Single UM171 Expanded Cord Blood Permits Transplantation of Better HLA Matched Cords with Excellent Gvhd Relapse Free Survival

Abstract Cord blood (CB) transplants have fallen into disfavor in large part due to low cell dose leading to prolonged hospitalizations and high transplant related mortality (TRM). UM171, a novel and potent agonist of hematopoietic stem cell (HSC) self-renewal could solve this major limitation, allowing for CB's important qualities of lower risk of chronic GVHD and relapse to prevail. In addition, UM171 could permit transplantation of smaller, better HLA matched cords, associated with lower TRM. Hence, we initiated a clinical trial to test the safety and efficacy of UM171 expanded CB (eCB). Our goal was to design a clinically viable eCB transplant with a TRM as low or lower than other HSC sources all the while maintaining CB's low relapse rate. Patients (pts) received a myeloablative conditioning regimen. On day (D)-7 of transplant, CB was thawed and CD34+ selected. The CD34- lymphocyte containing fraction was cryopreserved and infused on D+1. The CD34+ component was placed in a closed culture system with UM171 and media was injected once a day until D0, when cells were washed and infused. This fed-batch culture system allowed for small culture volumes, saving cost and labor. Between 7/16-6/18, 21 adult pts (median age 44 years) were transplanted with an eCB. Median final culture volume and net viable CD34 fold expansion were 670 mL and 35, respectively. Median 1st day of 100 and 500 neutrophils were D+10 and D+18, respectively. Achieving 100 neutrophils was 5 days faster than seen with our pts receiving peripheral blood (PB) or marrow (BM) and appeared cell dose independent, suggesting that clinically meaningful expansion of an early repopulating myeloid progenitor is at saturation even with smaller CBs. In contrast, attaining 500 neutrophils was accelerated but dependent on cell dose. More importantly, pts appeared to derive clinical benefit beyond neutrophil engraftment (defined as 500 neutrophils). Pts' median last day of fever prior to 500 neutrophils was D+8, much earlier than engraftment and 4 days earlier than seen with our PB-BM pts. We offer 2 hypotheses as explanation: i) 100 neutrophils, which are attained early, provide significant defense against infection, ii) the graft contains a significant proportion of dendritic cell precursors (30-40%) which offer mucosal protection during severe neutropenia. Duration of hospitalization was shorter by 12 days and longer by 2 days compared to our non eCB and PB-BM transplants, respectively. In addition, because cell dose requirements were lower, 12/21 pts received a better HLA matched CB, thus >80% of patients were transplanted with a ≥6/8 HLA matched eCB. As a result of lower minimal cell dose criteria, we can now use ∼half the CBs in the banks instead of only 5% for a 70 kg patient. Platelet engraftment occurred at a median of 42 days. With a median follow up of 14 months, there has been no CMV disease, no PTLD, 2 adenovirus cystitis, 2 (10%) grade 3-4 acute GVHD, no moderate/severe chronic GVHD and 1 TRM (5%) despite a median comorbidity index of 2 (0-5). Full donor chimerism was achieved in all cell subsets. Immune recovery was faster than seen in our unrelated donor transplants who routinely receive ATG prophylaxis with 196, 300 and 413 CD4+/µL at 3, 6 and 12 months, respectively. Interestingly, transcriptome analysis of UM171-eCB cells shows an enhanced lymphoid progenitor-associated gene signature when compared to DMSO exposed cells. Animals transplanted with UM171-eCB cells showed a 20 to 35-fold increase in thymic cellularity at 8 weeks post-transplant. Despite some very high risk pts in our trial, only 3 relapsed. Overall, progression free, and GVHD/relapse free survival (GRFS) are excellent at 95, 77 and 67%, respectively, at 12 months. A 7 day UM171 single eCB protocol is feasible and provides clinical benefits beyond faster engraftment with fewer infectious complications, better HLA matching and very low TRM, all the while saving production and hospitalization costs. Nevertheless, longer follow up will be required to better assess relapse howbeit encouraging preliminary results. Furthermore, patients' quality of life is paramount and best evaluated by GRFS which is excellent thanks to a very low rate of significant chronic GVHD all the while maintaining a low risk of relapse. In conclusion, this 1st trial documents the potency of UM171 and positions UM171-eCB as a promising HSC source which could compete with the current standard of care. Figure. Figure. Disclosures Cohen: ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Lachance:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:Hopital Maisonneuve Rosemont: Patents & Royalties: Author on patent; Kiadis Pharma: Other: Travel support; University of Montreal: Patents & Royalties: Author on patent. Busque:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Kiss:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Caudrelier:ExCellThera: Employment. Zandstra:ExCellThera: Equity Ownership. Sauvageau:ExCellThera: Employment, Equity Ownership.

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Single UM171 Expanded Cord Blood Transplant Is Feasible, Safe, and Permits Transplantation of Better HLA Matched Cords with Very Low Transplant Related Mortality

Blood ◽

10.1182/blood.v130.suppl_1.658.658 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 658-658

Author(s):

Sandra Cohen ◽

Jean Roy ◽

Silvy Lachance ◽

Anne Marinier ◽

Denis-Claude Roy ◽

...

Keyword(s):

Board Of Directors ◽

Culture System ◽

Research Funding ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Advisory Committees ◽

