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

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.

Download Full-text

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

Blood ◽

10.1182/blood-2018-99-110188 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4658-4658 ◽

Cited By ~ 2

Author(s):

Sandra Cohen ◽

Jean Roy ◽

Silvy Lachance ◽

Anne Marinier ◽

Jean-Sébastien Delisle ◽

...

Keyword(s):

Board Of Directors ◽

Culture System ◽

Research Funding ◽

Chronic Gvhd ◽

Relapse Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Cell Dose ◽

Equity Ownership

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.

Download Full-text

Administration of BPX-501 Cells Following Αβ T and B-Cell-Depleted HLA-Haploidentical HSCT (haplo-HSCT) in Children with Malignant or Non-Malignant Disorders

Blood ◽

10.1182/blood-2018-99-119635 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2171-2171

Author(s):

Mattia Algeri ◽

Pietro Merli ◽

Waseem Qasim ◽

Mary Slatter ◽

Melissa Kuhn ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Board Of Directors ◽

Unrelated Donor ◽

Matched Unrelated Donor ◽

Advisory Committees ◽

Graft Versus Host ◽

Life Threatening ◽

Equity Ownership

Abstract Background Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment for children with leukemia or life-threatening non-malignant disorders. Approximately 25% of patients have a HLA-matched sibling and ~50% have a suitable matched unrelated donor, leaving ~25% of patients who require an alternative donor. HLA-partially matched (haploidentical, haplo) donors represent a suitable alternative for these children; extensive T-cell depletion of the graft is largely employed to minimize the risk of graft-versus-host disease (GvHD). 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 CD3+ CD19+ T-cells following transplant. The polyclonal nature of the BPX-501 T cells 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. Aims To evaluate the safety and efficacy of BPX-501 T cells administered after a T-cell receptor αβ and B-cell-depleted haplo-HSCT in pediatric patients with malignant or non-malignant disorders. The primary endpoint is event-free survival at 180 days (events include TRM (or NRM for malignant patients), severe GVHD (acute Grade 2-4 organ or extensive chronic GVHD) and life-threatening infections (Grade 4). Methods This multicenter EU (NCT02065869), prospective trial utilizes αβ-T and B-cell-depleted haplo-HSCT followed by infusion of donor lymphocytes genetically modified with iC9 (BPX-501). BPX-501 cells were 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 dimerizing rimiducid activating iC9. The efficacy evaluable population (EEP) was defined as any patient who received HSCT, BPX-501 infusion and at least one follow-up assessment. Results At the time of clinical cut-off (June 30, 2018) 166 patients met the EEP definition. All patients were from EU sites. Key baseline and transplant characteristics are shown in Table 1. In patients who obtained sustained engraftment of donor cells, the median time for neutrophil and platelet engraftment was 16 (15-17) and 11 (11-12) days, respectively. No patients experienced graft failure. Thirty-one patients developed Grade I-IV aGvHD (18.7% [95% CI;12.8 - 24.7%]). Three patients developed Grade III-IV aGvHD (1.8% [95% CI; 5.2 - 14.1%]). Of 132 evaluable patients, 9 developed cGvHD (7.2% [95% CI; 2.6 - 11.7%]) with only 2 patients experiencing moderate - severe cGvHD (95% CI: 0.0 - 3.1). Rimiducid was administered to 11 patients. Ten patients had ≥ 1 response assessment following administration of rimiducid. The best overall response rate (CR/PR) was 100% with 9 patients (90%) achieving complete response. At the time of clinical cut off, EFS at 180 days was 92.7% (95% CI: 88.7 - 96.7%). An interim analysis with approximately 100 patients from a concurrent Matched Unrelated Donor (MUD) HSCT comparator trial and previously published data is planned for the time of the congress. At a median follow-up of 17.6 mos (1.5 - 43.7 mos) 5 patients experienced transplant related mortality (TRM) (3.3% [95% CI: 0.4 - 6.2%]). DFS was 89.4% (95% CI: 84.7 - 94.2%). Overall survival (OS) was 94.2% (95% CI: 90.5 - 97.9%). CD3+ and CD3+CD4+ T cells above 500 cells/ml were achieved by day 100. IgA and IgM levels achieved normal values by day 180. The percentage of circulating and median absolute BPX-501 T-cells at Day 100 were 9.06% ± 10.52% (0 - 54.9%) and 109.49 ± 213.99 cells/ml (0 - 1001 cells/ml), respectively. Conclusion Preliminary evaluation of the primary endpoint and additional time-dependent efficacy outcomes, shows that the adoptive transfer of BPX-501 T cells following αβ-T and B-cell depleted haplo-HSCT followed by infusion of BPX-501 represents a novel and highly effective transplantation strategy for pediatric patients with malignant or non-malignant disorders. Despite the addition of BPX-501, overall rates of GvHD were low with few cases of high-grade aGvHD or cGvHD. Rimiducid was shown to be an effective treatment for patients who developed steroid-refractory GvHD. Disclosures Qasim: Bellicum: Research Funding; Autolus: Equity Ownership; Servier: Research Funding; Orchard: Equity Ownership. Slatter:Medac: Other: Travel assistance. Locatelli:bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Administration of BPX-501 Cells Following Αβ- T and B-Cell-Depleted HLA-Haploidentical HSCT in Children with Fanconi Anemia

