function abnormalities, weight gain, and 1 episode of colitis requiring hospitalization. Three patients opted to skip the third cycle of dexamethasone. Conclusion: A regimen of rituximab + 2–3 courses of dexamethasone is active in patients with pretreated ITP with appreciable but usually manageable toxicity. It appears to yield superior results if administered to patients within one year of diagnosis. This combination merits further exploration in a prospective clinical trial. Disclosures: Bussel: Portola: Consultancy; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc.: Membership on an entity's Board of Directors or advisory committees; Cangene: Research Funding; Genzyme: Research Funding.

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Stem Cell Transplantation Can Provide Durable Disease Control in Blastic Plasmacytoid Dendritic Cell Neoplasia (BPDC): A Retrospective Study From the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽

10.1182/blood.v118.21.3077.3077 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3077-3077

Author(s):

Sascha Dietrich ◽

Damien Roos-Weil ◽

Ariane Boumendil ◽

Emanuelle Polge ◽

Jian-Jian Luan ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Nk Cell ◽

Plasmacytoid Dendritic Cell ◽

Advisory Committees

Abstract Abstract 3077 Blastic plasmacytoid dendritic cell neoplasm (BPDC), formerly known as blastic NK cell lymphoma, is a rare hematopoietic malignancy preferentially involving the skin, bone marrow and lymph nodes. The overall prognosis of BPDC is dismal. Most patients show an initial response to acute leukemia-like chemotherapy, but relapses with subsequent drug resistance occur in virtually all patients resulting in a median overall survival of only 9–13 months. However, anecdotal long-term remissions have been reported in young patients who received early myeloablative allogeneic stem cell transplantation (alloSCT). We therefore performed a retrospective analysis of patients identified in the EBMT registry in order to evaluate the outcome of autologous stem cell transplantation (autoSCT) or alloSCT for BPDC. Eligible were all patients who had been registered with a diagnosis of BPDC or Blastic NK cell lymphoma and had received autologous stem cell transplantation (autoSCT) or alloSCT in 2000–2009. Centres were contacted to provide a written histopathology and immunophenotyping report and information about treatment and follow-up details. Patients who did not have a diagnostic score ≥ 2 as proposed by Garnache-Ottou et al. (BJH 2009) were excluded. RESULTS: Overall, 139 patients could be identified in the database who fulfilled the inclusion criteria (alloSCT 100, autoSCT 39). Of 74 patients for whom the requested additional information could be obtained, central review confirmed the diagnosis of BPDC in 39 patients (34 alloSCT, 5 autoSCT). The 34 patients who had undergone alloSCT had a median age of 41 years (range: 10–70 years), were transplanted from a related (n=11) or unrelated donor (n=23); received peripheral blood stem cells (n=9), bone marrow stem cells (n=19) or cord blood (n=6); and had been treated with a reduced intensity conditioning regimen (RIC, n=9) or myeloablative conditioning (MAC, n=25). Nineteen of 34 patients were transplanted in CR1. After a median follow up time of 28 months (range: 4–77+ months), 11 patients relapsed (median time to relapse: 8 months, range: 2–27 months) of whom 8 died due to disease progression. 9 patients died in the absence of relapse. No relapse occurred later than 27 months after transplant. Median disease free survival (DFS) was 15 months (range: 4–77+ months) and median overall survival (OS) was 22 months (range: 8–77+ months; Figure 1a). However, long-term remissions of up to 77 months after alloSCT could be observed. Patients allografted in CR1 tended to have a superior DFS (p=0.119) and OS (p=0.057; Figure 1b). MAC was associated with a better OS (p=0.001) which was attributable to the significantly higher non-relapse mortality (NRM) rate of patients after RIC (p=0.014), who had been significantly older (age RIC: 56 years, age MAC: 36 years, p=0.0014). The relapse rate was not different in patients after RIC and MAC, respectively. However, there was no survivor after RIC. Median age in the autoSCT group was 47 years (range: 14–62 years). Three of 5 patients were transplanted in CR1 of whom 1 patient relapsed after 8 months, 1 patient experienced treatment related mortality and 1 patient remained in CR for 28 months. The 2 remaining patients had more advanced disease at autoSCT and relapsed 4 and 8 months thereafter. CONCLUSION: AlloSCT is effective in BPDC and might provide curative potential in this otherwise incurable disease, especially when performed in CR1. However, it remains to be shown by prospective studies if the potential benefit of alloSCT in BPDC is largely due to conditioning intensity, or if there is a relevant contribution of graft-versus-leukemia activity. Disclosures: Tilly: Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses; Genentech: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Janssen Cilag: Speakers Bureau.