Cell Dose ◽

Equity Ownership ◽

Related Mortality ◽

Neutrophil Engraftment

Abstract Cord blood (CB) transplants are hampered by low cell dose and high transplant related mortality (TRM). UM171, a novel and potent agonist of hematopoietic stem cell (HSC) self-renewal could solve this major limitation, allowing for CB's important qualities as lower risk of chronic GVHD and relapse to prevail. Hence, we initiated a clinical trial to test the safety and efficacy of UM171 expanded CB (eCB). The procedure was designed to be non-labor intensive and of short duration for it to be clinically viable. Patients (pts) received a myeloablative conditioning regimen. On day(D)-7 of transplant, CB was thawed and CD34+ selected. The CD34- lymphocyte containing fraction was cryopreserved and infused on day of transplant. The CD34+ component was placed in a closed culture system with UM171 and media was injected once a day until D0, when cells were washed and infused. The first 3 pts also received a 2nd nonmanipulated CB (neCB) to permit documentation of eCB engraftment. This fed-batch culture system allowed for small culture volumes, saving cost and labor. Between 6/16-7/17, 16 adults with a median weight and age of 77 kg and 44 years, respectively, were transplanted with a single eCB (13 pts) or with an eCB and a neCB (3 pts). Median final culture volume was 609 mL. The median net viable (v)CD34 fold expansion was 36. Median 1st day of 100 and 500 neutrophils were D+10 and D+19, respectively. Achieving 100 neutrophils was faster than expected and cell dose independent, suggesting that clinically meaningful expansion of an early repopulating myeloid progenitor is at saturation even with smaller CBs. In contrast, attaining 500 neutrophils was accelerated but dependent on infused vCD34+ cell dose. More importantly, patients appeared to derive clinical benefit beyond neutrophil engraftment defined as the 1st of 3 consecutive days of 500 neutrophils. Patients' last day of fever prior to neutrophil engraftment was Day +7, which occurred much earlier than D+19 of engraftment. We offer 2 hypotheses as explanation: i) 100 neutrophils, which are attained much earlier at D+10, provide significant defence against infection, ii) the graft contains a significant proportion of dendritic cell precursors (>25%) which offer protection during severe neutropenia. When compared to our pts who have received the same conditioning regimen with peripheral blood or marrow, eCB pts were free of fever much earlier (D+7 vs D+15 p<.001). Duration of hospitalization was reduced by 11 days when compared to our non UM171 CB transplants. In addition, because cell dose requirements were lower, 11/16 pts received a better HLA matched CB and 2 pts required a single CB instead of a double CB. Platelet engraftment occurred at a median of 42 days. With a median follow up of 4 months (range 1-13), there has been no CMV disease, no PTLD, 1 adenovirus cystitis, 1 grade 3-4 acute GVHD, 2 mild chronic GVHD and no TRM. Full donor chimerism was achieved in all cell subsets. These results favorably compare to those of other expansion trials which utilize much larger (up to 20L) and longer (up to 21 days) cultures. Moreover, and in contrast to others, we have already initiated our dose reduction study with smaller, better HLA matched CBs, proven to reduce TRM. Despite preliminary data, it appears that a 7 day UM171 single eCB protocol is feasible and provides clinical benefit beyond faster engraftment with fewer infectious complications, better HLA matching and low TRM, all the while saving production and hospitalization costs. In conclusion, this 1st trial documents the potency of UM171 and positions UM171-expanded CB as a viable HSC source. Disclosures Cohen: University of Montreal: Patents & Royalties: royalties. Marinier: ExCellThera: Equity Ownership. Busque: Novartis Canada Inc.: Honoraria; Bristol Myer Squibb: Honoraria; Pfizer: Honoraria; Paladin: Honoraria. Caudrelier: ExCellThera: Employment. Kiss: Otsuka: Membership on an entity's Board of Directors or advisory committees, Other: meeting attendance support, Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zandstra: ExCellThera: Equity Ownership. Sauvageau: ExCellThera: Equity Ownership, Patents & Royalties: royalties.

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Interim Results from a Phase 1/2 Clinical Study of Lentiglobin Gene Therapy for Severe Sickle Cell Disease

Blood ◽

10.1182/blood.v128.22.1176.1176 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1176-1176 ◽

Cited By ~ 19

Author(s):

Julie Kanter ◽

Mark C. Walters ◽

Matthew M. Hsieh ◽

Lakshmanan Krishnamurti ◽

Janet Kwiatkowski ◽

...

Keyword(s):

Gene Therapy ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Globin Gene ◽

Advisory Committees ◽

Cell Dose ◽

Cd34 Cells ◽

Equity Ownership

Abstract β-globin gene transfer into hematopoietic stem cells (HSCs) has the potential to reduce or eliminate the symptoms and long-term complications of severe sickle cell disease (SCD). LentiGlobin Drug Product (DP) is a gene therapy product containing autologous CD34+ cells transduced with the BB305 lentiviral vector. BB305 encodes a human β-globin gene containing a single point mutation (AT87Q) designed to confer anti-sickling properties similar to those observed in fetal hemoglobin (γ-globin). In two ongoing studies, subjects with transfusion-dependent β-thalassemia (Studies HGB-204 and HGB-205) or SCD (Study HGB-205) receiving LentiGlobin DP have demonstrated sustained expression of 3-9 g/dL therapeutic hemoglobin (HbAT87Q) and have shown marked improvements in clinical symptoms 1 year post-treatment. Study HGB-206 is a multi-center, Phase 1/2 safety and efficacy study of LentiGlobin DP in adults with severe SCD. We previously (ASH 2015) presented results from 2 subjects, who had 3 and 6 months of follow-up after LentiGlobin treatment. We now present data from 7 treated subjects, 4 of whom have ≥6 months of follow-up data. Subjects (≥18 years of age) with severe SCD (history of recurrent vaso-occlusive crisis [VOC], acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of >2.5 m/s) were screened for eligibility. Following bone marrow harvest (BMH), CD34+ cells were transduced with the BB305 vector. Subjects underwent myeloablative conditioning with busulfan prior to infusion of the transduced cells. Safety assessments include adverse events (AEs), integration site analysis (ISA) and surveillance for replication competent lentivirus (RCL). After infusion, subjects are monitored for hematologic engraftment, vector copy number (VCN), HbAT87Q expression, and other laboratory and clinical parameters. As of July 2016, 7 subjects with severe SCD (median age: 26 years, range 18-42 years) have received LentiGlobin DP in this study. All subjects successfully underwent BMH, with a median of 2 harvests required (range 1-4). Fifteen Grade 3 AEs in 5 subjects were attributed to BMH: pain (n=10), anemia (n=3) and VOC (n=2); all resolved with standard measures. Table 1 summarizes cell harvest, DP characteristics, and lab results. The median LentiGlobin DP cell dose was 2.1x10e6 CD34+ cells/kg (range 1.6-5.1) and DP VCN was 0.6 (0.3-1.3) copies/diploid genome. Median post-infusion follow-up as of July 2016 is 7.1 months (3.7-12.7 months). All subjects successfully engrafted after receiving LentiGlobin DP, with a median time to neutrophil engraftment of 22 days (17-29 days). The toxicity profile observed from start of conditioning to latest follow-up was consistent with myeloablative conditioning with single-agent busulfan. To date, there have been no DP-related ≥Grade 3 AEs or serious AEs, and no evidence of clonal dominance or RCL. The BB305 vector remains detectable at low levels in the peripheral blood of all subjects infused, with median VCN 0.08 (0.05-0.13, n=7) at last measurement. All subjects express HbAT87Q, with a median of 0.4g/dL (0.1-1.0 g/dL, n=7) at 3 months; most subjects demonstrated modest increases over time, and the 2 subjects with the longest follow-up expressed 0.31 and 1.2 g/dL HbAT87Q at 9 months. All 4 subjects with ≥6 months of follow-up experienced multiple VOCs in the 2 years prior to study entry (2-27.5 VOCs annually). Since LentiGlobin DP infusion, 3 of these 4 subjects have had fewer VOCs, although this trend may be confounded by the short follow-up, the effects of transplant conditioning, and/or post-transplant RBC transfusions. The decrease in VCN between DP and peripheral cells contrasts with previous reports of successful LentiGlobin gene therapy in ongoing studies HGB-204 and HGB-205. The relatively low in vivo VCN in this study appears to result in the lower HbAT87Q expression seen to date. We are exploring multiple hypotheses as to the etiology of the VCN drop between DP and peripheral blood, including the adverse impact of sickle marrow pathology on HSCs, the adequacy of myeloablation, and the magnitude of the transduced cell dose. We will provide an update on study data and ongoing efforts to increase in vivo VCN in patients with SCD, such as increasing the transduced cell dose through alternate HSC procurement methods or enhancing the DP VCN through manufacturing improvements. Disclosures Kanter: Novartis: Consultancy. Walters:Bayer HealthCare: Honoraria; AllCells, Inc./LeukoLab: Other: Medical Director ; ViaCord Processing Laboratory: Other: Medical Director ; Leerink Partners, LLC: Consultancy; Kiadis Pharma: Honoraria; bluebirdBio, Inc: Honoraria. Kwiatkowski:Ionis pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shire Pharmaceuticals: Consultancy; Sideris Pharmaceuticals: Consultancy; Apopharma: Research Funding; Luitpold Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. von Kalle:bluebird bio: Consultancy; GeneWerk: Equity Ownership. Kuypers:Children's Hospital Oakland Research Institute: Employment; bluebird bio: Consultancy. Leboulch:bluebird bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Joseney-Antoine:bluebird bio: Employment, Equity Ownership. Asmal:bluebird bio: Employment, Equity Ownership. Thompson:bluebird bio: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Eli Lily: Research Funding.

