Gene transfer into hematopoietic stem cells has been used successfully for correcting lymphoid but not myeloid immunodeficiencies. Here we report on two adults who received gene therapy after ...nonmyeloablative bone marrow conditioning for the treatment of X-linked chronic granulomatous disease (X-CGD), a primary immunodeficiency caused by a defect in the oxidative antimicrobial activity of phagocytes resulting from mutations in gp91(phox). We detected substantial gene transfer in both individuals' neutrophils that lead to a large number of functionally corrected phagocytes and notable clinical improvement. Large-scale retroviral integration site-distribution analysis showed activating insertions in MDS1-EVI1, PRDM16 or SETBP1 that had influenced regulation of long-term hematopoiesis by expanding gene-corrected myelopoiesis three- to four-fold in both individuals. Although insertional influences have probably reinforced the therapeutic efficacy in this trial, our results suggest that gene therapy in combination with bone marrow conditioning can be successfully used to treat inherited diseases affecting the myeloid compartment such as CGD.
•Manageable safety and encouraging preliminary efficacy support extra evaluation of BCL-2/MDM2 inhibition in AML.•IDH1/2 and RUNX1 mutations were associated with ven-idasa sensitivity; TP53 mutations ...were unfavorable.
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This phase 1b trial (NCT02670044) evaluated venetoclax-idasanutlin in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) ineligible for cytotoxic chemotherapy. Two-dimensional dose escalation (DE, n = 50) was performed for venetoclax daily with idasanutlin on days 1 to 5 in 28-day cycles, followed by dosing schedule optimization (n = 6) to evaluate reduced venetoclax schedules (21-/14-day dosing). Common adverse events (occurring in ≥40% of patients) included diarrhea (87.3% of patients), nausea (74.5%), vomiting (52.7%), hypokalemia (50.9%), and febrile neutropenia (45.5%). During DE, across all doses, composite complete remission (CRc; CR + CR with incomplete blood count recovery + CR with incomplete platelet count recovery) rate was 26.0% and morphologic leukemia-free state (MLFS) rate was 12%. For anticipated recommended phase 2 doses (venetoclax 600 mg + idasanutlin 150 mg; venetoclax 600 mg + idasanutlin 200 mg), the combined CRc rate was 34.3% and the MLFS rate was 14.3%. Pretreatment IDH1/2 and RUNX1 mutations were associated with higher CRc rates (50.0% and 45.0%, respectively). CRc rate in patients with TP53 mutations was 20.0%, with responses noted among those with co-occurring IDH and RUNX1 mutations. In 12 out of 36 evaluable patients, 25 emergent TP53 mutations were observed; 22 were present at baseline with low TP53 variant allele frequency (median 0.0095% range, 0.0006-0.4). Venetoclax-idasanutlin showed manageable safety and encouraging efficacy in unfit patients with R/R AML. IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity, even in some patients with co-occurring TP53 mutations; most emergent TP53 clones were preexisting. Our findings will aid ongoing/future trials of BCL-2/MDM2 inhibitor combinations. This trial was registered at www.clinicaltrials.gov as #NCT02670044.
Daver and colleagues report on a phase 1b trial combining venetoclax and the MDM inhibitor idasanutlin in patients with relapsed/refractory acute myeloid leukemia (AML) who are ineligible for cytotoxic chemotherapy. Composite complete remissions are seen in 25-40% of patients; however, response duration is short. Patients with AML bearing IDH1/2 and RUNX1 mutations respond better, and those with TP53 mutations do less well. Of note, 12 of 36 evaluable patients developed emergent TP53 mutation-bearing clones, almost all of which had been present at baseline but at very low variant allele frequency, suggesting a possible need to screen and select patients best suited for this combination.
Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited ...immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1). One subject died from overwhelming sepsis 27 months after gene therapy, whereas a second subject underwent an allogeneic HSC transplantation. Our data show that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.