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Long-Term Efficacy and Safety in COMFORT-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy for the Treatment of Myelofibrosis: 5-Year Final Study Results

Blood ◽

10.1182/blood.v126.23.59.59 ◽

2015 ◽

Vol 126 (23) ◽

pp. 59-59 ◽

Cited By ~ 4

Author(s):

Claire N. Harrison ◽

Alessandro M. Vannucchi ◽

Jean-Jacques Kiladjian ◽

Haifa Kathrin Al-Ali ◽

Heinz Gisslinger ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Spleen Volume ◽

Phase 3 ◽

Advisory Committees ◽

Safety And Efficacy ◽

Final Study ◽

Study Results

Abstract BACKGROUND: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that has demonstrated rapid and durable improvements in splenomegaly and symptoms as well as improved survival in the two phase 3 COMFORT studies in patients (pts) with myelofibrosis (MF). In COMFORT-II, significantly more pts achieved the primary endpoint (a ≥ 35% decrease in spleen volume from baseline at wk 48) with RUX compared with best available therapy (BAT) (28% vs 0%; P ˂ .0001). The 3-year follow-up confirmed that spleen volume reductions were sustained and RUX treatment remained tolerable with long-term use. Here, we report final study results on longer-term safety and efficacy after 5 years of RUX treatment in COMFORT-II. METHODS: COMFORT-II is a randomized (2:1), open-label phase 3 study of RUX vs BAT in pts with intermediate-2- or high-risk primary MF, post-PV MF, or post-ET MF. Pts initially received RUX 15 or 20 mg bid based on their platelet counts at baseline (100-200 and > 200 x 109/L, respectively), and doses were individually titrated to maximize safety and efficacy. Pts were allowed to cross over from the BAT arm to receive RUX upon protocol-defined progression (primarily progressive splenomegaly, a ≥ 25% increase in spleen volume from on-study nadir). All pts randomized to BAT had crossed over or discontinued by Nov 2011. The date of final database lock for the study is 20 Apr 2015. RESULTS: Pts were randomized to RUX (n = 146) or BAT (n = 73). Baseline characteristics were well balanced between arms and have been described previously (Harrison, N Engl J Med, 2012); disease and hematologic characteristics were representative of a population of pts with advanced primary or secondary MF. At study completion (median follow-up, 4.3 years), 39 pts (26.7%) in the RUX arm and 11 of the 45 pts (24.4%) who crossed over from BAT completed 5 years of on-study treatment. Primary reasons for premature discontinuation before 5 years were adverse events (AEs; 24.0%) and disease progression (21.9%) in the RUX arm and withdrawal of consent and other in the BAT arm (12.3% each). Overall 78 pts (53.4%) in the RUX arm achieved a ≥ 35% reduction in spleen volume from baseline at any time during treatment; the median duration of maintenance of spleen volume reduction was 3.2 years. The K-M estimated probability of maintaining this reduction was 0.51 (95% CI, 0.38-0.62) at 3 years and 0.48 (95% CI, 0.35-0.60) at 5 years. Approximately