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Administration of BPX-501 Cells Following Aβ T and B-Cell-Depleted HLA Haploidentical HSCT (haplo-HSCT) in Children with Acute Leukemias

Blood ◽

10.1182/blood-2018-99-119481 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 307-307 ◽

Cited By ~ 2

Author(s):

Franco Locatelli ◽

Annalisa Ruggeri ◽

Pietro Merli ◽

Swati Naik ◽

Rajni Agarwal ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Pediatric Patients ◽

Unrelated Donor ◽

Relapse Free Survival ◽

Advisory Committees ◽

Steroid Resistant ◽

Free Survival ◽

Equity Ownership

Abstract Background Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established treatment for children with Acute Leukemia (AL). For patients lacking a compatible matched related or unrelated donor, HLA-haploidentical HSCT (haplo-HSCT) from a relative represents a viable alternative. Promising results were reported with a novel method of selective depletion of αβ T and B cells (Locatelli, Blood 2017). This approach is associated with limitations such as suboptimal adaptive immune reconstitution, increased risk of infection and disease relapse. BPX-501 is an allogeneic product consisting of T cells modified to express the inducible caspase-9 (iC9) safety switch and truncated CD19 to allow monitoring and expansion of BPX-501 following transplant. The polyclonal nature of the BPX-501 provides broad virus and tumor-specific immunity, while the safety switch provides the unique ability to promptly and durably resolve graft-versus-host disease (GvHD) symptoms following the administration of rimiducid which induces dimerization and activation of iC9, inducing apoptosis of BPX-501. Aims To evaluate the safety and efficacy of BPX-501 administered after a αβ T and B-cell depleted haplo-HSCT in pediatric patients with AL in morphological complete remission (CR). The objective was to determine whether BPX-501 infusion can increase relapse-free survival (RFS) and overall survival (OS) through an enhanced graft-versus-leukemic (GvL) effect, while maintaining a low risk of GvHD. Methods This multicenter US (NCT03301168) and EU (NCT02065869), prospective trial utilizes αβ-T and B-cell-depleted haplo-HSCT followed by infusion of donor lymphocytes genetically modified with iC9 safety switch (BPX-501) in patients with malignant or non-malignant disorders. A subset of patients had acute high-risk leukemias (AML and ALL). BPX-501 was planned to be infused on day14±4 after the allograft. No post-transplant pharmacological GvHD prophylaxis was employed. Patients who develop GvHD resistant to conventional steroid therapy could receive ≥1 dose of rimiducid to activate iC9. The efficacy-evaluable population (EEP) was defined as any patient with AL who received HSCT, BPX-501 infusion, and at least one follow-up assessment. Results At clinical cut-off (June 30, 2018), 100 patients (EU: 75, US: 25) with AL met the EEP definition. Median follow-up was 14.7 mos (1 - 40.6 mos). Key baseline characteristics are shown in Table 1. The median time for neutrophil and platelet engraftment was 16 (15 - 17) and 12 (11 - 12) days, respectively. Four patients (4.1% [95% CI: 0 - 8%]) experienced primary graft failure. Of 96 evaluable patients, 21 patients developed Grade I-IV aGvHD (21.7% [95% CI: 13.5 - 29.8%]). Five patients developed Grade III-IV aGvHD (3.1% [95% CI: 0 - 6.5%]). Of 82 evaluable patients, 12 patients developed cGvHD (18.1% [95% CI: 8.2 - 22%]), with only three cases being moderate-severe. Rimiducid was administered to 10 patients with steroid-resistant acute GvHD. Best overall clinical response of CR or PR post-rimiducid administration was seen in 8 patients (80%). Among responding patients, 7 patients (87.5%) had a CR. Six patients died after transplantation (6.6% [95% CI: 1.4 - 11.7%]). Relapse Free Survival (RFS) was 82.2% (95% CI: 74.5 - 89.7%). Overall Survival (OS) was 90.1% (95% CI: 83.9 - 96.3%). Efficacy outcomes (TRM, RFS and OS) in AL subsets (AML and ALL) are shown in Table 2. CD3+ and CD3+CD4+ T cells above 500 cells/ml were achieved by 180 and 270 days, respectively. IgA and IgM levels achieved normal values by 180 days. The percentage of circulating and median absolute BPX-501 cells at Day 100 were 9.96% ± 11.6% (0 - 54.9%) and 85.58 ± 165.57 cells/ul (0 - 1001 cells/ml), respectively. Conclusion The adoptive transfer of BPX-501 following αβ-T and B-cell depleted haplo-HSCT represents a novel and highly effective transplantation strategy for pediatric patients with AL. Compared to data from children receiving only αβ T and B-cell depleted haplo-HSCT or matched unrelated donor HSCT (https://bloodcell.transplant.hrsa.gov/research/transplant_data/us_tx_data/survival_data/survival.aspx), this novel approach resulted in a comparable risk of transplant-related mortality and a lower risk of recurrence. Rimiducid was also an effective treatment for patients who developed steroid-resistant GvHD. Disclosures Locatelli: bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Qasim:Orchard: Equity Ownership; Autolus: Equity Ownership; Servier: Research Funding; Bellicum: Research Funding. Nemecek:Novartis Pharmaceuticals Corporation: Other: advisory boards.