The trifunctional antibody catumaxomab is a targeted immunotherapy for the intraperitoneal treatment of malignant ascites. In a Phase II/III trial in cancer patients (n = 258) with malignant ascites, ...catumaxomab showed a clear clinical benefit vs. paracentesis and had an acceptable safety profile. Human antimouse antibodies (HAMAs), which could be associated with beneficial humoral effects and prolonged survival, may develop against catumaxomab as it is a mouse/rat antibody. This post hoc analysis investigated whether there was a correlation between the detection of HAMAs 8 days after the fourth catumaxomab infusion and clinical outcome. HAMA‐positive and HAMA‐negative patients in the catumaxomab group and patients in the control group were analyzed separately for all three clinical outcome measures (puncture‐free survival, time to next puncture and overall survival) and compared to each other. There was a strong correlation between humoral response and clinical outcome: patients who developed HAMAs after catumaxomab showed significant improvement in all three clinical outcome measures vs. HAMA‐negative patients. In the overall population in HAMA‐positive vs. HAMA‐negative patients, median puncture‐free survival was 64 vs. 27 days (p < 0.0001; HR 0.330), median time to next therapeutic puncture was 104 vs. 46 days (p = 0.0002; HR 0.307) and median overall survival was 129 vs. 64 days (p = 0.0003; HR 0.433). Similar differences between HAMA‐positive and HAMA‐negative patients were seen in the ovarian, nonovarian and gastric cancer subgroups. In conclusion, HAMA development may be a biomarker for catumaxomab response and patients who developed HAMAs sooner derived greater benefit from catumaxomab treatment.
•Ven-cobi showed limited efficacy, similar to venetoclax alone, in R/R AML.•Ven-cobi had additional toxicity versus venetoclax alone in patients with R/R AML.•High MCL-1 levels and TP53/signaling ...mutations may promote ven-cobi resistance.•These findings may optimize future trials of BCL-2/MAPK inhibitor combinations.
Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies.
This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle.
Thirty patients (median range age: 71.5 years 60-84) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission CR + CR with incomplete blood count recovery + CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRc + morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway.
Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations.
Treatment options for patients who have acute myeloid leukemia (AML) which has come back (relapsed) or stopped responding to treatment (refractory) are limited. In this study, 30 patients with relapsed/refractory AML received 2 drugs (venetoclax and cobimetinib). Venetoclax-cobimetinib had limited responses with unwanted side effects, compared with venetoclax alone. However, these findings will help future trials of similar drug combinations.
Gene transfer into hematopoietic stem cells has been successfully used to correct immunodeficiencies affecting the lymphoid compartment. However, similar results have not been reported for diseases ...affecting myeloid cells, mainly due to low engraftment levels of gene-modified cells observed in unconditioned patients. Here we review the developments leading to a gene therapy approach for the treatment of Chronic Granulomatous Disease (CGD), a primary life threatening immunodeficiency caused by a defect in the oxidative antimicrobial activity of phagocytes. Although the disease can be cured by bone marrow transplantation, this treatment is only available to patients with HLA-identical sibling or matched unrelated donors. One therapeutic option for patients without suitable donor is the genetic modification of autologous hematopoietic stem cells. Although early attempts to correct CGD by gene therapy were unsuccessful, these studies demonstrated the safety and limitations of gene transfer into hematopoietic stem cells (HSC) of CGD patients using retroviral vectors. The recent development of advanced gene transduction protocols together with improved retroviral vectors, combined with low intensity chemotherapy conditioning, allowed partial correction of the granulocytic function with a significant clinical benefit in treated patients. These results may have important implications for future applications of gene therapy in myeloid disorders and inherited diseases using hematopoietic stem cells.
Vector-associated side effects in clinical gene therapy have provided insights into the molecular mechanisms of hematopoietic regulation in vivo. Surprisingly, many retrovirus insertion sites (RIS) ...present in engrafted cells have been found to cluster nonrandomly in close association with specific genes. Our data demonstrate that these genes directly influence the in vivo fate of hematopoietic cell clones. Analysis of insertions thus far has been limited to individual clinical studies. Here, we studied >7,000 insertions retrieved from various studies. More than 40% of all insertions found in engrafted gene-modified cells were clustered in the same genomic areas covering only 0.36% of the genome. Gene classification analyses displayed significant overrepresentation of genes associated with hematopoietic functions and relevance for cell growth and survival in vivo. The similarity of insertion distributions indicates that vector insertions in repopulating cells cluster in predictable patterns. Thus, insertion analyses of preclinical in vitro and murine in vivo studies as well as vector insertion repertoires in clinical trials yielded concerted results and mark a small number of interesting genomic loci and genes that warrants further investigation of the biological consequences of vector insertions.