one-third of evaluable JAK2 V617F-positive pts had a ˃ 20% reduction in allele burden at 3.2 years (38.3%) and 3.7 years (31.0%). With RUX treatment, 23 pts (15.8%) had improved fibrosis (including 4 who improved to grade 0 from baseline fibrosis grades of 1 [n = 1], 2 [n = 2], and 3 [n = 1]), 47 pts (32.2%) had stable fibrosis, and 27 (18.5%) had a worsening at their last assessment. There was no relevant increase in the incidence of AEs with longer exposure (median: RUX arm, 2.6 years; BAT arm, 0.87 years; RUX after crossover, 1.2 years) compared with previous reports. The most commonly reported AEs in pts who received RUX any time (randomized treatment, extension phase or after cross over from BAT) were thrombocytopenia (52.4%), anemia (49.2%), diarrhea (35.6%), and peripheral edema (33.0%); grade 3/4 AEs included anemia (22.5%), thrombocytopenia (15.2%), pneumonia (5.8%), general physical health deterioration (4.2%), and dyspnea (4.2%). 8 pts (5.5%) and 5 pts (6.8%) developed leukemia in the RUX and BAT arms, respectively. There were no new or unexpected AEs. Overall, 59 (40.4%) and 35 (47.9%) deaths were reported in the RUX and BAT arms, respectively. Median OS was not reached in the RUX arm and was 4.1 years in the BAT arm. There was a 33% reduction in risk of death with RUX compared with BAT (HR, 0.67; 95% CI, 0.44-1.02; P = .06). The K-M estimated probability of survival at 5 years was 56% with RUX and 44% with BAT. As expected, the confounding effect on OS of crossover from BAT to RUX became apparent in this extended follow up compared with previous analyses; an analysis of OS correcting for crossover will be presented. SUMMARY/CONCLUSIONS: The immediate benefits of RUX treatment, such as improvements in spleen size, were maintained with long-term therapy. The previously reported OS benefit was maintained, although results are confounded by extensive crossover from the BAT arm following the primary analysis at wk 48, which becomes more apparent with longer follow-up. Long term safety and tolerability was consistent with previous findings. Disclosures Harrison: Novartis: Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria; Sanofi: Honoraria, Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Shire: Speakers Bureau. Vannucchi:Shire: Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Incyte Corporation: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Novartis: Consultancy. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gisslinger:AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Geron: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Consultancy. Knoops:Novartis: Consultancy. Cervantes:Novartis: Consultancy, Speakers Bureau; CTI-Baxter: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy. Jones:Incyte Corporation: Employment. Sun:Incyte Corporation: Employment. Descamps:Novartis Pharma S.A.S: Employment. Stalbovskaya:Novartis Pharma AG: Employment, Equity Ownership. Gopalakrishna:Novartis Pharma AG: Employment. Barbui:Novartis: Speakers Bureau.