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Prognostic Factors of Long-Term Outcomes In Low- or Int-1-Risk MDS with del5q Treated with Lenalidomide (LEN): Results From a Randomized Phase 3 Trial (MDS-004)

Blood ◽

10.1182/blood.v116.21.4027.4027 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4027-4027

Author(s):

Pierre Fenaux ◽

Aristotles Giagounidis ◽

Odile Beyne-Rauzy ◽

Ghulam Mufti ◽

Moshe Mittelman ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase 3 ◽

Advisory Committees ◽

Free Survival ◽

Lower Baseline ◽

Younger Age ◽

Equity Ownership ◽

Rbc Transfusion

Abstract Abstract 4027 Background: Transfusion dependence is a significant negative predictor of overall survival (OS) and risk of AML-progression in MDS (Malcovati L, et al. JCO 2007;25:3503-10). LEN 5 mg and 10 mg induced significant RBC-transfusion independence (TI) versus placebo (PBO) in a randomized, phase 3, multicenter, double-blind (DB) study (MDS-004) in RBC transfusion-dependent patients (pts) with Low- or Int-1-risk MDS with del5q (Fenaux P, et al. Blood 2009;114:Abstract 944). The aim of this analysis is to identify prognostic factors for AML-free survival and OS during LEN treatment in the MDS-004 study after prolonged follow-up (pts enrolled between July 8, 2005 and July 26, 2007; last pt visit June 14, 2010; final data cutoff July 9, 2010). Methods: LEN-naïve pts with RBC transfusion-dependent Low- or Int-1-risk del5q MDS were randomized to receive LEN 5 mg on days 1–28 or LEN 10 mg on days 1–21, both of every 28-day cycle, or PBO. First response was assessed at 16 wks. Responders continued DB treatment for up to 52 wks, until erythroid relapse or disease progression. Pts who completed 52 wks of therapy could enter an open label (OL) extension phase at their current LEN dose. PBO and LEN 5 mg recipients who did not respond by wk 16 or who had erythroid relapse could receive LEN 5 or 10 mg, respectively, in the OL phase. This analysis included data through completion of the OL phase for pts randomized to LEN 5 and 10 mg combined in the DB phase; pts randomized to PBO were excluded as all except 11 pts crossed-over to LEN 5 mg. LEN 5 and 10 mg dose groups were comparable, allowing data for the two groups to be combined. A Cox proportional hazard model was used to evaluate effect of potential baseline risk factors, with RBC-TI ≥ 26 wks and cytogenetic response (CyR) as time-dependent covariates on AML-free survival and OS. The full model with all covariates and the final model, based on backward model selection method, are presented. Results: All 138 pts randomized to LEN who received ≥ 1 dose were included: median age 68 y (range 36–86); 74% of pts were female; 66% had an isolated del5q abnormality and 28% had ≥ 1 additional abnormality; and 43% of pts had WHO-based Prognostic Scoring System (WPSS) low/int risk, 32% high/very high, and 25% missing data. At baseline, median time since diagnosis was 2.7 y (range 0.2–29.2) and median RBC transfusion requirement was 6 units/8 wks (range 1–25). Duration of LEN was 12.9 mo (range 0.3–36.7); 54 of 62 responders entered the OL phase. Median follow-up for the cohort was 36 mo (range 0.4–59.4). Overall, 31 (22%) pts progressed to AML (median time to AML progression 4.01 y; 95% confidence interval [CI] 3.17–4.03) and 66 (48%) died (median OS 3.68 y; 95% CI 2.93–not estimable). The cumulative 3-year AML-progression rate was 34.8% and the 3-year OS rate was 56.0%. Multivariate results are presented in the Table. Achieving RBC-TI ≥ 26 wks was associated with a 45% and 51% reduction in the risk of AML progression (P=0.022) and death (P=0.008), respectively. Lower baseline ferritin level and younger age were associated with a reduced risk of AML-progression and death. Conclusion: Achievement of RBC-TI with LEN was associated with a significantly reduced risk of AML progression and death. Other predictors for longer AML-free survival and OS were lower baseline ferritin levels and younger age. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; J&J: Honoraria; Merck: Honoraria; Cephalon: Honoraria; Novartis: Honoraria. Giagounidis:Celgene: Consultancy, Honoraria. Beyne-Rauzy:Amgen: Consultancy; Celgene: Consultancy, Research Funding; Roche: Research Funding; Novartis: Consultancy. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mittelman:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Sanz:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Backstrom:Celgene: Employment, Equity Ownership. Fu:Celgene: Employment, Equity Ownership. Hellström-Lindberg:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Impact of KIR/HLA Incompatibilities after Posttransplant Cyclophosphamide Based T Cell-Replete Haploidentical Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-125243 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3340-3340

Author(s):

Sarah Lindner ◽

Tobias Berg ◽

Christian Seidel ◽

Franziska Kalensee ◽

Michael A. Rieger ◽

...

Keyword(s):

T Cell ◽

Nk Cells ◽

Board Of Directors ◽

Research Funding ◽

Chronic Gvhd ◽

Relapse Free Survival ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Free Survival ◽