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Introduction: Elderly pts with R/R AML not eligible for cytotoxic therapy have limited therapeutic options, and dismal outcomes with available therapies. In preclinical studies, inhibition of BCL-2 ...and MDM2 with Ven and Idasa, respectively, has demonstrated potent synergistic apoptotic activity. In this ongoing, open-label, Phase Ib study, the safety, tolerability, and preliminary efficacy of Ven+cobimetinib (Arm A) and Ven+Idasa (Arm B) is being assessed in R/R AML (NCT02670044). Initial analysis indicated a tolerable safety profile for Ven+Idasa. Here, we present updated safety and efficacy results from Arm B.
Methods: Pts (≥60 years) with R/R AML or secondary AML, previously treated for an antecedent hematologic disease but treatment naïve for AML, and ineligible for cytotoxic therapy/allogeneic stem cell transplant were enrolled. The maximum tolerated dose of Ven+Idasa was determined by two-dimensional dose escalation. Pts received Ven orally (PO) daily (400 or 600mg) + Idasa PO daily on Days (D) 1-5 (150mg, 200mg, or 400mg) in 28-day cycles. Responses were assessed according to revised International Working Group Response Criteria 2003. Pharmacokinetic (PK) analyses were performed on plasma samples on Cycles (C) 1 and 2, D1 and 5, and C4, D1. Exploratory assessments included minimal residual disease (MRD), assayed centrally at Covance Laboratories using 8-color flow cytometry. Data cut-off was June 21, 2019.
Results: At data cut-off, 49 pts were treated with Ven+Idasa. Median age was 72 years (range 62-93); Eastern Cooperative Oncology Group performance status 0-1: 84%; refractory AML: 57%; relapsed AML: 33%; and secondary previously untreated AML: 10%; Intermediate-I or Intermediate-II European Leukemia Net (ELN) risk classification: 66%; adverse ELN classification: 30%; de novo (49%) versus secondary (51%) AML; and median prior lines of treatment: 1 (range 1-4). Most common adverse events (AEs; any grade) irrespective of attribution were diarrhea (90%) and nausea (78%); the most common grade ≥3 AEs were febrile neutropenia (45%), neutropenia (27%), and thrombocytopenia (25%; Table 1). Laboratory tumor lysis syndrome occurred in 3 pts; none resulted in treatment discontinuation. Ven and Idasa treatment discontinuation due to AEs were noted in 18% and 20%, respectively, most commonly due to infections. 30- and 60-day mortality rates were 6% and 17%, respectively. No apparent PK drug-drug interaction was found between Ven and Idasa; overlap in Ven and Idasa exposure was substantial over the doses tested. Anti-leukemic response rate (complete response CR + CR with incomplete platelet count recovery CRp + CR with incomplete blood count recovery CRi + partial response PR + morphologic leukemia-free state MLFS) across all dose levels was 41% (Table 2). Across the two Ven 600mg cohorts being considered for the recommended Phase II dose (RP2D), the anti-leukemic response rate was 50% (CR+CRp+CRi rate 29%). Median time to CR+CRp+CRi+PR was 1.4 months (range 1-3), with a median response (CR+CRp+CRi) duration of 4.9 months (range 0.6-9.7). Median overall survival in all pts and in the Ven 600mg cohorts was 4.4 months and 5.7 months, respectively, with a median follow-up of 3.4 months (range 0.03-18). Individual pt responses are shown in Figure 1. MRD negativity (<0.1%) was achieved in 45% (5/11) of pts with CR+CRp+CRi. Updated pre- and post-therapy mutation and BCL-2 family protein data and association with clinical response will be presented.