Blood ◽

10.1182/blood-2018-99-119534 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4654-4654

Author(s):

Swati Naik ◽

Susanne H.C. Baumeister ◽

Victor Aquino ◽

Annalisa Ruggeri ◽

Daria Pagliara ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Board Of Directors ◽

Median Time ◽

Fanconi Anemia ◽

Pediatric Patients ◽

Chronic Gvhd ◽

Advisory Committees ◽

Family Donor

Abstract Background Allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to rescue trilineage cytopenias and to prevent occurrence of myeloid malignancies in patients with Fanconi Anemia (FA). HLA-identical family donor HSCT is a recommended treatment strategy with an ≥80% cure rate, and outcomes of HSCT from unrelated donors have progressively improved over time. However, HLA-partially matched (haplo) HSCTs have been historically associated with inferior results. Innovative approaches of graft manipulation, such as selective depletion of αβ-T and B cells, have recently been reported to improve the outcomes of haplo-HSCT in children with non-malignant disorders, however obstacles remain, such as delayed recovery of adaptive immunity with a risk of life-threatening infections. Novel strategies aimed at accelerating immune reconstitution are warranted to optimize the outcomes of patients transplanted from a HLA-haploidentical family donor. 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 (acceleration of immune recovery and prevention of transplant-related mortality while maintaining low rates of acute and chronic GvHD) of BPX-501 administered after a αβ T and B-cell depleted haplo-HSCT in pediatric patients with FA. Methods This is a multicenter US (NCT03301168) and EU (NCT02065869), prospective trial utilizing αβ-T- and B-cell-depleted haplo-HSCT followed by infusion of donor lymphocytes genetically modified to express iC9 (BPX-501 T cells). BPX-501 cells were planned to be infused on day14±4 after the allograft per protocol. No post-transplant pharmacological GvHD prophylaxis was employed. Patients who develop GvHD resistant to conventional steroid therapy were eligible to receive ≥1 dose of dimerizing rimiducid activating iC9. The efficacy-evaluable population (EEP) was defined as any patient with FA who received HSCT, BPX-501 infusion and had at least one follow-up assessment. Results At the time of clinical cut-off (June 30th, 2018), 14 patients met the EEP definition. Nine and 5 patients were transplanted in the EU and US, respectively. The median follow-up was 23.5 mos (0.75 - 42 mos). Key baseline and transplant characteristics are detailed in Table 1. The median time for neutrophil and platelet engraftment was 14 (11-15) and 10 (8 - 11) days, respectively. One patient experienced primary graft failure (7.7% [95% CI: 0-22.2%]). Only one patient developed Grade I aGvHD (7.7% [95% CI: 0-22.2%]). Two patients developed cGvHD (19.2% [95% CI: 4-43.2%]), both cases being moderate. Rimiducid was not administered to any patient. One patient died after transplantation due to brain hemorrhage 25 days post HSCT. The event was unrelated to BPX-501 (TRM 7.1% [95% CI: 0-20.6%]). No patients died of infectious complications. The probability of both overall survival (OS) and disease-free survival (DFS) was 92.9% (95% CI: 79.4-100%). The median time from last red blood cell (RBC) transfusion was 23.6 mos (0.2 - 41.9 mos). CD3+ and CD3+CD4+ T cells above 500 cells/ml were achieved by 180 and 360 days, respectively. IgA and IgM levels achieved normal values by 30 and 180 days, respectively. The percentage of circulating and median absolute BPX-501 cells at Day 100 were 3.35% ± 2.94% (0 - 8.4%) and 29.09 ± 39.56 cells/ml (0 - 135 cells/ml), respectively. Conclusion These data indicate that 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 FA. Further, despite the addition of BPX-501, low rates and severity of both acute and chronic GvHD was observed, a finding that could translate into significant long-term benefit, in terms of reduction of squamous cell carcinoma a well-known complication occurring in FA patients after HSCT. Disclosures Aldinger: Bellicum Pharmaceuticals, Inc.: Employment. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