The Impact

Introduction: Posttransplantation cyclophosphamide (PTCy) based T cell-replete haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) is a valid option for patients with indication for allogeneic HSCT without a human leucocyte antigen (HLA) matched donor. However, selection criteria to determine the optimal among several available haplo donors are still a matter of debate. Especially, the impact of killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen (HLA) incompatibilities (inc) in the setting of PTCy T cell-replete haplo HSCT is unclear. PTCy has been reported to eliminate most mature donor NK cells infused with the graft, including single KIR+ NK cells, thereby blunting NK cell alloreactivity in this setting (Russo et al., Blood 2018). Willem et al. (J Immunol 2019) reported (i) a significant loss of KIR2DL2/3+ NK cells at day +30 in patients with inhibitory KIR/HLA incompatibility (inc.) suggesting that PTCy might target responsive KIR NK cells and (ii) a correlation of genetic KIR2DL/HLA inc. with less relapse, but more graft-versus-host-disease (GvHD). Similarly, NK alloreactivity defined as KIR receptor-ligand mismatch or group B KIR haplotype with the presence of KIR2DS2 has been correlated with improved survival (Salomon et al., BBMT 2018). Aims of our study were to evaluate the impact of (i) HLA/KIR inc, (ii) donor KIR genotype and (iii) HLA-DP mismatch status on survival and incidence of relapse, acute and chronic GvHD in our homogeneously treated, independent patient cohort. Patients and methods: We retrospectively analyzed the outcome of 51 consecutively transplanted patients (AML/MDS (n=28/5), ALL (n=9), HD (n=2), NHL (n=5), CML (n=1), PMF (n=1)) receiving a PTCy based T cell-replete haplo HSCT between 01/2011-12/2018. All patients received a myeloablative conditioning regimen (fludarabine/total body irradiation (FTBI) or thiotepa/busulfan/fludarabine (TBF)) with unmanipulated bone marrow (98%) as the preferred graft (median CD34+ cells: 3.02 x 106/kg (range, 1.50-6.90) and median CD3+ T cells: 3.54 x 107/kg (range 1.52-43.74)). GvHD prophylaxis with ciclosporin A started on day 0, mycophenolate-mofetil on day +1, PTCy was applied on day +3 and +5. Results: Patient, donor and transplant characteristics as detailed in table 1 were well balanced between the inh. KIR/HLA inc. group (n=29) vs. no inh. KIR/HLA inc. group (n=22) with the exception of the median donor age (41.7 (range, 23.4-73.7) vs. 33.6 years (range, 19.0-56.2), resp. All patients engrafted. At day +28 (range, 20-29; n=26) CD3+ cells were 88.5/nL (range, 3-665), CD3+CD4+ cells 22.5/nL (range, 0-277.0), CD3+CD8+ cells 117.0/nL (range, 7-478), CD19+ cells 1.0/nL (range, 0-12), CD56bright cells 74.4/nL (range11.1-93.4), CD56dim cells 25.5/nL (range, 6.4-88.9) measured by flow cytometry and without differences between the inh. KIR/HLA inc. group vs. no inh. KIR/HLA inc. group. Cytomegalovirus (CMV) reactivation occurred in 73.3% of patients at risk and median time of occurrence was 32 days (range, 12-97) without difference between groups. Median follow-up for surviving patients was 26.1 months (range, 2.8-92.8) and we found no significant differences in 2-year overall survival (OS; 65.3±10.3 vs. 89.6±7.0, p=0.311), 2-year relapse-free survival (RFS; 66.0±9.4 vs 77.8±10.2, p=0.235), GvHD- and relapse-free survival (GRFS; 48.4±9.8 vs 60.5±12.0, p=0.182) as well as cumulative incidence (CI) of relapse (23.3% vs 16.2%, p= 0.283), acute GvHD grade 2-4 (27.6% vs 31.8, p=0.563), moderate-severe chronic GvHD (22.2% vs. 9.9%, p=0.227) and NRM (16.3% vs 5.3%, p=0.283) between the inh. KIR/HLA inc. group vs. no inh. KIR/HLA inc. group. This was also the case for donor KIR genotype AA vs AB (n=46; 2-y OS: 74.9±13.0% vs. 73.0±9.9%, p=0.844; 2-y RFS: 60.0±14.8% vs 74.5±8.4%, p=0.645) and HLA-DP-identical/permissive mismatch (MM) vs non permissive MM (n=45; 2-y OS: 70.7±10.0% vs 72.7±13.4%, p=0.945; 2-y RFS: 73.2±8.2% vs 63.6.0±14.5%, p=0.798) Conclusion: Our outcome data support the hypothesis of PTCy eliminating mature donor NK cells infused with the graft and thereby reducing the impact of alloreactivity in this setting. However, our patient number is quite small and the findings need to be validated in larger cohorts and preferably prospective studies. Disclosures Lindner: Celegene, Sanofi, Neovii: Honoraria, Research Funding. Berg:Riemser Pharma GmbH: Consultancy, Honoraria; Incyte, Abbvie, Astellas, Alexion and Celgene: Other: travel support. Bug:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Neovii: Other: travel grant; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Hexal: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Sanofi: Other: travel grants. Schwaeble:Uniqure BV: Research Funding. Ullrich:CellGenix: Honoraria, Research Funding; Novartis: Research Funding.

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Low-Dose Anti-Thymocyte Globulin for Graft-Versus-Host-Disease Prophylaxis in Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplant

Blood ◽

10.1182/blood.v128.22.5782.5782 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5782-5782

Author(s):

Adam Bryant ◽

Ranjeeta Mallick ◽

Lothar B. Huebsch ◽

David S. Allan ◽

Harold Atkins ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Relapse Free Survival ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Free Survival ◽

Related Donor

Abstract Background Graft-versus-host disease (GVHD) is a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT). Prophylactic in-vivo T-Cell depletion with antithymocyte globulin (ATG) has recently been reported as leading to decreased GVHD rates in matched unrelated and related donor HSCT, without increases in relapse or death. Understanding that higher rates of GVHD are observed with matched unrelated versus matched related donor HSCT, we have always had a local policy to give ATG as part of GVHD prophylaxis in patients undergoing HSCT from an unrelated donor. Here we report and compare clinical outcomes of patients who did and did not receive ATG at our transplant center using a unique, substantially lower ATG dose than previously reported. Methods We conducted a retrospective single-center database study comparing outcomes in 110 matched unrelated donor (MUD; ATG-exposed) and 78 matched related donor (MRD; ATG-unexposed) HSCT patients transplanted for any malignant indication at The Ottawa Hospital from 2009 to 2014. Patients were exposed to a rabbit ATG formulation (Thymoglobulin ®) at 0.5 mg/kg on day -2 and 2.0 mg/kg on day -1 prior to stem cell infusion, to total 2.5 mg/kg. Primary outcomes assessed were incidence of acute and chronic GVHD, defined as new-onset GVHD requiring systemic immunosuppressive therapy at less or more than 100 days post HSCT, respectively. Secondary outcomes included disease relapse and survival. Results At baseline there were no significant differences in median age at transplant, sex, disease indication or risk index, graft source, conditioning regimen and intensity between ATG exposed (MUD) and unexposed (MRD) cohorts. The majority of patients in both cohorts had intermediate or high disease risk index. There were significant baseline differences between the ATG exposed and unexposed cohorts with respect to proportion of 7/8 mismatched unrelated donor transplants (14 v 6% respectively, p = 0.015) and median CD34+ dose (4.9 v 7.6 x 108 cells; p < 0.001). No differences were noted in platelet engraftment. ATG exposed patients had significantly shorter time to neutrophil engraftment than the unexposed cohort (16 v 19 days respectively; p=0.007). ATG exposed patients had significantly lower rates of GVHD compared to the unexposed cohort (57 v 79%; p=0.005), with differences noted predominantly in rates of chronic GVHD (18 v 44%, p= 0.009). The proportion of patients off immune suppression one year after HSCT was not significantly different between the cohorts.At median follow-up of 13 (1-73) months for the ATG exposed cohort and 20 (0-69) months for the ATG unexposed cohort, no significant differences in overall survival (median overall survival not met for either cohort), cumulative incidence of relapse (26 v 29%; p=0.73) or relapse-free survival (not met in ATG exposed; 26.2 months in ATG unexposed, p=0.22) were observed between groups (Figure 1). Significant differences were observed with respect to GVHD-Free Relapse-Free Survival (GRFS) between ATG exposed and unexposed cohorts, with a two-year GRFS of 23 v 3% respectively (p = 0.003). There were no significant differences between cohorts in proportion of patients with post HSCT infectious episodes or ICU admissions. Conclusions Here we report significantly lower rates of chronic GVHD and significant improvement in GVHD-free relapse-free survival in our ATG exposed MUD HSCT cohort compared to our ATG unexposed MRD. These findings were observed without differences in relapse or survival outcomes, infectious complications or ICU admissions. While in keeping with other recent reports on ATG use for GVHD prophylaxis, our findings indicate that a lower dose of ATG may be effective in preventing GVHD. Our study suggests that a broader exploration into the optimal dosing of this prophylactic GVHD agent is warranted. Disclosures Bence-Bruckler: Lundbeck: Membership on an entity's Board of Directors or advisory committees. Sabloff:Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Lundbeck: Research Funding; Alexion: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding.