Conclusions: The non-chemotherapy combination of Ven+Idasa demonstrated encouraging safety and efficacy in elderly pts with R/R AML who were ineligible for cytotoxic chemotherapy. The anti-leukemic response rate at the dose levels being considered for the RP2D was 50%, with a CR+CRp+CRi rate of 29%. Updated predictive biomarker data will be presented. Evaluation of Ven+Idasa RP2D is ongoing, and will be followed by dose expansion.
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Daver:Otsuka: Consultancy; NOHLA: Research Funding; Jazz: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding; Celgene: Consultancy; Pfizer: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Genentech: Consultancy, Research Funding; Glycomimetics: Research Funding; Servier: Research Funding; Incyte: Consultancy, Research Funding. Garcia:Abbvie: Research Funding; Genentech: Research Funding. Jonas:AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses. Kelly:Novartis, Bayer, Janssen, Pharmacyclics, Celgene, Astrazeneca, Seattle Genetics: Honoraria, Speakers Bureau; Takeda: Research Funding; Genentech, Verastem: Consultancy. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Brandwein:Celgene: Consultancy, Honoraria, Research Funding; Jazz Pharma: Consultancy, Honoraria; Otsuka: Honoraria; Roche: Research Funding; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding. Olin:Ignyta: Research Funding; Clovis: Research Funding; Spectrum: Research Funding; Revolution Medicine: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria; Pfizer: Research Funding; Genentech: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Mirati Therapeutics: Research Funding; MedImmune: Research Funding; AstraZeneca: Research Funding. Martinelli:Amgen: Consultancy, Other: trial grant; Ariad: Consultancy, Other: trial grant; Incyte: Consultancy, Other: trial grant; Pfizer: Consultancy, Other: trial grant; Roche: Consultancy, Other: trial grant; Celgene: Consultancy, Honoraria, Other: trial grant; Janssen: Consultancy, Other: trial grant; Abbvie: Consultancy, Honoraria, Other: trial grant; Novartis: Consultancy, Other: trial grant; Daiichi Sankyo: Consultancy, Honoraria. Pigneux:Novartis: Honoraria; Roche: Honoraria; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Astellas: Honoraria; Daichi: Honoraria; Abbvie: Honoraria; Jazz: Honoraria; Amgen: Honoraria. Pollyea:Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Powell:Rafael Pharmaceuticals: Consultancy, Research Funding; Janssen: Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding. Roboz:Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory
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Introduction
Effective therapies for R/R AML remain limited. MEK or MDM2 inhibition can downregulate MCL1, overcoming resistance to BCL2 inhibition. Preclinical synergy was seen when combining BCL2 ...inhibitor Ven with MEK inhibitor cobimetinib (cobi) or MDM2 inhibitor idasa (Han et al. ASH 2016; Pan et al. Cancer Cell 2017), supporting clinical evaluation in AML. Preliminary data in a Phase Ib dose-escalation study (NCT02670044) evaluating Ven+cobi/idasa in R/R AML suggested both combinations were tolerable (Daver et al. ASH 2017). However, Ven+cobi was closed due to limited clinical activity. Here we present data for additional pts, longer follow-up and biomarker analyses for Ven+idasa.
Methods
This ongoing, open-label, multicenter study evaluates safety, tolerability and efficacy of Ven+idasa in R/R AML or secondary AML previously treated for an antecedent hematologic disease. Pts >60 yrs of age and ineligible for cytotoxic therapy/allogeneic stem cell transplant were enrolled. A 2-dimensional dose escalation was used to establish the maximum tolerated dose: pts received doses of Ven orally (PO) daily (400mg or 600mg) + idasa PO daily on Days 1-5 (150mg, 200mg, or 400mg) in 28-day cycles.
Plasma samples were taken for PK analysis at Cycles 1 and 2 Days 1 and 5, and Cycle 4 Day 1. BCL2, BCLxL and MCL1 status and minimal residual disease (MRD) were assayed centrally at Covance Laboratories using multicolor flow cytometry. Mutation (mut) sequencing was performed by Foundation Medicine using FoundationOne Heme at screening and from last bone marrow collected on study.