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Factors Influencing Long-Term Hematopoietic Function Following Autologous Stem Cell Transplantation

Blood ◽

10.1182/blood.v128.22.2186.2186 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2186-2186

Author(s):

Alissa Visram ◽

Natasha Kekre ◽

Christopher N. Bredeson ◽

Jason Tay ◽

Lothar B. Huebsch ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Infection Rates ◽

Advisory Committees ◽

Cd34 Cells ◽

Significant Difference

Abstract Background/Objective: Mobilized peripheral blood hematopoietic progenitor cells are the most common stem cell source for autologous hematopoietic stem cell transplantation (auto-HSCT). Successful short-term stem cell engraftment requires collection of at least 2x106 CD34+ cells/kg. The American Society of Bone Marrow Transplantation (ASBMT) recommends a stem cell infusion target of 3-5 x106 cells/kg (Giralt et al. 2014). However, the number of CD34+ cells to reinfuse to ensure long-term engraftment has not been established. Plerixafor, a reversible CXCR4 antagonist, increases CD34+ cell yield at collection even in patients who are predicted poor mobilizers (PPM). Although plerixafor could be used universally for all collections, this may not be the most cost-effective strategy (Veltri et al. 2012). This study sought to determine the minimum number of CD34+ cells/kg required for adequate long-term hematopoiesis, identify factors associated with poor long-term hematopoiesis, and determine if plerixafor mobilization improved long-term peripheral blood counts. Methods: A retrospective chart review was conducted on patients who underwent auto-HSCT between January 2004 and September 2013 at The Ottawa Hospital, for management of hematological malignancies. Peripheral blood cell counts were collected from 1 to 5 years after auto-HSCT, or until disease relapse. Poor long-term hematopoiesis was defined as an ANC <1 x109/L, hemoglobin <100 g/L, or platelets <100 x109/L. Patients were stratified into groups based on the infused CD34+ concentration (in cells/kg), and the proportion of patients with poor long-term hematopoiesis at 1, 2, 3, 4, and 5 years post auto-HSCT was compared with chi square tests. Long-term clinical outcomes (platelet and packed red blood cell transfusions, and post auto-HSCT infection rates) were compared between plerixafor-mobilized patients and PPM (defined as patients with pre-collection CD34+ <2 x 106 cells/kg) with standard mobilization regimens. Results: This study included 560 patients who underwent auto-HSCT, 210 with multiple myeloma and 350 with lymphoma. At 1 and 5 years post auto-HSCT 377 and 104 patients were included, respectively. A dose dependent improvement 1 year after auto-HSCT was seen in patients who received 0-2.99 x 106 CD34+ cells/kg (24.4%, n= 41) compared to patients who received 5-9.99 x 106 CD34+ cells/kg (11%, n=154, p=0.051) and ³10 x 106 CD34+ cells/kg (4.5%, n=66, p=0.006). Though there was a trend towards lower CD34+ infusions and poorer hematopoietic function (see table 1), there was no statistically significant difference in hematopoietic function based on CD34+ infusion concentrations after 1 year post auto-HSCT. 10 patients received <2 x106 CD34+ cells/kg, of whom the rate of inadequate hematopoiesis was 33% at 1 year (n=6) and 0% (n=1) at 5 years post auto-HSCT. Factors that increased the risk of poor hematopoiesis over the course of study follow up, based on a univariate analysis, included advanced age (OR 1.189, p=0.05), multiple prior collections (OR 2.978, p=0.035), and prior treatment with more than two chemotherapy lines (OR 2.571, p=0.02). Plerixafor-mobilized patients (n=25), compared to PPM (n=197), had a significantly higher median CD34+ cell collection (4.048 x109/L and 2.996 x109/L cells/kg, respectively, p=0.005). There was no significant difference in overall cytopenias, transfusion requirements, or infection rates between plerixafor-mobilized and PPM patients over the course of the study follow up. Conclusion: Low pre-collection CD34+ counts, advanced age, multiple prior collections, and more than two prior chemotherapy treatments adversely affected long-term hematopoiesis post auto-HSCT. We support the transfusion target of 3-5 x 106 cells/kg, as proposed by the ASBMT, given that at 5 years post auto-HSCT there was no statistical or clinically significant difference in hematopoietic function with higher CD34+ infusion targets. While mobilization with plerixafor significantly increased overall CD34+ cell collection when compared with PPM, long-term hematopoietic function and clinical outcomes were not different. This finding supports the practise of limiting plerixafor use only to patients who are PPM, thereby facilitating adequate stem cell collection and early engraftment, as opposed to universal plerixafor mobilization. Disclosures Sabloff: Lundbeck: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; Alexion: Honoraria.

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Final Overall Survival Results of a Randomized Trial Comparing Bortezomib Plus Pegylated Liposomal Doxorubicin with Bortezomib Alone in Subjects with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.3448.3448 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3448-3448

Author(s):

Robert Z. Orlowski ◽

Arnon Nagler ◽

Pieter Sonneveld ◽

Joan Bladé ◽

Roman Hajek ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Pharmaceutical Research ◽