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.

Download Full-text

A First-In-Human Phase 1 Study Of The Antibody-Drug Conjugate SGN-CD19A In Relapsed Or Refractory B-Lineage Acute Leukemia and Highly Aggressive Lymphoma

Blood ◽

10.1182/blood.v122.21.1437.1437 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1437-1437 ◽

Cited By ~ 7

Author(s):

Uma Borate ◽

Amir T. Fathi ◽

Bijal D. Shah ◽

Daniel J. DeAngelo ◽

Lewis B. Silverman ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Pediatric Patients ◽

Antibody Drug Conjugate ◽

Employment Equity ◽

Advisory Committees ◽

Drug Conjugate ◽

Equity Ownership ◽

Antibody Drug

Abstract Background CD19, a member of the immunoglobulin superfamily, is a B-cell specific marker that is found on B cells as early as the pro-B cell stage. CD19 is maintained upon malignant transformation and is expressed in the majority of patients with B-lineage leukemia and non-Hodgkin lymphoma (NHL). SGN-CD19A is a novel antibody-drug conjugate composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl (mc) linker. Upon binding to CD19, SGN-CD19A internalizes and releases cys-mcMMAF, which binds to tubulin and induces G2/M arrest and apoptosis in the targeted cells. Methods A first-in-human, phase 1, open-label, dose-escalation study has been initiated to investigate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-CD19A in adult and pediatric patients with relapsed or refractory (R/R) B-cell leukemia or highly aggressive B-cell lymphoma (CT.gov NCT01786096). Eligible patients must have a pathologically confirmed diagnosis of B-cell acute leukemia (B-ALL), Burkitt leukemia or lymphoma, or B-cell lymphoblastic lymphoma (B-LBL), and be R/R to at least 1 (adults) or 2 (pediatric) prior systemic regimens. A modified continual reassessment method is being used for dose allocation and maximum tolerated dose (MTD) estimation. SGN-CD19A is administered IV on Days 1 and 8 of 21-day cycles at up to 7 cohort-specific doses (0.3–2.3 mg/kg). Results Thirteen patients (11 adults, 2 pediatric) with R/R leukemia (9 B-ALL) or lymphoma (3 B-LBL, 1 Burkitt lymphoma) have been treated in this ongoing study. Adults (73% female) have a median age of 60 years (range, 26–74) and have received a median of 2 prior systemic therapies (range, 1–6). Four of the 11 adults (36%) have also received an allogeneic stem cell transplant (SCT). The pediatric patients, 2 females 13-and 14-years-old, have each received 3 prior systemic therapies; one of the pediatric patients has also received 2 allogeneic SCTs. To date, patients have been treated at 0.3 mg/kg (2 patients), 0.6 mg/kg (3 patients), 1.0 mg/kg (3 patients), and 1.3 mg/kg (5 patients). The maximum number of cycles received by a patient is 7. Four patients remain on treatment and 9 patients have discontinued treatment (7 due to progressive disease, 1 because of investigator decision, and 1 due to death). One patient with B-ALL treated at 1.0 mg/kg developed cardiac arrest in the setting of pre-existing electrolyte abnormalities and died 7 days after the first dose of SGN-CD19A; although this event was considered unrelated to study drug by the investigator, a possible relationship could not be excluded due to temporal association. Treatment-emergent