Results
As of April 6 2018, 34 pts received Ven+idasa across all dose cohorts (Table 1). Median age: 74 (range 64-93) yrs; median prior therapies: 1 (range 1-4); ECOG performance status 2: 18%; refractory: 56%; secondary AML: 53%; adverse cytogenetics: 27%. Pre-therapy mut data were available for 32 pts; most common muts were RUNX1 14 (41%), ASXL1 11 (32%), SRSF2 11 (32%). Other significant pre-therapy muts: TP53 6 (18%), IDH2 7 (21%), IDH1 1 (3%), FLT3 4 (13%).
The most common adverse events (AEs) were diarrhea (88%) and nausea (71%); the most common grade (Gr) ≥3 AEs were neutropenia (32%), febrile neutropenia (32%), thrombocytopenia (29%; Table 2). After 2 cases of Gr 3 diarrhea in the Ven 600mg cohorts, mandatory prophylaxis was implemented; no further cases of Gr ≥3 diarrhea were seen in the following 10 pts. Laboratory tumor lysis syndrome occurred in 3 pts (9%); none required treatment discontinuation. There was no apparent PK drug-drug interaction between Ven and idasa. PK was dose-proportional over the ranges tested for Ven and idasa. The recommended Phase II dose (RP2D) has not been identified yet.
Across all dose cohorts, 30/34 pts were response-evaluable; the remaining 4 were still on study treatment without post-baseline response assessment. The anti-leukemic response rate (CR+CRp+CRi+MLFS+PR) was 37% (11/30). Across the 2 Ven 600mg cohorts, which are being considered for RP2D, the anti-leukemic response rate was 9/18 (50%) (Table 1, Figure 1). MRD negativity (<0.1%) was achieved in 43% (3/7) of pts with CR+CRp+CRi (Table 3).
The median time to CR+CRp+CRi+PR (all pts) was 1.8 mo (range 0.8-2.7), with median response duration of 8.1 mo (range 0.3-9.7). Median overall survival in all pts and in the Ven 600mg cohorts was 3.9 mo and 5.3 mo (range 0.2-17.6), respectively; median follow-up was 2.9 mo (range 0-18). The anti-leukemic response rate was 86% in pts with IDH2 mut and 57% in pts with a RUNX1 mut, but only 20% in pts with a TP53 mut (Table 4). 8/20 pts with end-of-treatment mut data had either new TP53 muts or an increase in mut TP53 allele frequency (Figure 2). In 14 evaluable pts, those with AML blasts with a high ratio of BCL2:BCLxL or BCL2:MCL1 had a response rate of 100% (5/5) versus 11% (1/9) in pts with low ratios (Table 4).
Conclusion
Ven+idasa has a tolerable safety profile with appropriate prophylaxis in this R/R AML population. An anti-leukemic response rate of 50% was seen at dose levels being considered for RP2D (Ven 600mg + idasa 150/200mg). Overall, responses appeared deep and durable. Preliminary biomarker data indicate that the relative ratio of BCL2 to BCLxL and MCL1 may be important for Ven+idasa activity, whereas pts with baseline TP53 muts had lower response rates. To confirm the clinical benefit and safety of Ven+idasa, the combination will be further evaluated in an expansion arm, after confirmation of the RP2D.