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Gvhd and Relapse Free Survival (GRFS) after Allogeneic Transplantation for Idiopathic Severe Aplastic Anemia: An Analysis from the Saawp Data Quality Initiative Program of EBMT

Blood ◽

10.1182/blood-2020-141757 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-4

Author(s):

Raynier Devillier ◽

Dirk-Jan Eikema ◽

Paul Bosman ◽

Carlo Dufour ◽

Mahmoud Aljurf ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Graft Failure ◽

Acute Gvhd ◽

Cox Model ◽

Chronic Gvhd ◽

Relapse Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Grade 3

Background Survival after Allo-HSCT for severe idiopathic aplastic anemia (SAA) has improved over past 20 years, approaching 75% at 5 years. However, beyond survival, a SAA-adapted composite endpoint GVHD and relapse free survival (GRFS) may more accurately assess patient outcomes, becoming a meaningful study endpoint. We analyzed GRFS aiming to identify risk factors and specific causes of GRFS failure. Methods This retrospective analysis from the SAAWP Data Quality Initiative (DQI registry database) program of EBMT included patients with: diagnosis of idiopathic SAA; first Allo-HSCT from 2005 to 2016; and matched related (MRD) or unrelated donor (UD) (no cord blood). Relevant events for Kaplan-Meier calculation of GRFS were: relapse (including primary and secondary graft failure); grade 3-4 acute GVHD; extensive chronic GVHD; and death. In addition, we used a competing-risk model to analyze cumulative incidences of specific causes of GRFS failure. Results We analyzed 580 patients (385 adults and 195 younger than 18 years), with a median age of 23 years (<0.1-77). Donor was matched related and unrelated in 337 and 243 patients, respectively. Median time from diagnosis to Allo-HSCT was 6 months (IQR: 2-15) and 310 (53%) patients underwent Allo-HSCT without prior treatment. GRFS at 5 years was 69% (65-73) in the whole cohort. Median follow up was 61 months (95%CI: 56-67). Multivariate cox model including age (continuous), graft source, conditioning intensity, sex mismatch, CMV-serostatus, donor type, time from diagnosis to Allo-HSCT (< vs. > 6 months) and previous treatment before Allo-HSCT showed that age (HR=1.02, [1.01-1.03], p<0.001) and CMV serostatus other than negative-donor to negative-recipient [D-/R-] (HR=1.51, [1.02-2.23], p=0.041) were the only independent factors associated with worse GRFS. Using cause specific cox model, we analyzed the risk of the different causes of GRFS failure and found that CMV-serostatus other than D-/R- was associated with higher risk of graft failure/relapse (HR=2.88, [1.12-7.38], p=0.028) while age influenced the risk of grade 3-4 acute GVHD (HR=1.03, [1.00-1.05], p=0.043), extensive chronic GVHD (HR=1.03, [1.01-1.06], p=0.008) and death without prior failure (HR=1.03, [1.01-1.04], p<0.001). Among the 209 patients who underwent upfront Allo-HSCT from a MRD, 5-year GRFS was 77% (71-84). In multivariate analysis, time from diagnosis to Allo-HSCT (HR=2.64, [1.38-5.03], p=0.003) and age (HR=1.03, [1.00-1.05], p=0.039) independently influenced GRFS. When investigating the causes of GRFS failure in this subset of patients who underwent upfront MRD Allo-HSCT, time from diagnosis to Allo-HSCT was the only remaining factors significantly associated with the risk of death without prior failure (HR=0.29, [0.10-0.84], p=0.022). No factor was found specifically associated with any other causes of GRFS failure. Conclusions We observed 5-year GRFS of 69%, meaning that most of patients who underwent Allo-HSCT for idiopathic SAA are cured without experiencing severe forms of acute and chronic GVHD. In the context of upfront MRD Allo-HSCT, GRFS was even more promising (77%). In this particular setting, time from diagnosis to Allo-HSCT was the most important factor influencing GRFS, suggesting the need to proceed to Allo-HSCT as quick as possible when a MRD is available. Disclosures Ganser: Novartis: Consultancy; Celgene: Consultancy. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Treatment with the Thrombopoietin (TPO)-Receptor Agonist Romiplostim in Thrombocytopenic Patients (Pts) with Low or Intermediate-1 (int-1) Risk Myelodysplastic Syndrome (MDS): Follow-up AML and Survival Results of a Randomized, Double-Blind, Placebo (PBO)-Controlled Study

Blood ◽

10.1182/blood.v120.21.421.421 ◽

2012 ◽

Vol 120 (21) ◽

pp. 421-421 ◽

Cited By ~ 7

Author(s):

Hagop M. Kantarjian ◽

Ghulam J. Mufti ◽

Pierre Fenaux ◽

Mikkael A. Sekeres ◽

Jeffrey Szer ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Survival Rates ◽