adverse events reported for ≥10% of adult patients were nausea (64%); fatigue and pyrexia (55% each); chills (36%); headache (27%); and dyspnea, hypertension, oral pain, thrombocytopenia, tumor lysis syndrome, and vomiting (18% each). Drug-related AEs in adult patients were pyrexia (55%); nausea (45%); chills (36%); fatigue (27%); and headache, oral pain, and blurred vision (9% each). Drug-related AEs reported for the pediatric patients were abdominal pain, cough, diarrhea, dyspepsia, hyperuricemia, nausea, peripheral neuropathy, pruritus, pyrexia, tachycardia, and urticaria (all Grade 1 or 2, each in one patient). Preliminary data demonstrate rapid clearance of antibody-drug conjugate at low doses in patients with leukemia, suggesting target-mediated drug disposition. To date, best responses for patients with lymphoma are stable disease (2 patients) and progressive disease (2 patients). Best responses for the 8 leukemia patients with available response assessments are complete remission (1 adult at 1.3 mg/kg); resistant disease with clinical benefit, i.e., improvement in leukemia-related symptoms (4 patients); and progressive disease (3 patients). Conclusions MTDs have not yet been identified for adult or pediatric patients and dose-escalation continues in both populations. Antitumor activity has been observed, including 1 complete remission in a heavily pretreated B-ALL patient. Nonlinear clearance of the antibody-drug conjugate in leukemia patients suggests target-mediated disposition. Updated safety, PK, and response data will be presented at the meeting. A second trial is evaluating SGN-CD19A every 3 weeks in aggressive B-cell NHL (CT.gov NCT01786135). Disclosures: Borate: Seattle Genetics, Inc.: Research Funding; Genoptix: Consultancy. Fathi:Millennium: Research Funding; Seattle Genetics, Inc.: Advisory/Scientific board membership Other, Research Funding; Agios: Membership on an entity’s Board of Directors or advisory committees; Teva: Membership on an entity’s Board of Directors or advisory committees. Shah:Seattle Genetics, Inc.: Research Funding; NCCN: Membership on an entity’s Board of Directors or advisory committees; SWOG: Membership on an entity’s Board of Directors or advisory committees; Celgene: Speakers Bureau; Janssen/Pharmacyclics: Speakers Bureau. DeAngelo:Seattle Genetics, inc.: Research Funding. Silverman:Seattle Genetics, Inc.: Advisory/scientific board membership Other. Cooper:Seattle Genetics, Inc.: Research Funding. Albertson:Seattle Genetics, Inc.: Employment, Equity Ownership. O'Meara:Seattle Genetics, Inc.: Employment, Equity Ownership. Sandalic:Seattle Genetics, Inc.: Employment, Equity Ownership. Stevison:Seattle Genetics, Inc.: Employment, Equity Ownership. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel expenses Other.

Download Full-text

Administration of Rimiducid Following Haploidentical BPX-501 Cells in Children with Malignant or Non-Malignant Disorders Who Develop Graft-Versus-Host-Disease (GvHD)

Blood ◽

10.1182/blood-2018-99-119792 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2207-2207

Author(s):

Reem Elkeky ◽

David A. Jacobsohn ◽

Rajni Agarwal ◽

Swati Naik ◽

Neena Kapoor ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Board Of Directors ◽