Daver:Kiromic: Research Funding; ImmunoGen: Consultancy; Sunesis: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Novartis: Consultancy; Incyte: Research Funding; Daiichi-Sankyo: Research Funding; Sunesis: Consultancy; Karyopharm: Research Funding; Alexion: Consultancy; Pfizer: Consultancy; ARIAD: Research Funding; BMS: Research Funding; Otsuka: Consultancy; Incyte: Consultancy; Karyopharm: Consultancy. Pollyea:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Gilead: Consultancy; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Garcia:Celgene: Consultancy. Jonas:Genentech/Roche: Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy; Glycomimetics: Research Funding; Esanex: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; LP Therapeutics: Research Funding; Tolero: Consultancy; Forma: Research Funding; Celgene: Consultancy, Research Funding; Accelerated Medical Diagnostics: Research Funding; Kalobios: Research Funding; Daiichi Sankyo: Research Funding. Yee:Agensys, Astex, GSK, Onconova, Genentech/Roche: Research Funding; Celgene, Novartis, Otsuka: Membership on an entity's Board of Directors or advisory committees. Fenaux:Otsuka: Honoraria, Research Funding; Roche: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Assouline:Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding. Olin:Daiichi Sankyo, Astellas, Genentech: Research Funding. Roboz:Cellectis: Research Funding; Janssen Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Roche/Genentech: Consultancy; Novartis: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Orsenix: Consultancy; Pfizer: Consultancy; Argenx: Consultancy; Otsuka: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Roche/Genentech: Consultancy; Celgene Corporation: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; AbbVie: Consultancy; Novartis: Consultancy; Sandoz: Consultancy; Argenx: Consultancy; Eisai: Consultancy; Aphivena Therapeutics: Consultancy; Celgene Corporation: Consultancy; Orsenix: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Eisai: Consultancy; Celltrion: Consultancy; Cellectis: Research Funding; Celltrion: Consultancy; Sandoz: Consultancy. Kirschbrown:Roche: Other: Ownership interests PLC; Genentech: Employment. Green:Genentech: Employment. Ma:Genentech: Employment. Dail:Genentech: Employment, Equity Ownership. Wang:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Ott:Roche: Other: Ownership interests PLC. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Phuong:Genentech Inc: Employment, Equity Ownership, Other: Ownership interests PLC. Hong:Genentech Inc/Roche: Employment, Other: Ownership interests PLC. Konopleva:Stemline Therapeutics: Research Funding. Andreeff:Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Equity Ownership; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; SentiBio: Equity Ownership; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; Astra Zeneca: Research Funding; Reata: Equity Ownership; Amgen: Consultancy, Research Funding; Jazz Pharma: Consultancy.
The potential of gene therapy to cure inherited immunodeficiencies of the lymphoid compartment has been demonstrated in clinical trials of ADA-SCID and SCID-X1. To circumvent the missing in vivo ...selection advantage of the corrected cells in myeloid diseases the two patients in the recent successful chronic granulomatous disease (CGD) gene therapy trial received nonmyeloablative conditioning before transplantation of the corrected cells. 3 months after transplantation 20% and 10% of the granulocytes in the peripheral blood expressed gp91phox in patient 1 and patient 2, respectively. 5 to 9 months after therapy a 3 to 4 fold expansion of marked granulocytes in the peripheral blood appeared in both patients. The proportion of gene-corrected granulocytes in both patients was then stable until 524 days post transplantation in patient 1 and 343 days post transplantation in patient 2 which were the last time points analyzed. To characterize the clonality of the hematopoietic repopulation, the long term activity of individual clones and the distribution of the SFFV vector integration sites we analyzed peripheral blood leucocytes and sorted cells derived from different time points post transplantation with linear amplification mediated PCR (LAM-PCR) and accomplished high throughput sequencing and mapping of the insertion sites. For patient 1 we could identify 435 exactly mappable insertion sites. For patient 2 330 unique integrations could be assigned to the human genome. We detected 3 common integrations sites (CIS) in or near the loci of the zinc finger transcription factor homologous MDS1/EVI1 and PRDM16 in both patients and SETBP1 as a third CIS gene in patient 1. RNA analysis demonstrated an activating influence of the retroviral vector on the CIS genes in both patients. LAM-PCR analysis of CFU-GM and BFU-E derived colonies from both patients revealed that 1 to 4 integrations are present per cell and confirmed the increasing dominance of one MDS1/EVI1 clone in patient 1 seen in the peripheral blood LAM-PCR pattern. Our data show that the upregulation of specific human genes as a side effect of retroviral integration may lead to an unprecedented in vivo expansion of the concerned cell clones and have therefore great impact on future gene therapy strategies.
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