Study Drug ◽

Employment Equity ◽

Advisory Committees ◽

Free Survival ◽

Equity Ownership

Abstract Abstract 421 Background: There are few therapies for thrombocytopenia in MDS, which is found in ∼50% of pts with low/int-1 MDS and is associated with shortened survival. In a June 2011 analysis of a 58-wk study (2:1 romiplostim:PBO), romiplostim reduced clinically significant bleeding events (HR 0.83, 95% CI: 0.66, 1.05, P = 0.13) and platelet transfusions (RR 0.77, 95% CI: 0.66, 0.88), and increased HI-P rates (OR 15.6, 95% CI: 4.7, 51.8). Increases in peripheral blast counts to >10% were more frequent with romiplostim (25/167, 15%) than PBO (3/83, 3.6%), and in most cases resolved after discontinuation. Through 58 wk, acute myeloid leukemia (AML) was diagnosed in 10 romiplostim pts (6.0%) and 2 PBO pts (2.4%) (HR 2.51, 95% CI: 0.55, 11.47); the differences for romiplostim vs. PBO 58-wk overall survival (OS) and AML-free survival were not statistically significant. This report updates the previous results, with a particular emphasis on AML incidence. Methods: Eligible pts had IPSS low/int-1 MDS and were receiving supportive care, with platelets 1) ≤20×109/L or 2) ≤ 50×109/L with a history of bleeding. AML progression was defined as: 1) ≥20% blasts in the bone marrow or peripheral blood after 4 wk off romiplostim, 2) pathology consistent with leukemia (eg, chloroma or leukemia cutis), or 3) anti-leukemic treatment initiation. Due to data monitoring committee concerns that the potential small benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to AML and that transient increases in blast cell counts may put pts at risk for diagnosis of and treatment for AML, study drug was stopped in February 2011. Pts were then moved into the long-term follow-up (LTFU) portion of the study. At the time of the 2011 analysis, not all pts had been on study 58 wk, thus the 58-wk data have been updated with LTFU data. Results: Results are presented by randomization group, although study drug was stopped in February 2011. Of 250 pts in the study (randomized 2:1 romiplostim:PBO), 224 entered LTFU, and 134 remained on study as of July 2012; the median (Q1, Q3) follow-up was 17.8 (10.8, 25.1) months. Through 58 wk, the proportions of deaths were romiplostim: 18.0% (30 pts), PBO: 20.5% (17 pts), for an OS HR of 0.86 (95% CI: 0.48, 1.56). Since June 2011, 2 additional AML cases were reported in the PBO arm which occurred within the 58-wk study period, but were not recorded in time for the primary analysis in 2011. Updated 58-wk AML rates were romiplostim: 6.0% (10 pts), PBO: 4.9% (4 pts), for an HR of 1.20 (95% CI: 0.38, 3.84). The resulting AML-free survival rates were romiplostim: 19.8% (33 pts), PBO: 22.9% (19 pts), for an HR of 0.86 (95% CI: 0.49, 1.51). For data to date (beyond 58 wk), proportions of deaths were romiplostim: 38.3% (64 pts), PBO: 37.3% (31 pts), for an OS HR of 1.09 (95% CI: 0.71, 1.68). AML rates were romiplostim: 8.9% (15 pts), PBO: 8.5% (7 pts), for an HR of 1.15 (95% CI: 0.47, 2.85). The resulting AML-free survival rates were romiplostim: 39.5% (66 pts), PBO: 38.6% (32 pts), for an HR of 1.11 (95% CI: 0.72, 1.70) (Figure). Twelve of the 22 AML cases occurred in pts who were RAEB-1 and 5 cases were diagnosed by anti-AML treatment alone (Table). In LTFU, pt-reported rates of MDS therapy use (e.g., azacitidine, cyclosporine, and romiplostim) were romiplostim: 31.1%, PBO: 23.2%. Reported rates of AML therapy use (e.g., azacitidine and chemotherapy) were romiplostim: 6.0%, PBO: 7.2%. A retrospective review of all available bone marrow aspirates and biopsies, including samples from pts diagnosed as having progressed to AML, was conducted by an independent hematopathologist; analyses are ongoing. Conclusion: Following the 2011 decision to stop study drug, study results have been updated with more time on study. Specifically, with the additional AML cases in the PBO arm during the 58-wk study period and data from the LTFU period, the HRs for progression to AML were 1.20 and 1.15, respectively, in contrast with the finding of a year ago (HR of 2.51 for 58-wk). As LTFU continues, additional data will be evaluated. Safety concerns regarding risk of disease progression to AML are still being investigated. Disclosures: Kantarjian: Amgen: Research Funding. Off Label Use: The use of romiplostim in MDS was examined in this trial. Mufti:Celgene: Consultancy, Research Funding. Fenaux:GlaxoSmithKline: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Amgen: Consultancy; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Novartis: Consultancy. Kuendgen:Celgene: Honoraria. Gaidano:Amgen: Honoraria. Wiktor-Jedrzejczak:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy; Janssen-Cilag: Consultancy; Celgene: Speakers Bureau; Genzyme: Speakers Bureau; Genopharm: Speakers Bureau. Bennett:Onconova: Consultancy; Amgen: Consultancy; GlaxoSmithKline: Consultancy; Ambit: Consultancy; Pfizer: Consultancy; Celgene: Consultancy. Meibohm:Merck: Employment, Equity Ownership; Amgen: Consultancy; Ockham: Employment. Yang:Amgen: Employment, Equity Ownership. Giagounidis:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Updated 18-Month Results from Dasfree: A Study Evaluating Dasatinib Discontinuation in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Deep Molecular Response (DMR)

Blood ◽

10.1182/blood-2018-99-116563 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4253-4253 ◽

Cited By ~ 5

Author(s):

Neil P. Shah ◽

Jose Valentín García Gutiérrez ◽

Antonio Jiménez-Velasco ◽

Sarah Larson ◽

Susanne Saussele ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Kinase Inhibitor ◽

Safety Data ◽

Chronic Phase ◽

Molecular Response ◽

Relapse Free Survival ◽

Advisory Committees ◽

Free Survival

Abstract Introduction: Tyrosine kinase inhibitor (TKI) discontinuation is being investigated in pts with CML-CP with sustained DMR (defined here as MR4.5 or BCR-ABL1 ≤ 0.0032% on the International Scale [IS]), with the goal of treatment-free remission (TFR). Successful TFR has been reported previously for pts enrolled in DASFREE (CA180-406/NCT01850004), which showed that 48% of CML-CP pts with DMR for ≥ 1 year were able to stop dasatinib and maintain major molecular response (MMR) 12 months after discontinuation. Here we present updated results from pts followed for a minimum of 18 months, in order to understand the durability of TFR beyond 12 months. Methods: DASFREE is a phase 2, open-label, single-arm study in adult pts with CML-CP on dasatinib for ≥ 2 years as 1st-line or subsequent therapy. Eligible pts had dasatinib-induced DMR (MR4.5) confirmed at a local lab for ≥ 1 year prior to enrollment, with a 1-log reduction in BCR-ABL1 from baseline within 3-6.5 months of starting dasatinib. MR4.5 was confirmed at a central lab twice within 3 months prior to dasatinib discontinuation (screening phase). BCR-ABL1 was monitored centrally after discontinuation every month in the 1st year, then every 3 months. Pts resumed dasatinib at their previous dose if MMR was lost. The primary endpoint is the rate of MMR 12 months after dasatinib discontinuation. Secondary endpoints include BCR-ABL1 kinetics, molecular relapse-free survival (MRFS; no loss of MMR), relapse-free survival (RFS; no loss of MMR, complete cytogenetic response, or complete hematologic response, or progression to accelerated/blast phase [AP/BP] CML), rate of transformation to AP/BP, progression-free survival, and overall survival. Exploratory analyses include frequency of adverse events (AEs) after discontinuation and during dasatinib treatment, and MMR after reinitiating dasatinib. Results: In total, 84 pts enrolled between February 2014 and June 2016 discontinued dasatinib; all had ≥ 18 months of follow-up after discontinuation at the time of this analysis. Pt characteristics were previously reported (the majority [64%] had low Sokal scores; no pt had prior interferon; 37 pts were on 1st-line dasatinib, 47 on subsequent lines of dasatinib). At 18 months after discontinuation, the RFS rate was 48% (95% CI 37-58) in all pts (Figure), 54% (95% CI 38, 70) in 1st-line pts, and 42% (95% CI 28, 57) in pts who received subsequent-line therapy. With longer follow-up, 1 additional pt lost MMR at 18 months following discontinuation. Of the 45 pts who lost MMR and restarted treatment, 44 regained MMR (1 pt discontinued after only 1 molecular assessment) in a median of 2 months (range 1-4) and 42 regained MR4.5 in a median of 3 months (range 2-18). Analyses of baseline pt characteristics revealed that for the 40 pts who did not lose MMR after discontinuation, 15 (37.5%) were able to maintain MR4.5. Additionally, the median time in prior MR4.5 was 28 months (range 13-116) for all pts, and was similar for 1st-line pts who maintained (27 months [range 13-56]) or lost MMR (27 months [range 15-68]) at 12 months. With longer follow-up, AEs (any cause) identified were consistent with previous reports and were found to be similar on and off treatment: 8 (10%) pts off treatment and 8 (18%) pts on treatment experienced grade 3/4 AEs of any cause after restarting dasatinib (4.4% were drug related). No transformation events or deaths occurred. Of the 13 reported withdrawal events occurring in 8 (9.5%) pts, 10 were resolved (5 off treatment, 5 resolved after restarting treatment due to loss of MMR) after a median of 5 months (range 1-12) after onset. One pt discontinued after restarting dasatinib due to malignancy unrelated to treatment. In addition to efficacy and safety data, multivariate analyses evaluating prognostic factors for MMR will be presented. Conclusions: Additional follow-up of pts enrolled in DASFREE revealed that TFR remained durable at 18 months after discontinuing dasatinib. AEs reported here were consistent with the known safety profile of dasatinib, and withdrawal was well tolerated. Collectively, this trial, the largest dasatinib discontinuation trial to date, continues to support the feasibility and practicality of TFR in pts with CML-CP in DMR treated with dasatinib in the 1st line and beyond. Figure. Figure. Disclosures Shah: ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding. García Gutiérrez:Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Larson:Bristol-Myers Squibb: Consultancy; Takeda: Speakers Bureau. Saussele:Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria. Rea:Incyte: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Mahon:Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Gómez-Casares:Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau. Pane:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy. Nicolini:Incyte: Consultancy, Honoraria, Speakers Bureau; Sun Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Mauro:Pfizer: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding. Sy:Bristol-Myers Squibb: Employment. Martin Regueira:Bristol-Myers Squibb: Employment, Equity Ownership. Lipton:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