Pediatric Patients ◽

Immune Recovery ◽

Advisory Committees ◽

Donor T Cells ◽

Evaluable Population

Abstract Background Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) constitutes a curative treatment for children with malignant and non-malignant disorders. HLA-partially matched haploidentical (haplo) donors represent a viable alternative option for those children who lack an HLA-compatible donor. T-cell depletion approaches with positive (CD34 selection) or negative selection (alpha/beta T-cell and CD19+ B-cell-depletion) may allow engraftment of donor cells with a low risk of GvHD; however, success is limited by delayed immune recovery, increasing the risk of fatal infections. Infusion of unmanipulated donor T cells (DLI) to accelerate immune recovery is associated with high risk of fatal GVHD. In contrast, adoptive transfer of donor T cells genetically manipulated to include a safety switch can be a suitable strategy to render DLI safer and more widely applicable. BPX-501 is an allogeneic product consisting of T cells modified to express the inducible caspase-9 (iC9) safety switch. The polyclonal natural of these modified T cells can provide viral immunity following stem cell transplant, with the unique ability to promptly and durably resolve GvHD symptoms following the administration of rimiducid, an inert, lipid-permeable compound that rapidly induces dimerization and activation of iC9, inducing apoptosis of the gene modified T cells. Aims To evaluate the safety and efficacy of rimiducid in the treatment of GvHD following administration of BPX-501 T cells in pediatric patients with malignant or non-malignant disorders given an αβ T-cell receptor and B-cell depleted haplo-HSCT. A key objective of this study is to assess the activity of rimiducid infusion following onset of GvHD which is refractory to standard of care therapies. Methods Two multicenter (US [NCT03301168] and EU [NCT02065869]), prospective trials utilized αβ-T-cell and B-cell-depleted haplo-HSCT followed by infusion of a titrated number of donor lymphocytes genetically modified with iC9 (BPX-501 T cells) in patients with malignant or non-malignant disorders. BPX-501 T-cells were 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 dimerizing rimiducid to activate the iC9 safety gene. The efficacy evaluable population is defined as any patient who received ≥ 1 dose of rimiducid for the treatment of GvHD and had a follow up response assessment. Results At the time of clinical cut-off (June 30th, 2018) 249 patients with a malignant (41.4%) or non-malignant disorder (58.6%) were enrolled. The conditioning regimens varied according to the original disease and were Treosulfan-based (14.9%), Busulfan-based (28.9%), TBI-based (34.9%) or other (19.3%). The donor was a parent in 229 children (92 %), a sibling in 17 (6.8 %), and a half-sibling in the remaining 3 (1.2 %). The median time to BPX-501 infusion was 18 days (10 - 66 days). Fifty-two patients developed Grade I-IV aGvHD (cumulative incidence [CI] 21.9 % [95% confidence interval (CoI): 16.7 - 27.2]). Twenty-six patients developed Grade II-IV aGvHD (CI 10.9 %). Five patients developed Grade III-IV aGvHD (CI 2.1 %). Eight patients developed cGvHD (CI of 4.6% [95% CoI: 1.3 - 7.8]). Twenty-one patients met the rimiducid efficacy evaluable population definition. An overall clinical response rate of 86% was observed. A CR or PR to rimiducid was observed in 12 and 6 patients, respectively. Median time to initial response was 2 days (1-61 days). Median number of doses received was 1 (1 - 2). At a median follow-up of 7.8 months (2.3 - 30.8 months), 77% of the initial responders were still in either complete (n=8) or partial response (n=6). Conclusion These data suggest that administration of rimiducid for treatment of steroid-refractory GvHD represents a novel and highly effective treatment approach in pediatric patients with non-malignant or malignant disorders who received a αβ-T-cell and B-cell depleted haplo-HSCT followed by infusion of BPX-501 cells. The administration of rimiducid in children given BPX-501 T cells allows for effective control of GvHD occurring after the adoptive transfer of genetically modified T cells. Disclosures Slatter: Medac: Other: Travel assistance. Merli:Neovii Biotech: Honoraria; AMGEN: Honoraria. Aldinger:Bellicum Pharmaceuticals, Inc.: Employment. Locatelli: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; Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy.

Download Full-text

Use of Tyrosine Kinase Inhibitors Post-Allogeneic Stem Cell Transplant in Patients with Philadelphia or BCR-ABL Positive Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood.v128.22.2778.2778 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2778-2778 ◽

Cited By ~ 3

Author(s):

Elena Liew ◽

Sunita Ghosh ◽

Lalit Saini

Keyword(s):