Phase Iii ◽

Advisory Committees ◽

Grant Support ◽

Johnson Pharmaceutical Research

Abstract Introduction Previous results of an open-label, randomized, controlled, multicenter phase III study (DOXIL-MMY-3001) demonstrated that bortezomib+pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in treating subjects with relapsed or refractory multiple myeloma (MM) whose disease had failed one or more lines of prior therapy. The risk of developing disease progression was significantly reduced by 45% with bortezomib+PLD (median time to progression (TTP) with bortezomib+PLD: 9.3 months, bortezomib: 6.5 months; HR=1.82, 95% confidence interval (CI) [1.41, 2.35]; p=0.000004). In the interim analysis, the 15-month overall survival (OS) rate for bortezomib+PLD was 76% (95% CI [70%, 83%]) compared with 65% (95% CI [58%, 73%]) for bortezomib alone (p=0.03)(Orlowski et al JCO 25: 3892-3901, 2007). A protocol-defined analysis of the final survival data of this study is provided here. Methods Subjects with confirmed MM, ECOG status 0 to 1, platelets ≥75,000/mm3, hemoglobin ≥8.0 g/dL, absolute neutrophils ≥1,000/mm3, and creatinine clearance ≥30 mL/min were randomized to bortezomib (bortezomib 1.3 mg/m2, intravenous, days 1, 4, 8, and 11 of an every 21-day cycle), or bortezomib+PLD (same bortezomib+PLD 30 mg/m2 intravenous on day 4). Randomization was stratified according to serum β2-microglobulin levels (≤2.5, >2.5 and ≤5.5, or >5.5 mg/L) and response to prior treatment (response followed by progression, or primary refractory). The primary endpoint was TTP; secondary efficacy endpoints included overall survival, progression-free survival (PFS) and overall response rate (complete response [CR] + partial response [PR]). Results A total of 646 subjects (bortezomib+PLD: 324; bortezomib: 322) were randomized between December 2004 and March 2006. In the pre-planned interim analysis, the study met its primary and other secondary end points. The study continued for long-term survival follow-up. At the clinical cutoff of 16 May, 2014, for the final survival analysis with a median follow-up of 103 months, 79% of subjects were dead (bortezomib+PLD: 253 [78%]; bortezomib: 257 [80%]), 6% withdrew consent, 4% were lost to follow-up, and 11% were still alive. Median OS in bortezomib+PLD–treated subjects was 33.0 months (95% CI [28.9, 37.1]) versus 30.8 months (95% CI [25.2, 36.5]) in bortezomib-treated subjects (HR=1.05, 95% CI [0.88, 1.25]; p=0.6068). The types of salvage therapies utilized included dexamethasone (49.1%), thalidomide (31.0%), cyclophosphamide (28.5%), melphalan (22.9%), lenalidomide (21.8%), bortezomib (20.4%) and doxorubicin (8.0%), which were well-balanced between the two treatment groups. Conclusion Despite inducing a superior TTP, long-term follow-up revealed that PLD+bortezomib-treatment did not improve the OS compared with bortezomib alone in subjects with relapsed or refractory MM. The inability to confirm the early survival advantage may be due to the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase III trials. Disclosures Orlowski: Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sonneveld:Orthobiotech;: Consultancy. Bladé:Celgene: Grant support, Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Spencer:Hospira: Research Funding. Robak:MorphoSys AG: Research Funding. Dmoszynska:Johnson & Johnson Pharmaceutical Research & Development: Research Funding. Horvath:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Research Funding. Sutherland:OrthoBiotech: Consultancy. Xiu:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Employment, Equity Ownership. Parekh:Johnson & Johnson Pharmaceutical Research & Development: Employment, Equity Ownership. Miguel:Janssen Cilag: Consultancy, Honoraria.

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Sickle-Cell Disease Patients' Attitudes Towards Their Treatment with Hydroxycarbamide

Blood ◽

10.1182/blood-2019-125673 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1013-1013

Author(s):

Frédéric Galactéros ◽

Ersi Voskaridou ◽

Anoosha Habibi ◽

Giovanna Cannas ◽

Laure Joseph ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Fetal Hemoglobin ◽