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Updated Analysis of Overall Survival in Randomized Phase III Study of Idelalisib in Combination with Bendamustine and Rituximab in Patients with Relapsed/Refractory CLL

Blood ◽

10.1182/blood.v128.22.231.231 ◽

2016 ◽

Vol 128 (22) ◽

pp. 231-231 ◽

Cited By ~ 3

Author(s):

Andrew D. Zelenetz ◽

Jennifer R. Brown ◽

Julio Delgado ◽

Herbert Eradat ◽

Paolo Ghia ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Opportunistic Infections ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Prior Therapy ◽

Equity Ownership

Abstract Introduction: Therapies able to improve overall survival in patients with relapsed/refractory (RR) CLL are needed. We have previously reported that idelalisib (IDELA), a selective PI3K delta inhibitor, administered in combination withbendamustine/rituximab (BR) improves progression-free survival compared with BR alone after a medianfollowup of 12 months. This study (NCT01569295) was unblinded by the independent data monitoring committee at first interim analysis for efficacy. We now present updated data on overall survival (OS). Methods: Between June 2012 and August 2014, 416 patients (pts) with RR CLL were enrolled in the study across 19 countries. The current analysis data cutoff date of May 2016 represents a median follow-up of 21 months. Progression-free survival based on independent review committee assessment was the primary endpoint of this study, with OS as a secondary endpoint. All pts had completed study treatment with BR. Key eligibility criteria included pts with RR CLL requiring therapy, having received previous purine analog or bendamustine (ineligible if refractory to bendamustine); and anti-CD20 antibody; relapsing or progressing within 36 months of the completion of the last therapy. Patients were randomized to BR for 6 cycles Q 28 days (B = 70 mg/m2 D1, D2 of each cycle; R = 375 mg/m2 C1 and 500 mg/m2 C2-6) and IDELA 150 mg BID or placebo (administered until IRC-confirmed PD), death, intolerable toxicity, or withdrawal of consent. Stratification was based on presence/absence ofdel(17p) and/or p53 mutation (mut), immunoglobulin heavy chain variable region (IGHV) mutated/unmutated (analysis performed by a central lab), and disease status refractory (CLL progression <6 months from completion of prior therapy) vs relapsed (CLL progression ≥6 months from completion of prior therapy). Crossover was not permitted at the time of PD or unblinding. Results: The ITT population reflects 207/209 pts in the IDELA + BR/BR + placebo arm: 76% male; 42% ≥65 years; Rai stage III/IV 46%; median time since completion of last prior therapy 16 months; pts with high-risk features (del[17p]/p53mut 32.9%, unmutated IGHV 83.2%, refractory 29.8%); median number of prior therapies: 2 (range 1-13); and median follow-up 21 months. All pts have completed study treatment with BR. A total of 65 pts remain on study treatment: 64 on IDELA monotherapy and 1 pt on placebo. Overall by ITT and IRC, 260/416 pts (IDELA/placebo 95/165) have met the primary endpoint of PD or death. Median OS (mo) of IDELA + BR vs BR + placebo was not reached vs 41 (HR = 0.67; p value 0.036; 95% CI 0.47, 0.96) (Figure 1). The safety findings were similar to what we previously reported: Serious AEs occurred in 147 (71%)/94 (5%) IDELA/placebo arms, respectively. The commonly occurring SAEs by system organ class were infections and infestations (41%/23%) and by MEDRA-preferred terms febrile neutropenia 43 (21%)/10 (5%) and pneumonia 35 (17%)/16 (8%) in the IDELA/placebo arms respectively. The total number of pts with opportunistic infections (Pneumocystis jirovecii pneumonia [PJP]/cytomegalovirus [CMV]) in the IDELA arm was 5/13 vs 0/3 in the placebo arm. Conclusion: IDELA in combination with BR is superior to BR alone with regard to OS in RR CLL. The improvement in OS was observed across risk categories. Opportunistic infections (PJP, CMV) and SAEs were more frequent in the IDELA vs placebo arm. Results of IDELA-containing regimens may be further improved with implementation of adequate PJP prophylaxis and CMV monitoring measures. This regimen represents an important new option for pts with RR CLL. Figure 1. Kaplan-MeierCurve: Overall Survival. Figure 1. Kaplan-MeierCurve: Overall Survival. Disclosures Zelenetz: Gilead Sciences: Research Funding. Brown:Celgene: Consultancy; Sun BioPharma: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Gilead Sciences: Consultancy; Janssen: Consultancy; Infinity: Consultancy; Abbvie: Consultancy. Delgado:Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; GSK/Novartis: Honoraria; Abbvie: Consultancy. Eradat:Genentech: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria. Ghia:Adaptive: Consultancy; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Jurczak:Celltrion, Inc: Research Funding; Acerta: Research Funding; Gilead Sciences: Research Funding; Bayer: Research Funding; Janssen: Research Funding. Loscertales:Roche: Honoraria, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees. MacDonald:Gilead Sciences: Speakers Bureau. Morschhauser:Celgene: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Honoraria. De la Serna:Abbvie: Consultancy; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Speakers Bureau. Shadman:Pharmacyclics: Honoraria, Research Funding. Pocock:Gilead Sciences: Other: Sponsorship to attend the EHA 2016 Meeting; Janssen: Speakers Bureau; Takeda: Honoraria. Adewoye:Gilead Sciences: Employment, Equity Ownership. Kim:Gilead Sciences: Employment, Equity Ownership. Simpson:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Stilgenbauer:Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding.

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