Systematic Review ◽

Board Of Directors ◽

Pediatric Patients ◽

Kinase Inhibitors ◽

Lymphoblastic Leukemia ◽

Meta Analysis ◽

Relapse Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Relapse Rates

Abstract Background: The use of tyrosine kinase inhibitors (TKIs) in the treatment of Philadelphia chromosome (Ph+) or BCR-ABL positive acute lymphoblastic leukemia (ALL) has improved remission rates allowing more eligible patients to proceed on to allogeneic hematopoietic stem cell transplantation (alloHSCT). Since many patients relapse following alloHSCT, some guidelines have recommended TKIs post alloHSCT (Couban, 2014, Giebel, 2016). Although some studies have demonstrated the benefits of this strategy, others have indicated that, owing to the immunomodulatory effects of TKIs, this approach may be harmful, leading to higher relapse rates. Given this uncertainty, we conducted a systematic review and meta-analysis of published studies comparing the outcomes of patients post alloHSCT who did or did not receive TKIs. Methods: We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, ACP Journal Club, Scopus and conference abstracts focusing on the period during which TKIs were available (2000 to March 2016). Studies were included if they were retrospective or prospective cohort/randomized studies of adult patients with Ph+ or BCR-ABL+ ALL who underwent alloHSCT and received post-transplant TKIs. Studies that did not include a comparative group of patients who did not receive TKIs, duplicate studies, abstracts later published and studies of only pediatric patients were excluded from further analyses. Two reviewers with ALL expertise independently evaluated all abstracts and performed study selection. Results: The literature search identified 868 unique references, 195 of which were reviewed in detail. Seven studies, 6 retrospective and 1 prospective, comprising 1441 patients met all inclusion criteria (Table 1). Three studies contained one or more pediatric patients and four included patients beyond first complete remission including some with hematological relapse at the time of alloHSCT. All studies had a mix of donor sources including matched related, matched unrelated, mismatched related and mismatch unrelated. Pre-transplant conditioning was myeloablative in 3, reduced intensity in 1 and a combination of the two in the remaining 3 studies. TKIs were administered prophylactically (prior to hematological or minimal residual disease relapse) or pre-emptively (prior to hematological relapse). Data on the TKI used was not available in one study. Amongst the remaining 6 studies, imatinib at 400 - 600mg was the most commonly used TKI with dasatinib being used in 3 studies and nilotinib in 1 study. TKIs were initiated 0.5 - 60 months after alloHSCT and continued for 1-64 months after initiation. Overall, 346 patients received a TKI post alloHSCT while 1095 patients did not. Using a fixed effects model there was no difference in the relapse free survival (HR =0.838, 95% CI 0.678 - 1.036, p=0.102) or overall survival (HR=0.868, 95% CI 0.675 - 1.117, p=0.27) for those who received a TKI compared to those who did not. In contrast, there was a significant increase in relapse rates for those who were treated with TKI post-HSCT (HR 1.204, 95% CI 1.044 - 1.387, p=0.011). Conclusions: While there are compelling theoretical reasons to recommend TKIs post alloHSCT (Couban, 2014), this meta-analysis suggests that their use is not associated with improvements in overall survival or relapse free survival and may be associated with higher relapse rates. However, given the heterogeneous nature of the studies, these results must be viewed with caution. Nonetheless, the results are compelling and highlight the need for larger prospective controlled studies evaluating the role of TKI post alloHSCT in patients with Ph+ ALL. Disclosures Liew: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

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.

Download Full-text

Incorporation of Thiotepa in a Reduced Intensity Conditioning Regimen Leads to Improved Engraftment after Stem Cell Transplant for Patients with Hemophagocytic Lymphohistiocytosis

Blood ◽

10.1182/blood-2019-132120 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3273-3273

Author(s):

Swati Naik ◽

Olive S. Eckstein ◽

Ghadir Sasa ◽

Robert A. Krance ◽

Carl E. Allen ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Graft Failure ◽