Treatment Discontinuation ◽

Cell Disease ◽

Advisory Committees

Hydroxyurea (HU) is approved in the EU and USA for prevention of vaso-occlusive crises (VOC) including acute chest syndromes (ACS) in patients over 2 years with sickle-cell disease (SCD). The major benefits of HU in SCD are directly related to its abilities to increase HbF, decrease sickling of red blood cells and hemolysis, leading to reduction of vaso-occlusive episodes, need for blood transfusions and consequently reduction of morbidity and mortality. Adherence to the treatment is paramount for effectiveness, but in spite of proven benefits, barriers to adherence persist.[1] ESCORT-HU study (European Sickle Cell Disease COhoRT - HydroxyUrea), is a multicentric, prospective, non-interventional European study designed to evaluate the safety profile of HU in real life. Patients were enrolled from January 2009 to June 2017 with a follow-up of up to 10 years. All interruptions and resumptions of HU treatment exceeding 15 days were recorded in this study. We hereby present the analysis of the group of patients who self-discontinued HU at least once during the study before informing their caregiver, with a view to identify potential barriers to long-term adherence. In total, 1906 patients were enrolled in ESCORT-HU from 63 centers in France, Germany, Greece and Italy. Of these, 619 patients (32%) stopped HU for over 15 days at least once, and around a third (11% of all patients) were due to patient's will. The mean duration of HU treatment before the first discontinuation was 4.8 ± 5.1 years. Data are summarized in table 1. Compared to the rest of the cohort, the 'treatment discontinuation' group had similar distribution by gender and indication for HU prescription, but a higher proportion of adults stopped HU more than 15 days. It is notable that the proportion of patients with SC genotype was higher in the 'treatment discontinuation' group (4.5% vs 1.7%). The patients in the 'treatment discontinuation' group had more frequent SCD symptoms before enrolment in the study (table 2). Hematological and clinical improvement compared to the baseline was observed in both groups. However, average mean Corpuscular Volume (MCV) and Fetal Hemoglobin percentage (HbF%) were lower and mean percentages of patients with SCD symptoms were higher over the three years of follow-up in the 'treatment discontinuation' group, suggesting that HU daily dose was insufficient (table 2). Sixty patients have no treatment resumption date reported which suggest a permanent interruption of their treatment. Among them 32% preferred to switch to another HU medicinal product and 13% have safety issue (table 3). Understanding and managing self-discontinuation of HU before taking medical advice is challenging for the physician. It is tempting to speculate that it may be due, at least in part, to lack of effectiveness potentially due to an underdosage of the treatment. Resistance to the treatment may also be suggested based on past literature data revealing a great variability in the response (determined by HbF%) to HU therapy. There is evidence that genetic modifiers affect individual response to HU.[2],[3] Finally, weariness from long-term use may also explain the patient's wish to discontinue HU. But treatment at optimal effective should be the primary goal of caregivers. [1]Smaldone A., Manwani D., Green NS, Greater number of perceived barriers to hydroxyurea associated with poorer health-related quality of life in youth with sickle cell disease, Pediatr Blood Cancer. 2019 [2] Steinberg MH, Voskaridou E, Kutlar A, Loukopoulos D, Koshy M, et al. (2003). Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease. Am J Hematol 72: 121-126 [3] Ware RE, Despotovic JM, Mortier NA, Flanagan JM, He J, et al. (2011) Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood 118: 4985-4991 Disclosures Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Voskaridou:Celgene Corporation: Consultancy, Research Funding; Protagonist: Research Funding; Genesis: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees. Cannas:Addmedica: Membership on an entity's Board of Directors or advisory committees.

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Predictive Factors of Response and Survival of Lenalidomide and Rituximab As Initial Treatment of Follicular Lymphoma

Blood ◽

10.1182/blood-2019-129311 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1533-1533 ◽

Cited By ~ 1

Author(s):

Paolo Strati ◽

Ralph J. Johnson ◽

Sheryl G Forbes ◽

Loretta J. Nastoupil ◽

Felipe Samaniego ◽

...