Unrelated Donor ◽

Advisory Committees ◽

Donor Chimerism ◽

Equity Ownership

Introduction: Hematopoietic stem cell transplantation (HSCT) for patients with hemophagocytic lymphohistiocytosis (HLH) following myeloablative conditioning regimens (MAC) is associated with high rates of non-relapse mortality. A previously reported prospective, phase 2 multi-center trial (RICHI) using using RIC strategy of fludarabine, melphalan and alemtuzumab (day -14) for HLH and primary immune deficiency syndromes (PIDS) demonstrated improved mortality rates but fewer than half the patients with HLH (41%) successfully engrafted without secondary graft failure, need for donor lymphocyte infusion (DLI) or second transplant. Incorporation of thiotepa during conditioning has been to shown to be safe and improve engraftment. We report the results of a retrospective analysis of nine consecutive patient treated with the inclusion of thiotepa into the RICHI backbone (RICHI+TT). Methods: Patients received a single additional dose of thiotepa 10mg/kg on day -3 added to the fludarabine/melphalan/alemtuzumab backbone (RICHI+TT) with the same graft-versus-host disease prophylaxis of methyprednisolone through day +28 and cyclosporine through day 180. To determine sustained engraftment, we used the same parameters the RICHI study defined as > 5 % donor chimerism without any intervention and alive at 1 year post-transplant. Results: Our cohort consisted of 8 males and 1 female with a median age of 7 years (range 1-18 years). Seven patients had HLH with proven pathogenic genetic mutations (biallelic PRF1 - 2, UNC13D - 2, STXBP1- 1, RAB27A-1, STAT3 gain of function-1), while the other 2 patients had HLH without identified pathogenic mutations (1- chronic active EBV, 1- juvenile idiopathic arthritis with refractory macrophage activation syndrome).The majority of patients received a bone marrow product (n = 8), one patient received a peripheral blood stem cell product; 6 patients received a graft from a matched related donor , two from a mismatched unrelated donor, and one from a matched unrelated donor. All patients engrafted at a median of 15 days post-transplant (8 patients at 100% donor chimera; 1 patient at 99% donor chimera at initial engraftment). Six of the 9 patients were evaluable to assess donor chimerism at 1 year as per study definitions with a median follow up of 875 days (range: 366 -1000 days). All 6 patients had > 5% donor chimerism and were alive at 1 year. Five of the 6 evaluable patients met criteria for sustained donor engraftment without need for intervention and all maintained 100% donor chimerism at last follow-up (Table 1). Only one of the six patients had evidence of falling donor chimerism; this stabilized at 40% donor chimerism after DLI. No patients had primary or secondary graft failure. Three patients were not evaluable for long-term assessment due to death prior to 1 year. Six of the 9 patients described here are alive and disease-free with stable long-term engraftment. The incorporation of Thiotepa to the RICHI backbone improved on previously reported sustained donor engraftment (Table 2). Conclusions: The RICHI+TT approach had better long-term donor engraftment with a decreased need for DLI or second transplant without increased rates of non-relapse mortality. Prospective studies are needed to determine the optimal treatment strategies for patients with HLH who require HSCT for cure. Disclosures Heslop: Cell Medica: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Marker Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Allovir: Equity Ownership; Gilead Biosciences: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Phase 2 Results of Clofarabine In Combination with Etoposide and Cyclophosphamide In Pediatric Patients with Refractory or Relapsed Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v116.21.866.866 ◽

2010 ◽

Vol 116 (21) ◽

pp. 866-866

Author(s):

Nobuko Hijiya ◽

Jo-Anne Paul ◽

Michael J. Borowitz ◽

Blythe Thomson ◽

Michael Isakoff ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Pediatric Patients ◽

Lymphoblastic Leukemia ◽

Phase 2 ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Abstract 866 Background: Dramatic improvements have been made in treating children with newly diagnosed acute lymphoblastic leukemia (ALL). However, poor outcomes are still observed in patients who are either refractory to or who have relapsed after conventional chemotherapy. Salvage therapy options are urgently needed for this patient population. Clofarabine is approved as a single agent for treatment of pediatric ALL in second relapse. Previously we reported the safety profile and response rates from the phase 1 study assessing clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory/relapsed acute leukemia (Hijiya, Leukemia, 2009). Here we report the phase 2 results. Methods: Patients (pts) aged 1–21 years with refractory/relapsed ALL were treated at the recommended phase 2 dose of clofarabine 40 mg/m2/day, cyclophosphamide 440 mg/m2/day, and etoposide 100 mg/m2/day. All 3 agents were given IV daily for 5 consecutive days in induction and 4 consecutive days in consolidation. Patients could receive up to 2 induction cycles, followed by consolidation (max 8 cycles including induction). The primary endpoint was overall remission rate (ORR: complete remission [CR] and CR without platelet recovery [CRp]). Secondary endpoints were safety and tolerability, rate of partial remission (PR), duration of remission (DOR), event-free survival (EFS), 4-month EFS, and overall survival (OS). Minimal residual disease (MRD) by flow cytometry was evaluated as an exploratory endpoint. Results: Phase 2 comprised 25 pts (median follow-up 10.7 weeks [wks]): 16 males and 9 females with a median age of 14.0 years. Twenty-one pts had pre-B cell ALL, 1 pt had T cell ALL and 3 pts had an unknown immunophenotype. Fourteen pts had 2 prior induction regimens, 7 pts had 3 prior induction regimens and 4 pts had 1 prior induction regimen. Fifteen pts (60%) were refractory to their immediately preceding regimen. Four pts had received a prior hematopoietic stem cell transplant (HSCT). The investigator-assessed ORR was 44%; 7 CR (28%) and 4 CRp (16%). Additionally, 3 pts (12%) achieved PR. Eight pts were evaluable for MRD after induction, 5 were MRD negative (defined as <0.01%) and 3 were positive. Overall, 10 pts proceeded to HSCT, including 7 of 11 responders (CR + CRp). The median DOR at the last known follow-up (not censored for alternative therapy) was 15.9 wks (range: 2.9–109.6+) for pts with CR, but was not estimable for pts with CRp (range: 30.1+-67.7+). Median DOR for responders censored at alternative therapy/HSCT was not estimable as most pts received alternate therapy or transplant prior to event occurrence (range: 0.1+-10.9+ wks). Median OS censored at the last known follow-up was 10.7 wks for all patients (range: 1.0–113.1+) and 80.9 wks for responders (range: 8.1–113.1+). The median EFS for responders was 73.9 wks and 44% of all 25 pts were free of events at 4 months. The median cumulative number of clofarabine cycles received was 1 (range: 1–3), with most pts (10 of 11 responders) achieving best response after 1 cycle. The treatment-related non-hematologic adverse events (AEs) occurring in ≥25% of phase 2 pts were vomiting (88%); nausea (72%); febrile neutropenia (60%), pyrexia (52%); decreased appetite (44%); ALT increased, AST increased, hypokalemia, and hypotension (36% each), diarrhea and hyperbilirubinemia (28% each). One pt discontinued study treatment due to treatment-related fungal sinusitis which occurred 17 days after the last dose of study drug. Serious treatment-related AEs, were reported in 84% of pts. Six pts (24%) died within 30 days of receiving last dose of study treatment. Deaths were due to hepatic veno-occlusive disease (2 pts), septic shock (2 pts), pulmonary edema (1 pt) and infection (1 pt). As reported previously, after 4 of the initial 8 pts developed severe hepatotoxicity, the protocol was amended to exclude pts with prior HSCT, viral hepatitis cirrhosis, or elevated conjugated bilirubin levels at study entry (Hijiya, ASH 2008). There were no additional events of severe hepatotoxicity observed in the remaining 17 pts. Conclusions: Combination treatment with clofarabine, etoposide and cyclophosphamide in pediatric pts with refractory or relapsed ALL resulted in an ORR of 44% and negative MRD in heavily treated pts. Ten pts including 7 of 11 responders proceeded to HSCT. The safety profile is acceptable in this relapsed/refractory population. Disclosures: Hijiya: Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Clofarabine (Clolar) is approved by the US FDA for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This trial examines the use of clofarabine in combination with etoposide and cyclophosphamide. Paul:Genzyme: Employment, Equity Ownership. Borowitz:genzyme: Research Funding; becton-dickinson: Research Funding; Alexion: Consultancy; beckman-coulter: Research Funding. Isakoff:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Silverman:Genzyme: Research Funding; Enzon : Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA: Honoraria, Membership on an entity's Board of Directors or advisory committees. Steinherz:Genzyme: Research Funding. Kadota:Genzyme: Employment, Equity Ownership. Pressey:Genzyme: Research Funding. Shen:Genzyme: Research Funding. Chu:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cooper:Genzyme: Research Funding. Jeha:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Razzouk:Genzyme: Research Funding. Rytting:Genzyme: Research Funding. Barry:Genzyme: Employment, Equity Ownership. Carroll:Genzyme: Research Funding. Gaynon:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text