Keyword(s):

Board Of Directors ◽

Initial Treatment ◽

Research Funding ◽

Advisory Board ◽

Advanced Stage ◽

Advisory Committees ◽

Long Term Follow Up ◽

Baseline Characteristics

Introduction. The combination of rituximab and lenalidomide (R2) is active in patients with untreated indolent lymphoma. Recent randomized trials (RELEVANCE) have demonstrated similar efficacy when compared to standard chemo-immunotherapy backbones. Long term follow up of patients receiving R2 as well as predictors of long term remission and survival have yet to be published. Methods. We prospectively evaluated patients with low grade advanced stage FL who received R2 as initial treatment at our institution between 07/2008 and 10/2014. Lenalidomide was given at 20 mg (day 1-21, in a 28 day cycle) for 6 cycles with rituximab monthly. Lenalidomide starting dose was 10 mg if baseline creatinine clearance was < 60 mL/min. Patients with an objective response continued with 10-20 mg of lenalidomide with rituximab for up to 12 more cycles. Response was evaluated according to 2014 Lugano criteria. Results. One-hundred and one patients were included in the analysis, baseline characteristics are shown in the Table. Median number of provided cycles was 7 (range, 1-20). Median dose of lenalidomide was 20 mg (range, 5-20 mg), and 29 (29%) patients required a dose reduction. Fifty-six (55%) patients experienced grade 3-4 treatment-related toxicities, the most common (> 5%) being neutropenia (39%), skin rash (20%), myalgia (16%) and fatigue (16%). Seven (7%) patients discontinued treatment before completion, after a median time of 4 months (range, 1-10 months): 4 because of toxicity (arterial thrombosis in 2, respiratory failure in 1, and skin rash in 1), and 3 because of progression. Ninety-eight patients were evaluable for response, while 3 patients discontinued treatment because of toxicity before first response assessment. Overall response rate was 98%, CR rate 90% (both achieved after a median of 6 months [range, 3-22 months]), and CR rate at 30 months (CR30) was 80%. Only female sex associated with a higher CR rate (96% vs 83%, p=0.05), while no baseline characteristic associated with CR30 rate. After a median follow-up of 88 months (95% confidence interval, 84-92 months), 31 (31%) patients progressed and/or died, 7-year progression-free survival (PFS) was 63%, and 13% of patients had a PFS < 24 months (PFS24). Failure to achieve CR was the only factor associated with significantly decreased PFS (10 months vs not reached, p<0.001) and higher likelihood of PFS24 (46% vs 5%, p<0.001). No association was observed with baseline characteristics, including FLIPI and FLIPI-2 score. At most recent follow-up, transformation was reported in 3 (3%) patients, after 30, 32 and 42 months, respectively. Two (2%) patients have died, 1 of unrelated comorbid health conditions, 1 of progressive disease, and 7-year overall survival was 98%. Second cancers (excluding transformation) were diagnosed in 8 (8%) patients, after a median of 55 months (range, 3-105 months). These included: breast adenocarcinoma (2), melanoma (2), pancreatic adenocarcinoma (1), esophageal adenocarcinoma (1), and therapy-related acute myeloid leukemia. Discussion. Long-term follow-up show very favorable outcomes for patients with advanced stage FL receiving R2 as initial treatment, independent of traditional prognostic factors relevant to patients treated with chemoimmunotherapy, including FLIPI and FLIPI-2 score. Combination strategies, aimed at increasing depth of response to R2, may further improve outcomes observed with this regimen. Table. Disclosures Nastoupil: Bayer: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria. Westin:Janssen: Other: Advisory Board, Research Funding; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Genentech: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding. Wang:AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; MoreHealth: Consultancy, Equity Ownership; Acerta Pharma: Consultancy, Research Funding; BioInvent: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Juno Therapeutics: Research Funding; Dava Oncology: Honoraria; Celgene: Honoraria, Research Funding; Aviara: Research Funding; Kite Pharma: Consultancy, Research Funding; Guidepoint Global: Consultancy; VelosBio: Research Funding; Loxo Oncology: Research Funding. Neelapu:Pfizer: Consultancy; Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Allogene: Consultancy; Novartis: Consultancy; BMS: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Cellectis: Research Funding; Acerta: Research Funding; Karus: Research Funding; Poseida: Research Funding; Incyte: Consultancy; Cell Medica: Consultancy; Unum Therapeutics: Consultancy, Research Funding. Fowler:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: lenalidomide and rituximab are not yet FDA-approved as frontline treatment for patients with FL

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